Static.cambridge.org



10. Supplementary material1. MGB literatureProportion of review articlesThere is a very high proportion of review articles in the MGB field, whichever search term is used."Gut brain bacteria” finds 326 reviews out of 768 articles (43%)“Gut-brain microbiota” finds 167 reviews out of 325 articles (51%)“Microbiota brain” finds 386 reviews out of 865 articles (45%).Those numbers only include whatever PubMed automatically lists as a review. The true numbers are probably higher. We discarded the reviews that turned up in our highly cited list in order to get at the core experimental corpus of the field.Most prolific authorsThe five most prolific authors in the field as of 22.05.2017 (represented by the 867 source articles):John F Cryan (81 articles, including >43 reviews)Timothy/Ted G Dinan (79 articles, including >44 reviews)Gerard Clarke (29 articles, including >17 reviews)John Bienenstock (21 articles, including >6 reviews)Premysl Bercik (19 articles, including >9 reviews)Cryan (a neuropharmacologist) and Dinan (a pharmacologist/psychiatrist) are both leaders of gut-brain microbiota axis at the APC Microbiome Institute (University College Cork, Ireland) and have authored 222 papers together. They have also published with Clarke, a neuropharmacologist/psychiatrist at UCC. Bienenstock, an immunologist (McMaster, Canada) and Bercik (McMaster), a neural gastroenterologist, are not directly connected to this group. Supplementary Table 1: The broad range of MGB-associated methods, with exemplar publications selected from 25 most-cited MGB experimental papers (see Section 4).General methodSpecific features of methodsAnimal modelsGerm-free (GF), specific pathogen free (SPF), and conventionalized rodents (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1113/jphysiol.2004.063388", "ISBN" : "1469-7793", "ISSN" : "0022-3751", "PMID" : "15133062", "abstract" : "Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.", "author" : [ { "dropping-particle" : "", "family" : "Sudo", "given" : "Nobuyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chida", "given" : "Yoichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aiba", "given" : "Yuji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sonoda", "given" : "Junko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oyama", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Xiao-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kubo", "given" : "Chiharu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koga", "given" : "Yasuhiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of physiology", "id" : "ITEM-1", "issue" : "Pt 1", "issued" : { "date-parts" : [ [ "2004", "7", "1" ] ] }, "page" : "263-75", "title" : "Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.", "type" : "article-journal", "volume" : "558" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sudo et al. 2004)", "manualFormatting" : "Sudo et al. 2004)", "plainTextFormattedCitation" : "(Sudo et al. 2004)", "previouslyFormattedCitation" : "(Sudo et al. 2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Sudo et al. 2004)Autism model rats (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2013.12.005", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "24333160", "abstract" : "Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.", "author" : [ { "dropping-particle" : "", "family" : "Theije", "given" : "Caroline G", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wopereis", "given" : "Harm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramadan", "given" : "Mohamed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eijndthoven", "given" : "Tiemen", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambert", "given" : "Jolanda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knol", "given" : "Jan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garssen", "given" : "Johan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kraneveld", "given" : "Aletta D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oozeer", "given" : "Raish", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "3" ] ] }, "page" : "197-206", "publisher" : "Elsevier Inc.", "title" : "Altered gut microbiota and activity in a murine model of autism spectrum disorders.", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(de Theije et al. 2014)", "manualFormatting" : "de Theije et al. 2014)", "plainTextFormattedCitation" : "(de Theije et al. 2014)", "previouslyFormattedCitation" : "(de Theije et al. 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }de Theije et al. 2014)Colitis model rodents (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ohland et al. 2013)", "manualFormatting" : "Ohland et al. 2013)", "plainTextFormattedCitation" : "(Ohland et al. 2013)", "previouslyFormattedCitation" : "(Ohland et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Ohland et al. 2013)Depression model rodents (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Park et al. 2013)", "manualFormatting" : "Park et al. 2013)", "plainTextFormattedCitation" : "(Park et al. 2013)", "previouslyFormattedCitation" : "(Park et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Park et al. 2013)Maternal immune activation rodents (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hsiao et al. 2013)", "manualFormatting" : "Hsiao et al. 2013)", "plainTextFormattedCitation" : "(Hsiao et al. 2013)", "previouslyFormattedCitation" : "(Hsiao et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Hsiao et al. 2013)Pups undergoing maternal separation (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(S. O\u2019Mahony et al. 2009)", "manualFormatting" : "O\u2019Mahony et al. 2009)", "plainTextFormattedCitation" : "(S. O\u2019Mahony et al. 2009)", "previouslyFormattedCitation" : "(S. O\u2019Mahony et al. 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }O’Mahony et al. 2009)Animal behavioural testsForced swim (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bravo et al. 2011)", "manualFormatting" : "Bravo et al. 2011)", "plainTextFormattedCitation" : "(Bravo et al. 2011)", "previouslyFormattedCitation" : "(Bravo et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Bravo et al. 2011)Step down (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bercik et al. 2011)", "manualFormatting" : "Bercik et al. 2011)", "plainTextFormattedCitation" : "(Bercik et al. 2011)", "previouslyFormattedCitation" : "(Bercik et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Bercik et al. 2011)Elevated plus maze (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1365-2982.2010.01620.x", "ISBN" : "1365-2982 (Electronic)\\n1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "21054680", "abstract" : "BACKGROUND There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "255-64, e119", "title" : "Reduced anxiety-like behavior and central neurochemical change in germ-free mice.", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Neufeld et al. 2011b)", "manualFormatting" : "Neufeld et al. 2011b)", "plainTextFormattedCitation" : "(Neufeld et al. 2011b)", "previouslyFormattedCitation" : "(Neufeld et al. 2011b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Neufeld et al. 2011b)Light-dark choice (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gareau et al. 2011)", "manualFormatting" : "Gareau et al. 2011)", "plainTextFormattedCitation" : "(Gareau et al. 2011)", "previouslyFormattedCitation" : "(Gareau et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Gareau et al. 2011)Open field (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1010529108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21282636", "abstract" : "Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.", "author" : [ { "dropping-particle" : "", "family" : "Diaz Heijtz", "given" : "Rochellys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Shugui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anuar", "given" : "Farhana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qian", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f6rkholm", "given" : "Britta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samuelsson", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibberd", "given" : "Martin L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forssberg", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettersson", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "2", "15" ] ] }, "page" : "3047-52", "title" : "Normal gut microbiota modulates brain development and behavior.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Diaz Heijtz et al. 2011)", "manualFormatting" : "Diaz Heijtz et al. 2011)", "plainTextFormattedCitation" : "(Diaz Heijtz et al. 2011)", "previouslyFormattedCitation" : "(Diaz Heijtz et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Diaz Heijtz et al. 2011)Object recognition (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.004", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25866195", "abstract" : "BACKGROUND There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. METHODS Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. RESULTS Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. CONCLUSIONS Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.", "author" : [ { "dropping-particle" : "", "family" : "Desbonnet", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Gerard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Traplin", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Sullivan", "given" : "Orla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crispie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "Rachel D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cotter", "given" : "Paul D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "165-73", "publisher" : "Elsevier Inc.", "title" : "Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Desbonnet et al. 2015)", "manualFormatting" : "Desbonnet et al. 2015)", "plainTextFormattedCitation" : "(Desbonnet et al. 2015)", "previouslyFormattedCitation" : "(Desbonnet et al. 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Desbonnet et al. 2015)Social interaction (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hsiao et al. 2013)", "manualFormatting" : "Hsiao et al. 2013)", "plainTextFormattedCitation" : "(Hsiao et al. 2013)", "previouslyFormattedCitation" : "(Hsiao et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Hsiao et al. 2013)Rodent gut, brain and blood biochemical assaysNeurochemical brain analysis and blood metabolites by high-performance liquid chromatography (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.77", "ISBN" : "1476-5578 (Electronic)\\n1359-4184 (Linking)", "ISSN" : "1476-5578", "PMID" : "22688187", "abstract" : "Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenham", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "R. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanahan", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "T. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "J. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "666-73", "title" : "The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Clarke et al. 2013)", "manualFormatting" : "Clarke et al. 2013)", "plainTextFormattedCitation" : "(Clarke et al. 2013)", "previouslyFormattedCitation" : "(Clarke et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Clarke et al. 2013)Microbial metabolites in faeces by gas chromatography (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Leclercq et al. 2014)", "manualFormatting" : "Leclercq et al. 2014)", "plainTextFormattedCitation" : "(Leclercq et al. 2014)", "previouslyFormattedCitation" : "(Leclercq et al. 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Leclercq et al. 2014)Measurements of neurotrophin, nerve growth factor protein (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1113/jphysiol.2004.063388", "ISBN" : "1469-7793", "ISSN" : "0022-3751", "PMID" : "15133062", "abstract" : "Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.", "author" : [ { "dropping-particle" : "", "family" : "Sudo", "given" : "Nobuyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chida", "given" : "Yoichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aiba", "given" : "Yuji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sonoda", "given" : "Junko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oyama", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Xiao-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kubo", "given" : "Chiharu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koga", "given" : "Yasuhiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of physiology", "id" : "ITEM-1", "issue" : "Pt 1", "issued" : { "date-parts" : [ [ "2004", "7", "1" ] ] }, "page" : "263-75", "title" : "Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.", "type" : "article-journal", "volume" : "558" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sudo et al. 2004)", "manualFormatting" : "Sudo et al. 2004)", "plainTextFormattedCitation" : "(Sudo et al. 2004)", "previouslyFormattedCitation" : "(Sudo et al. 2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Sudo et al. 2004), C-reactive protein (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Leclercq et al. 2014)", "manualFormatting" : "Leclercq et al. 2014)", "plainTextFormattedCitation" : "(Leclercq et al. 2014)", "previouslyFormattedCitation" : "(Leclercq et al. 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Leclercq et al. 2014), hormones (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bruce-Keller et al. 2015)", "manualFormatting" : "Bruce-Keller et al. 2015)", "plainTextFormattedCitation" : "(Bruce-Keller et al. 2015)", "previouslyFormattedCitation" : "(Bruce-Keller et al. 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Bruce-Keller et al. 2015), cytokines and chemokines by immunoassays (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ohland et al. 2013)", "manualFormatting" : "Ohland et al. 2013)", "plainTextFormattedCitation" : "(Ohland et al. 2013)", "previouslyFormattedCitation" : "(Ohland et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Ohland et al. 2013)Intestinal permeability assays (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hsiao et al. 2013)", "manualFormatting" : "Hsiao et al. 2013)", "plainTextFormattedCitation" : "(Hsiao et al. 2013)", "previouslyFormattedCitation" : "(Hsiao et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Hsiao et al. 2013)Blood endotoxin tests (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12295", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "24372793", "abstract" : "BACKGROUND A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(\u00ae) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(\u00ae) pretreated mice submitted to chronic psychological stress. METHODS Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were used to assess brain activity. In addition, gut permeability and tight junction (TJ) proteins levels were also determinated. KEY RESULTS We observed that a pretreatment with the probiotic formulation attenuated HPA axis and ANS activities in response to WAS, and reduced cFos expression in different brain areas but Lactobacillus salivarius (a negative control) treatment was ineffective on these parameters. Moreover, probiotic pretreatment prevented the WAS-induced decrease hippocampal neurogenesis and expression changes in hypothalamic genes involved in synaptic plasticity. These central effects were associated with restoration of TJ barrier integrity in stressed mice. CONCLUSIONS & INFERENCES These data suggest that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by a pretreatment with the Probio'Stick(\u00ae) formulation, suggesting that probiotics modulate neuroregulatory factors and various signaling pathways in the central nervous system involved in stress response.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colom", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braniste", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramalho", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marrot", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tompkins", "given" : "T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "510-20", "title" : "Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ait-Belgnaoui et al. 2014)", "manualFormatting" : "Ait-Belgnaoui et al. 2014)", "plainTextFormattedCitation" : "(Ait-Belgnaoui et al. 2014)", "previouslyFormattedCitation" : "(Ait-Belgnaoui et al. 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Ait-Belgnaoui et al. 2014)Human behavioural assessmentsHuman patient self-reports, depression and anxiety scales (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.003", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25862297", "abstract" : "BACKGROUND Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sellaro", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemert", "given" : "Saskia", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Jos A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colzato", "given" : "Lorenza S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "258-64", "publisher" : "Elsevier Inc.", "title" : "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Messaoudi et al. 2011; Steenbergen et al. 2015)", "manualFormatting" : "Messaoudi et al. 2011; Steenbergen et al. 2015)", "plainTextFormattedCitation" : "(Messaoudi et al. 2011; Steenbergen et al. 2015)", "previouslyFormattedCitation" : "(Messaoudi et al. 2011; Steenbergen et al. 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Messaoudi et al. 2011; Steenbergen et al. 2015)Experimental interventions in rodentsProbiotics (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2013.02.043", "ISBN" : "1528-0012 (Electronic)\\n0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "23474283", "abstract" : "BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.", "author" : [ { "dropping-particle" : "", "family" : "Tillisch", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labus", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kilpatrick", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Zhiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stains", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ebrat", "given" : "Bahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guyonnet", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legrain-Raspaud", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trotin", "given" : "Beatrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naliboff", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Emeran A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "1394-401, 1401.e1-4", "publisher" : "Elsevier Inc.", "title" : "Consumption of fermented milk product with probiotic modulates brain activity.", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tillisch et al. 2013)", "manualFormatting" : "Tillisch et al. 2013)", "plainTextFormattedCitation" : "(Tillisch et al. 2013)", "previouslyFormattedCitation" : "(Tillisch et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Tillisch et al. 2013)Microbiota transplants (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1010529108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21282636", "abstract" : "Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.", "author" : [ { "dropping-particle" : "", "family" : "Diaz Heijtz", "given" : "Rochellys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Shugui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anuar", "given" : "Farhana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qian", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f6rkholm", "given" : "Britta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samuelsson", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibberd", "given" : "Martin L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forssberg", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettersson", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "2", "15" ] ] }, "page" : "3047-52", "title" : "Normal gut microbiota modulates brain development and behavior.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Diaz Heijtz et al. 2011)", "manualFormatting" : "Diaz Heijtz et al. 2011)", "plainTextFormattedCitation" : "(Diaz Heijtz et al. 2011)", "previouslyFormattedCitation" : "(Diaz Heijtz et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Diaz Heijtz et al. 2011)Antibiotic treatments (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bercik et al. 2011)", "manualFormatting" : "Bercik et al. 2011)", "plainTextFormattedCitation" : "(Bercik et al. 2011)", "previouslyFormattedCitation" : "(Bercik et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Bercik et al. 2011)Dietary alterations (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ohland et al. 2013)", "manualFormatting" : "Ohland et al. 2013)", "plainTextFormattedCitation" : "(Ohland et al. 2013)", "previouslyFormattedCitation" : "(Ohland et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Ohland et al. 2013)Pathogen introduction (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gareau et al. 2011)", "manualFormatting" : "Gareau et al. 2011)", "plainTextFormattedCitation" : "(Gareau et al. 2011)", "previouslyFormattedCitation" : "(Gareau et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Gareau et al. 2011)Vagotomy (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bravo et al. 2011)", "plainTextFormattedCitation" : "(Bravo et al. 2011)", "previouslyFormattedCitation" : "(Bravo et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Bravo et al. 2011)Experimental interventions in humansProbiotics and dietary interventions (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2013.02.043", "ISBN" : "1528-0012 (Electronic)\\n0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "23474283", "abstract" : "BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.", "author" : [ { "dropping-particle" : "", "family" : "Tillisch", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labus", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kilpatrick", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Zhiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stains", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ebrat", "given" : "Bahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guyonnet", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legrain-Raspaud", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trotin", "given" : "Beatrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naliboff", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Emeran A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "1394-401, 1401.e1-4", "publisher" : "Elsevier Inc.", "title" : "Consumption of fermented milk product with probiotic modulates brain activity.", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tillisch et al. 2013)", "manualFormatting" : "Tillisch et al. 2013)", "plainTextFormattedCitation" : "(Tillisch et al. 2013)", "previouslyFormattedCitation" : "(Tillisch et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Tillisch et al. 2013)Antibiotic treatments (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0060042", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23565181", "abstract" : "UNLABELLED Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. METHODS Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. RESULTS There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. CONCLUSIONS Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. TRIAL REGISTRATION NCT01069133.", "author" : [ { "dropping-particle" : "", "family" : "Bajaj", "given" : "Jasmohan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heuman", "given" : "Douglas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanyal", "given" : "Arun J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hylemon", "given" : "Phillip B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sterling", "given" : "Richard K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stravitz", "given" : "R. 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The majority of these microbes reside within the intestines in largely stable but dynamically interactive climax communities that positively interact with their host. Studies from this laboratory have shown that stressor exposure impacts the stability of the microbiota and leads to bacterial translocation. The biological importance of these alterations, however, is not well understood. To determine whether the microbiome contributes to stressor-induced immunoenhancement, mice were exposed to a social stressor called social disruption (SDR), that increases circulating cytokines and primes the innate immune system for enhanced reactivity. Bacterial populations in the cecum were characterized using bacterial tag-encoded FLX amplicon pyrosequencing. Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines.", "author" : [ { "dropping-particle" : "", "family" : "Bailey", "given" : "Michael T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowd", "given" : "Scot E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Galley", "given" : "Jeffrey D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hufnagle", "given" : "Amy R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "Rebecca G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyte", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "397-407", "publisher" : "Elsevier Inc.", "title" : "Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.bbi.2015.03.016", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "25882912", "abstract" : "Studies using animal models have shown that depression affects the stability of the microbiota, but the actual structure and composition in patients with major depressive disorder (MDD) are not well understood. Here, we analyzed fecal samples from 46 patients with depression (29 active-MDD and 17 responded-MDD) and 30 healthy controls (HCs). High-throughput pyrosequencing showed that, according to the Shannon index, increased fecal bacterial \u03b1-diversity was found in the active-MDD (A-MDD) vs. the HC group but not in the responded-MDD (R-MDD) vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria strongly increased in level, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups compared with the HC group. Despite profound interindividual variability, levels of several predominant genera were significantly different between the MDD and HC groups. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium. A negative correlation was observed between Faecalibacterium and the severity of depressive symptoms. These findings enable a better understanding of changes in the fecal microbiota composition in such patients, showing either a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacterial genera. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and depression and to evaluate the suitability of the microbiome as a biomarker.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Haiyin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Zongxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Hongjin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Zhanping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Wenxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Zhonglin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shi", "given" : "Jianfei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lanjuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruan", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "186-94", "publisher" : "Elsevier Inc.", "title" : "Altered fecal microbiota composition in patients with major depressive disorder.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bailey et al. 2011; Jiang et al. 2015)", "manualFormatting" : "Bailey et al. 2011; Jiang et al. 2015)", "plainTextFormattedCitation" : "(Bailey et al. 2011; Jiang et al. 2015)", "previouslyFormattedCitation" : "(Bailey et al. 2011; Jiang et al. 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Bailey et al. 2011; Jiang et al. 2015)Comparison of host microbiomes before and after interventions (e.g., ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1053/j.gastro.2013.02.043", "ISBN" : "1528-0012 (Electronic)\\n0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "23474283", "abstract" : "BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.", "author" : [ { "dropping-particle" : "", "family" : "Tillisch", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labus", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kilpatrick", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Zhiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stains", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ebrat", "given" : "Bahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guyonnet", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legrain-Raspaud", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trotin", "given" : "Beatrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naliboff", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Emeran A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "1394-401, 1401.e1-4", "publisher" : "Elsevier Inc.", "title" : "Consumption of fermented milk product with probiotic modulates brain activity.", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Messaoudi et al. 2011; Tillisch et al. 2013)", "manualFormatting" : "Messaoudi et al. 2011; Tillisch et al. 2013)", "plainTextFormattedCitation" : "(Messaoudi et al. 2011; Tillisch et al. 2013)", "previouslyFormattedCitation" : "(Messaoudi et al. 2011; Tillisch et al. 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }Messaoudi et al. 2011; Tillisch et al. 2013)Supplementary Table 2: Probiotic methods in 25 most cited MGB publicationsPublicationProbioticModelBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Lactobacillus rhamnosusBALB/c miceMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Lactobacillus helveticus R0052Bifidobacterium longum R0175Wistar ratsHuman (clinical trial)Gareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gareau et al. 2011)", "manualFormatting" : "(2011)\r", "plainTextFormattedCitation" : "(Gareau et al. 2011)", "previouslyFormattedCitation" : "(Gareau et al. 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Lactobacillus rhamnosus R0011Lactobacillus helveticus R0052C57BL/6 miceAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2012.03.024", "ISBN" : "1873-3360; 0306-4530", "ISSN" : "1873-3360", "PMID" : "22541937", "abstract" : "BACKGROUND AND AIMS Intestinal barrier impairment is incriminated in the pathophysiology of intestinal gut disorders associated with psychiatric comorbidity. Increased intestinal permeability associated with upload of lipopolysaccharides (LPS) translocation induces depressive symptoms. Gut microbiota and probiotics alter behavior and brain neurochemistry. Since Lactobacillus farciminis suppresses stress-induced hyperpermeability, we examined whether (i) L. farciminis affects the HPA axis stress response, (ii) stress induces changes in LPS translocation and central cytokine expression which may be reversed by L. farciminis, (iii) the prevention of \"leaky\" gut and LPS upload are involved in these effects. METHODS At the end of the following treatments female rats were submitted to a partial restraint stress (PRS) or sham-PRS: (i) oral administration of L. farciminis during 2 weeks, (ii) intraperitoneal administration of ML-7 (a specific myosin light chain kinase inhibitor), (iii) antibiotic administration in drinking water during 12 days. After PRS or sham-PRS session, we evaluated LPS levels in portal blood, plasma corticosterone and adrenocorticotropic hormone (ACTH) levels, hypothalamic corticotropin releasing factor (CRF) and pro-inflammatory cytokine mRNA expression, and colonic paracellular permeability (CPP). RESULTS PRS increased plasma ACTH and corticosterone; hypothalamic CRF and pro-inflammatory cytokine expression; CPP and portal blood concentration of LPS. L. farciminis and ML-7 suppressed stress-induced hyperpermeability, endotoxemia and prevented HPA axis stress response and neuroinflammation. Antibiotic reduction of luminal LPS concentration prevented HPA axis stress response and increased hypothalamic expression of pro-inflammatory cytokines. CONCLUSION The attenuation of the HPA axis response to stress by L. farciminis depends upon the prevention of intestinal barrier impairment and decrease of circulating LPS levels.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durand", "given" : "Henri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "Christel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaumaz", "given" : "Gilles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eutamene", "given" : "H\u00e9l\u00e8ne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrier", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fioramonti", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bueno", "given" : "Lionel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "Vassilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2012", "11" ] ] }, "page" : "1885-95", "title" : "Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2012)", "plainTextFormattedCitation" : "(2012)", "previouslyFormattedCitation" : "(2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2012)Lactobacillus farciminisWistar ratsHsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Bacteroides fragilis C57BL/6N miceOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Lactobacillus helveticus129/SvEv miceAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12295", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "24372793", "abstract" : "BACKGROUND A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(\u00ae) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(\u00ae) pretreated mice submitted to chronic psychological stress. METHODS Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were used to assess brain activity. In addition, gut permeability and tight junction (TJ) proteins levels were also determinated. KEY RESULTS We observed that a pretreatment with the probiotic formulation attenuated HPA axis and ANS activities in response to WAS, and reduced cFos expression in different brain areas but Lactobacillus salivarius (a negative control) treatment was ineffective on these parameters. Moreover, probiotic pretreatment prevented the WAS-induced decrease hippocampal neurogenesis and expression changes in hypothalamic genes involved in synaptic plasticity. These central effects were associated with restoration of TJ barrier integrity in stressed mice. CONCLUSIONS & INFERENCES These data suggest that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by a pretreatment with the Probio'Stick(\u00ae) formulation, suggesting that probiotics modulate neuroregulatory factors and various signaling pathways in the central nervous system involved in stress response.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colom", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braniste", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramalho", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marrot", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tompkins", "given" : "T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "510-20", "title" : "Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.", "type" : "article-journal", "volume" : "26" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Lactobacillus helveticus R0052Bifidobacterium longum R0175 C57Bl6 miceSteenbergen et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.003", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25862297", "abstract" : "BACKGROUND Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sellaro", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemert", "given" : "Saskia", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Jos A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colzato", "given" : "Lorenza S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "258-64", "publisher" : "Elsevier Inc.", "title" : "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Bifidobacterium bifidum W23Bifidobacterium lactis W52Lactobacillus acidophilus W37Lactobacillus brevis W63Lactobacillus casei W56Lactobacillus salivarius W24Lactococcus lactisHuman (clinical trial)Supplementary Table 3: Microbiome methods in the 25 most cited MGB publications PublicationMethodCommentO’Mahony et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2009)", "plainTextFormattedCitation" : "(2009)", "previouslyFormattedCitation" : "(2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2009)DGGEDetects different profiles between two groups; an older qualitative method.Bercik et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)CultureDGGE + Sanger sequencingDetects different profiles between two groups; some specific taxa listed; an older qualitative method. Sanger sequencing superseded.Bailey et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2010.10.023", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "21040780", "abstract" : "The bodies of most animals are populated by highly complex and genetically diverse communities of microorganisms. The majority of these microbes reside within the intestines in largely stable but dynamically interactive climax communities that positively interact with their host. Studies from this laboratory have shown that stressor exposure impacts the stability of the microbiota and leads to bacterial translocation. The biological importance of these alterations, however, is not well understood. To determine whether the microbiome contributes to stressor-induced immunoenhancement, mice were exposed to a social stressor called social disruption (SDR), that increases circulating cytokines and primes the innate immune system for enhanced reactivity. Bacterial populations in the cecum were characterized using bacterial tag-encoded FLX amplicon pyrosequencing. Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines.", "author" : [ { "dropping-particle" : "", "family" : "Bailey", "given" : "Michael T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowd", "given" : "Scot E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Galley", "given" : "Jeffrey D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hufnagle", "given" : "Amy R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "Rebecca G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyte", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "397-407", "publisher" : "Elsevier Inc.", "title" : "Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)V4-V6 16S rRNA 454-pyrosequencingSuperseded sequencing and analysis methods, with a small number of reads obtained per sample. Some evidence for differences at time 0 from clustering, but not narrowed down to specific taxa.Gareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)16S rRNA qPCRSome taxa are estimated by qPCR. No mention of the exact normalization performed (e.g., Is rRNA copy number taken into account?).Bajaj et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0060042", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23565181", "abstract" : "UNLABELLED Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. METHODS Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. RESULTS There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. CONCLUSIONS Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. TRIAL REGISTRATION NCT01069133.", "author" : [ { "dropping-particle" : "", "family" : "Bajaj", "given" : "Jasmohan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heuman", "given" : "Douglas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanyal", "given" : "Arun J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hylemon", "given" : "Phillip B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sterling", "given" : "Richard K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stravitz", "given" : "R. Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuchs", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridlon", "given" : "Jason M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daita", "given" : "Kalyani", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monteith", "given" : "Pamela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noble", "given" : "Nicole A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "White", "given" : "Melanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Andmorgan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sikaroodi", "given" : "Masoumeh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rangwala", "given" : "Huzefa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillevet", "given" : "Patrick M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e60042", "title" : "Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.", "type" : "article-journal", "volume" : "8" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)V1-V2 16S rRNA GS-Junior pyrosequencingNo significant changes in profile are reported. A correlation network was built for microbiome and metabolome data, and connectivity of the network was compared.Park et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)DGGEDetection of different profiles between two groups via an older qualitative method.Hsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)V3-V5 16S rRNA 454-pyrosequencingAppropriate bioinformatic and statistical tools used.Tillisch et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2013.02.043", "ISBN" : "1528-0012 (Electronic)\\n0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "23474283", "abstract" : "BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.", "author" : [ { "dropping-particle" : "", "family" : "Tillisch", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labus", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kilpatrick", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Zhiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stains", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ebrat", "given" : "Bahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guyonnet", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legrain-Raspaud", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trotin", "given" : "Beatrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naliboff", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Emeran A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "1394-401, 1401.e1-4", "publisher" : "Elsevier Inc.", "title" : "Consumption of fermented milk product with probiotic modulates brain activity.", "type" : "article-journal", "volume" : "144" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)V5-V6 16S rRNA 454-pyrosequencing“Post-hoc analysis of fecal microbiota composition indicated a good randomization of the subjects at baseline. No significant change in microbiota composition vs baseline was found after intervention between groups” (p. 1397). In other words, the study did not observe any change in the microbiota.Ohland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)T-RFLPAn old-fashioned method that flattens the diversity in the sample to small number of distinguishable peaks. That flattening might be the reason for a very clear separation of the samples on the PCA plot.Leclercq et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)V1-V2 16S rRNA 454-pyrosequencing16S rRNA qPCRAppropriate bioinformatic and statistical tools used. de Theije et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2013.12.005", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "24333160", "abstract" : "Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.", "author" : [ { "dropping-particle" : "", "family" : "Theije", "given" : "Caroline G", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wopereis", "given" : "Harm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramadan", "given" : "Mohamed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eijndthoven", "given" : "Tiemen", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambert", "given" : "Jolanda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knol", "given" : "Jan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garssen", "given" : "Johan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kraneveld", "given" : "Aletta D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oozeer", "given" : "Raish", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "3" ] ] }, "page" : "197-206", "publisher" : "Elsevier Inc.", "title" : "Altered gut microbiota and activity in a murine model of autism spectrum disorders.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)V3-V5 16S rRNA 454-pyrosequencingAppropriate bioinformatic and statistical tools used.Jiang et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.03.016", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "25882912", "abstract" : "Studies using animal models have shown that depression affects the stability of the microbiota, but the actual structure and composition in patients with major depressive disorder (MDD) are not well understood. Here, we analyzed fecal samples from 46 patients with depression (29 active-MDD and 17 responded-MDD) and 30 healthy controls (HCs). High-throughput pyrosequencing showed that, according to the Shannon index, increased fecal bacterial \u03b1-diversity was found in the active-MDD (A-MDD) vs. the HC group but not in the responded-MDD (R-MDD) vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria strongly increased in level, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups compared with the HC group. Despite profound interindividual variability, levels of several predominant genera were significantly different between the MDD and HC groups. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium. A negative correlation was observed between Faecalibacterium and the severity of depressive symptoms. These findings enable a better understanding of changes in the fecal microbiota composition in such patients, showing either a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacterial genera. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and depression and to evaluate the suitability of the microbiome as a biomarker.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Haiyin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Zongxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Hongjin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Zhanping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Wenxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Zhonglin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shi", "given" : "Jianfei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lanjuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruan", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "186-94", "publisher" : "Elsevier Inc.", "title" : "Altered fecal microbiota composition in patients with major depressive disorder.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)V1-V3 16S rRNA 454-pyrosequencingAppropriate bioinformatic and statistical tools used but no beta-diversity/PCA presentation in the main figures, due to high variation. Instead, the authors perform multiple tests with the aim of finding significant taxa.Bruce-Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)V3-V4 16S rRNA Illumina MiSeq sequencingAppropriate bioinformatic and statistical tools used.Abbreviations DGGE: denaturing gel electrophoresis; T-RFLP: terminal restriction fragment length polymorphism; V1-V6 16S rRNA: 16S ribosomal RNA variable regions 1-6.Supplementary Tables 4a-d: Five categories of central nervous system-related foci and methods in 25 most cited MGB papersSupplementary Table 4a: Neuroendocrine “stress” axisPublicationHPA-axis assessmentSpeciesBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Forced swim, CortBALB/c miceSudo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1113/jphysiol.2004.063388", "ISBN" : "1469-7793", "ISSN" : "0022-3751", "PMID" : "15133062", "abstract" : "Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.", "author" : [ { "dropping-particle" : "", "family" : "Sudo", "given" : "Nobuyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chida", "given" : "Yoichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aiba", "given" : "Yuji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sonoda", "given" : "Junko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oyama", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Xiao-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kubo", "given" : "Chiharu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koga", "given" : "Yasuhiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of physiology", "id" : "ITEM-1", "issue" : "Pt 1", "issued" : { "date-parts" : [ [ "2004", "7", "1" ] ] }, "page" : "263-75", "title" : "Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.", "type" : "article-journal", "volume" : "558" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2004)", "plainTextFormattedCitation" : "(2004)", "previouslyFormattedCitation" : "(2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2004)Restraint, CRH, ACTH, CortBALB/c miceO’Mahony et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2009)", "plainTextFormattedCitation" : "(2009)", "previouslyFormattedCitation" : "(2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2009)Maternal separation, CortSprague Dawley ratsNeufeld et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1365-2982.2010.01620.x", "ISBN" : "1365-2982 (Electronic)\\n1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "21054680", "abstract" : "BACKGROUND There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "255-64, e119", "title" : "Reduced anxiety-like behavior and central neurochemical change in germ-free mice.", "type" : "article-journal", "volume" : "23" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011b)", "plainTextFormattedCitation" : "(2011b)", "previouslyFormattedCitation" : "(2011b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011b)Cort 48 h after arrival in labSwiss Webster miceMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Urinary 24 h CortHumanClarke et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.77", "ISBN" : "1476-5578 (Electronic)\\n1359-4184 (Linking)", "ISSN" : "1476-5578", "PMID" : "22688187", "abstract" : "Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenham", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "R. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanahan", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "T. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "J. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "666-73", "title" : "The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.", "type" : "article-journal", "volume" : "18" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Novel cage, CortSwiss Webster miceGareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Water avoidance stress, CortC57BL/6 miceAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2012.03.024", "ISBN" : "1873-3360; 0306-4530", "ISSN" : "1873-3360", "PMID" : "22541937", "abstract" : "BACKGROUND AND AIMS Intestinal barrier impairment is incriminated in the pathophysiology of intestinal gut disorders associated with psychiatric comorbidity. Increased intestinal permeability associated with upload of lipopolysaccharides (LPS) translocation induces depressive symptoms. Gut microbiota and probiotics alter behavior and brain neurochemistry. Since Lactobacillus farciminis suppresses stress-induced hyperpermeability, we examined whether (i) L. farciminis affects the HPA axis stress response, (ii) stress induces changes in LPS translocation and central cytokine expression which may be reversed by L. farciminis, (iii) the prevention of \"leaky\" gut and LPS upload are involved in these effects. METHODS At the end of the following treatments female rats were submitted to a partial restraint stress (PRS) or sham-PRS: (i) oral administration of L. farciminis during 2 weeks, (ii) intraperitoneal administration of ML-7 (a specific myosin light chain kinase inhibitor), (iii) antibiotic administration in drinking water during 12 days. After PRS or sham-PRS session, we evaluated LPS levels in portal blood, plasma corticosterone and adrenocorticotropic hormone (ACTH) levels, hypothalamic corticotropin releasing factor (CRF) and pro-inflammatory cytokine mRNA expression, and colonic paracellular permeability (CPP). RESULTS PRS increased plasma ACTH and corticosterone; hypothalamic CRF and pro-inflammatory cytokine expression; CPP and portal blood concentration of LPS. L. farciminis and ML-7 suppressed stress-induced hyperpermeability, endotoxemia and prevented HPA axis stress response and neuroinflammation. Antibiotic reduction of luminal LPS concentration prevented HPA axis stress response and increased hypothalamic expression of pro-inflammatory cytokines. CONCLUSION The attenuation of the HPA axis response to stress by L. farciminis depends upon the prevention of intestinal barrier impairment and decrease of circulating LPS levels.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durand", "given" : "Henri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "Christel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaumaz", "given" : "Gilles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eutamene", "given" : "H\u00e9l\u00e8ne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrier", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fioramonti", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bueno", "given" : "Lionel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "Vassilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2012", "11" ] ] }, "page" : "1885-95", "title" : "Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2012)", "plainTextFormattedCitation" : "(2012)", "previouslyFormattedCitation" : "(2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2012)Restraint, CRH, ACTH, CortWistar ratsCrumeyrolle-Arias et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2014.01.014", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "24636517", "abstract" : "BACKGROUND AND AIMS Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stress-sensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. METHODS Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we examined the behavior responses of rats to social interaction and open-field tests. Serum corticosterone concentrations, CRF mRNA expression levels in the hypothalamus, glucocorticoid receptor (GR) mRNA expression levels in the hippocampus, and monoamine concentrations in the frontal cortex, hippocampus and striatum were compared in rats that were either exposed to the open-field stress or not. RESULTS GF rats spent less time sniffing an unknown partner than SPF rats in the social interaction test, and displayed a lower number of visits to the aversive central area, and an increase in latency time, time spent in the corners and number of defecations in the open-field test. In response to the open-field stress, serum corticosterone concentrations were 2.8-fold higher in GF than in SPF rats. Compared to that of SPF rats, GF rats showed elevated CRF mRNA expression in the hypothalamus and reduced GR mRNA expression in the hippocampus. GF rats also had a lower dopaminergic turnover rate in the frontal cortex, hippocampus and striatum than SPF rats. CONCLUSIONS In stress-sensitive F344 rats, absence of the gut microbiota exacerbates the neuroendocrine and behavioral responses to acute stress and the results coexist with alterations of the dopaminergic turnover rate in brain upper structures that are known to regulate reactivity to stress and anxiety-like behavior.", "author" : [ { "dropping-particle" : "", "family" : "Crumeyrolle-Arias", "given" : "Mich\u00e8le", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jaglin", "given" : "Mathilde", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Aur\u00e9lia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vancassel", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardona", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daug\u00e9", "given" : "Val\u00e9rie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naudon", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rabot", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "207-17", "title" : "Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.", "type" : "article-journal", "volume" : "42" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Open field, CRH, CortF344 ratsOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Brain and fecal Cort129/sVEv micePark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Water avoidance stress, CRHC57BL/6 miceAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12295", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "24372793", "abstract" : "BACKGROUND A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(\u00ae) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(\u00ae) pretreated mice submitted to chronic psychological stress. METHODS Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were used to assess brain activity. In addition, gut permeability and tight junction (TJ) proteins levels were also determinated. KEY RESULTS We observed that a pretreatment with the probiotic formulation attenuated HPA axis and ANS activities in response to WAS, and reduced cFos expression in different brain areas but Lactobacillus salivarius (a negative control) treatment was ineffective on these parameters. Moreover, probiotic pretreatment prevented the WAS-induced decrease hippocampal neurogenesis and expression changes in hypothalamic genes involved in synaptic plasticity. These central effects were associated with restoration of TJ barrier integrity in stressed mice. CONCLUSIONS & INFERENCES These data suggest that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by a pretreatment with the Probio'Stick(\u00ae) formulation, suggesting that probiotics modulate neuroregulatory factors and various signaling pathways in the central nervous system involved in stress response.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colom", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braniste", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramalho", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marrot", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tompkins", "given" : "T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "510-20", "title" : "Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.", "type" : "article-journal", "volume" : "26" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Water avoidance stress, Cort, c-Fos PVHC57Bl6 miceDesbonnet et al. (2015)Restraint, CortNIH Swiss miceAbbreviationsACTH: adrenocorticotropic hormone; c-Fos: immediate early gene product often used as cellular activation marker; Cort: corticosterone; CRH: corticotropin-releasing hormone; PVH: paraventricular nucleus of the hypothalamusSupplementary Table 4b: Emotion-mood: AnxietyPublicationAnxiety assessmentSpeciesDiaz Heijtz et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1010529108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21282636", "abstract" : "Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.", "author" : [ { "dropping-particle" : "", "family" : "Diaz Heijtz", "given" : "Rochellys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Shugui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anuar", "given" : "Farhana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qian", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f6rkholm", "given" : "Britta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samuelsson", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibberd", "given" : "Martin L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forssberg", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettersson", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "2", "15" ] ] }, "page" : "3047-52", "title" : "Normal gut microbiota modulates brain development and behavior.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Light-dark box, elevated plus maze, open fieldNMRI miceHsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Open fieldC57BL/6N miceBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Elevated plus maze, fear conditioning, open fieldBALB/c miceBercik et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Light-dark box, step down testBALB/c miceO’Mahony et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2009)", "plainTextFormattedCitation" : "(2009)", "previouslyFormattedCitation" : "(2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2009)Open field fecal boliSprague Dawley ratsNeufeld et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1365-2982.2010.01620.x", "ISBN" : "1365-2982 (Electronic)\\n1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "21054680", "abstract" : "BACKGROUND There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "255-64, e119", "title" : "Reduced anxiety-like behavior and central neurochemical change in germ-free mice.", "type" : "article-journal", "volume" : "23" }, "suppress-author" : 1, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.4161/cib.4.4.15702", "ISBN" : "1942-0889 (Electronic)", "ISSN" : "1942-0889", "PMID" : "21966581", "abstract" : "The acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of many immune and metabolic systems integral to health and well-being. Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.1 Accordingly, we sought to investigate if there were other changes of brain function such as behavioral alterations in germ free (GF) mice, and if so, to compare these to behavior of mice with normal gut microbiota. Our recent paper showed reduced anxietylike behavior in the elevated plus maze (EPM) in adult GF mice when compared to conventionally reared specific pathogen-free (SPF) mice.2 Here, we present data collected when we next colonized the adult GF mice with SPF feces thereby introducing normal gut microbiota, and then reassessed anxiety-like behavior. Interestingly, the anxiolytic behavioral phenotype observed in GF mice persisted after colonization with SPF intestinal microbiota. These data show that gut-brain interactions are important to CNS development of stress systems and that a critical window may exist after which reconstitution of microbiota and the immune system does not normalize the behavioral phenotype.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "Nancy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Communicative & integrative biology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2011", "7" ] ] }, "page" : "492-4", "title" : "Effects of intestinal microbiota on anxiety-like behavior.", "type" : "article-journal", "volume" : "4" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011b, 2011a)", "plainTextFormattedCitation" : "(2011b, 2011a)", "previouslyFormattedCitation" : "(2011b, 2011a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011b, 2011a)Elevated plus mazeSwiss Webster miceMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Conditioned defensive probe buryingHADS anxiety subscaleWistar ratsHumanClarke et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.77", "ISBN" : "1476-5578 (Electronic)\\n1359-4184 (Linking)", "ISSN" : "1476-5578", "PMID" : "22688187", "abstract" : "Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenham", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "R. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanahan", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "T. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "J. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "666-73", "title" : "The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.", "type" : "article-journal", "volume" : "18" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Light-dark boxSwiss Webster miceGareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Water avoidance stress, light-dark box C57BL/6 miceLeclercq et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)State-trait anxiety inventoryAlcohol-dependent humansSteenbergen et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.003", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25862297", "abstract" : "BACKGROUND Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sellaro", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemert", "given" : "Saskia", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Jos A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colzato", "given" : "Lorenza S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "258-64", "publisher" : "Elsevier Inc.", "title" : "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Beck anxiety inventoryHumanBruce-Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Elevated plus maze, fear conditioning, open fieldC57BL/6 miceCrumeyrolle-Arias et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2014.01.014", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "24636517", "abstract" : "BACKGROUND AND AIMS Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stress-sensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. METHODS Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we examined the behavior responses of rats to social interaction and open-field tests. Serum corticosterone concentrations, CRF mRNA expression levels in the hypothalamus, glucocorticoid receptor (GR) mRNA expression levels in the hippocampus, and monoamine concentrations in the frontal cortex, hippocampus and striatum were compared in rats that were either exposed to the open-field stress or not. RESULTS GF rats spent less time sniffing an unknown partner than SPF rats in the social interaction test, and displayed a lower number of visits to the aversive central area, and an increase in latency time, time spent in the corners and number of defecations in the open-field test. In response to the open-field stress, serum corticosterone concentrations were 2.8-fold higher in GF than in SPF rats. Compared to that of SPF rats, GF rats showed elevated CRF mRNA expression in the hypothalamus and reduced GR mRNA expression in the hippocampus. GF rats also had a lower dopaminergic turnover rate in the frontal cortex, hippocampus and striatum than SPF rats. CONCLUSIONS In stress-sensitive F344 rats, absence of the gut microbiota exacerbates the neuroendocrine and behavioral responses to acute stress and the results coexist with alterations of the dopaminergic turnover rate in brain upper structures that are known to regulate reactivity to stress and anxiety-like behavior.", "author" : [ { "dropping-particle" : "", "family" : "Crumeyrolle-Arias", "given" : "Mich\u00e8le", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jaglin", "given" : "Mathilde", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Aur\u00e9lia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vancassel", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardona", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daug\u00e9", "given" : "Val\u00e9rie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naudon", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rabot", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "207-17", "title" : "Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.", "type" : "article-journal", "volume" : "42" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Open fieldF344 ratsOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Barnes maze129/sVEv micePark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Open field, step down testC57BL/6 miceDesbonnet et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.004", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25866195", "abstract" : "BACKGROUND There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. METHODS Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. RESULTS Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. CONCLUSIONS Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.", "author" : [ { "dropping-particle" : "", "family" : "Desbonnet", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Gerard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Traplin", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Sullivan", "given" : "Orla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crispie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "Rachel D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cotter", "given" : "Paul D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "165-73", "publisher" : "Elsevier Inc.", "title" : "Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Light-dark boxNIH Swiss miceAbbreviationsHADS: Hospital Anxiety and Depression ScaleSupplementary Table 4c: Mood disorder: DepressionPublicationDepression assessmentSpeciesBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Forced swim testBALB/c miceMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)HADS depression subscaleHumanJiang et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.03.016", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "25882912", "abstract" : "Studies using animal models have shown that depression affects the stability of the microbiota, but the actual structure and composition in patients with major depressive disorder (MDD) are not well understood. Here, we analyzed fecal samples from 46 patients with depression (29 active-MDD and 17 responded-MDD) and 30 healthy controls (HCs). High-throughput pyrosequencing showed that, according to the Shannon index, increased fecal bacterial \u03b1-diversity was found in the active-MDD (A-MDD) vs. the HC group but not in the responded-MDD (R-MDD) vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria strongly increased in level, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups compared with the HC group. Despite profound interindividual variability, levels of several predominant genera were significantly different between the MDD and HC groups. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium. A negative correlation was observed between Faecalibacterium and the severity of depressive symptoms. These findings enable a better understanding of changes in the fecal microbiota composition in such patients, showing either a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacterial genera. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and depression and to evaluate the suitability of the microbiome as a biomarker.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Haiyin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Zongxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Hongjin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Zhanping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Wenxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Zhonglin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shi", "given" : "Jianfei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lanjuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruan", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "186-94", "publisher" : "Elsevier Inc.", "title" : "Altered fecal microbiota composition in patients with major depressive disorder.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)DSM, Hamilton’s depression scale, Montgomery–Asberg Depression Rating ScaleHumanLeclercq et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Beck depression inventoryAlcohol-dependent humansSteenbergen et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.003", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25862297", "abstract" : "BACKGROUND Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sellaro", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemert", "given" : "Saskia", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Jos A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colzato", "given" : "Lorenza S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "258-64", "publisher" : "Elsevier Inc.", "title" : "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)LEIDS-r, Beck depression inventoryHumanPark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Tail suspension testC57BL/6 miceAbbreviationsDSM: Diagnostic and Statistical Manual of Mental DisordersSupplementary Table 4d: Autism spectrum/developmental disordersPublicationAutism spectrum assessmentSpeciesHsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Pre-pulse inhibition, marble burying, social interactionC57BL/6N micede Theije et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2013.12.005", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "24333160", "abstract" : "Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.", "author" : [ { "dropping-particle" : "", "family" : "Theije", "given" : "Caroline G", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wopereis", "given" : "Harm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramadan", "given" : "Mohamed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eijndthoven", "given" : "Tiemen", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambert", "given" : "Jolanda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knol", "given" : "Jan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garssen", "given" : "Johan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kraneveld", "given" : "Aletta D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oozeer", "given" : "Raish", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "3" ] ] }, "page" : "197-206", "publisher" : "Elsevier Inc.", "title" : "Altered gut microbiota and activity in a murine model of autism spectrum disorders.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Social interactionBALB/c miceSupplementary Table 4e: CognitionPublicationCognition assessmentSpeciesBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Fear conditioningBALB/c miceGareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Novel object recognition, TmazeC57BL/6 miceBajaj et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0060042", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23565181", "abstract" : "UNLABELLED Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. METHODS Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. RESULTS There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. CONCLUSIONS Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. TRIAL REGISTRATION NCT01069133.", "author" : [ { "dropping-particle" : "", "family" : "Bajaj", "given" : "Jasmohan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heuman", "given" : "Douglas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanyal", "given" : "Arun J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hylemon", "given" : "Phillip B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sterling", "given" : "Richard K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stravitz", "given" : "R. Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuchs", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridlon", "given" : "Jason M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daita", "given" : "Kalyani", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monteith", "given" : "Pamela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noble", "given" : "Nicole A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "White", "given" : "Melanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Andmorgan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sikaroodi", "given" : "Masoumeh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rangwala", "given" : "Huzefa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillevet", "given" : "Patrick M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e60042", "title" : "Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.", "type" : "article-journal", "volume" : "8" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)BDT and the psychometric hepatic encephalopathy score (PHES; consists of NCT-A, NCT-B, DST, line tracing test and serial dotting)Cirrhotic humansBruce-Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Fear conditioningC57BL/6 miceOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Elevated Barnes maze129/sVEv miceDesbonnet et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.004", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25866195", "abstract" : "BACKGROUND There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. METHODS Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. RESULTS Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. CONCLUSIONS Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.", "author" : [ { "dropping-particle" : "", "family" : "Desbonnet", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Gerard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Traplin", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Sullivan", "given" : "Orla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crispie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "Rachel D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cotter", "given" : "Paul D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "165-73", "publisher" : "Elsevier Inc.", "title" : "Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Novel object recognition, social transmission food preference (social memory)NIH Swiss miceTerminology evaluationWhen addressing anxiety and depression in animals, it is important to keep in mind that these categories depend on verbal reports of feelings in humans and can therefore not be assessed in the same way in animals. It can even be questioned if animals experience anxiety and depression, even though we can readily observe behavioural and physiological changes in test situations that we consider would induce fear or giving up an active coping strategy. To emphasize the distinction between human anxiety and depression and what scientists can assess in animals, it is considered good scientific practice to describe the results of such behavioural tests with terms such as “anxiety-like” or “depression-like” rather than directly inferring anxiety and depression. As shown in tables 5a and 5b, all MGB animal studies relevant to anxiety and depression employ appropriate “anxiety-like” and “depression-like” descriptive terms, even though they all also discuss anxiety and depression as such. Supplementary Table 5a: Behavioural tests and descriptive terms relative to anxietyPublicationBehavioural testDescriptionsDiaz Heijtz et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1010529108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21282636", "abstract" : "Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.", "author" : [ { "dropping-particle" : "", "family" : "Diaz Heijtz", "given" : "Rochellys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Shugui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anuar", "given" : "Farhana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qian", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f6rkholm", "given" : "Britta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samuelsson", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibberd", "given" : "Martin L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forssberg", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettersson", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "2", "15" ] ] }, "page" : "3047-52", "title" : "Normal gut microbiota modulates brain development and behavior.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Light-dark box, elevated plus maze, open field Anxiety, anxiety behaviour, anxiety-like behaviourHsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Open fieldAnxiety, anxiety-associated, anxiety-like behaviourBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Elevated plus maze, fear conditioning, open field Anxiety, anxiety behaviour, anxiety-like behaviour, anxiety-related, anxiety responsesBercik et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Light-dark box, step down testAnxiety, anxiety-like behaviourO’Mahony et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2009)", "plainTextFormattedCitation" : "(2009)", "previouslyFormattedCitation" : "(2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2009)Open field fecal boliAnxiety, anxiety-like behaviourNeufeld et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4161/cib.4.4.15702", "ISBN" : "1942-0889 (Electronic)", "ISSN" : "1942-0889", "PMID" : "21966581", "abstract" : "The acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of many immune and metabolic systems integral to health and well-being. Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.1 Accordingly, we sought to investigate if there were other changes of brain function such as behavioral alterations in germ free (GF) mice, and if so, to compare these to behavior of mice with normal gut microbiota. Our recent paper showed reduced anxietylike behavior in the elevated plus maze (EPM) in adult GF mice when compared to conventionally reared specific pathogen-free (SPF) mice.2 Here, we present data collected when we next colonized the adult GF mice with SPF feces thereby introducing normal gut microbiota, and then reassessed anxiety-like behavior. Interestingly, the anxiolytic behavioral phenotype observed in GF mice persisted after colonization with SPF intestinal microbiota. These data show that gut-brain interactions are important to CNS development of stress systems and that a critical window may exist after which reconstitution of microbiota and the immune system does not normalize the behavioral phenotype.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "Nancy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Communicative & integrative biology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2011", "7" ] ] }, "page" : "492-4", "title" : "Effects of intestinal microbiota on anxiety-like behavior.", "type" : "article-journal", "volume" : "4" }, "suppress-author" : 1, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/j.1365-2982.2010.01620.x", "ISBN" : "1365-2982 (Electronic)\\n1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "21054680", "abstract" : "BACKGROUND There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "255-64, e119", "title" : "Reduced anxiety-like behavior and central neurochemical change in germ-free mice.", "type" : "article-journal", "volume" : "23" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011a, 2011b)", "plainTextFormattedCitation" : "(2011a, 2011b)", "previouslyFormattedCitation" : "(2011a, 2011b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011a, 2011b)Elevated plus mazeAnxiety, anxiety-like behaviourMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Conditioned defensive probe buryingAnxiety, anxiety-like behaviour, anxiety relatedClarke et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.77", "ISBN" : "1476-5578 (Electronic)\\n1359-4184 (Linking)", "ISSN" : "1476-5578", "PMID" : "22688187", "abstract" : "Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenham", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "R. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanahan", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "T. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "J. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "666-73", "title" : "The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.", "type" : "article-journal", "volume" : "18" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Light-dark boxAnxiety, anxiety behaviour, anxiety-like behaviourGareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Water avoidance stress, light-dark box Anxiety, anxiety-like behaviourBruce-Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Elevated plus maze, fear conditioning, open fieldAnxiety, anxiety behaviour, anxiety-based behaviour, anxiety-like behaviourCrumeyrolle-Arias et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2014.01.014", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "24636517", "abstract" : "BACKGROUND AND AIMS Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stress-sensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. METHODS Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we examined the behavior responses of rats to social interaction and open-field tests. Serum corticosterone concentrations, CRF mRNA expression levels in the hypothalamus, glucocorticoid receptor (GR) mRNA expression levels in the hippocampus, and monoamine concentrations in the frontal cortex, hippocampus and striatum were compared in rats that were either exposed to the open-field stress or not. RESULTS GF rats spent less time sniffing an unknown partner than SPF rats in the social interaction test, and displayed a lower number of visits to the aversive central area, and an increase in latency time, time spent in the corners and number of defecations in the open-field test. In response to the open-field stress, serum corticosterone concentrations were 2.8-fold higher in GF than in SPF rats. Compared to that of SPF rats, GF rats showed elevated CRF mRNA expression in the hypothalamus and reduced GR mRNA expression in the hippocampus. GF rats also had a lower dopaminergic turnover rate in the frontal cortex, hippocampus and striatum than SPF rats. CONCLUSIONS In stress-sensitive F344 rats, absence of the gut microbiota exacerbates the neuroendocrine and behavioral responses to acute stress and the results coexist with alterations of the dopaminergic turnover rate in brain upper structures that are known to regulate reactivity to stress and anxiety-like behavior.", "author" : [ { "dropping-particle" : "", "family" : "Crumeyrolle-Arias", "given" : "Mich\u00e8le", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jaglin", "given" : "Mathilde", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Aur\u00e9lia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vancassel", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardona", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daug\u00e9", "given" : "Val\u00e9rie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naudon", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rabot", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "207-17", "title" : "Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.", "type" : "article-journal", "volume" : "42" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Open fieldAnxiety, anxiety-like behaviour, anxiety-like response, signs of anxietyOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Elevated Barnes mazeAnxiety, anxiety behaviour, anxiety-like behaviourPark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Open field, step down testAnxiety, anxiety-like behaviourDesbonnet et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.004", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25866195", "abstract" : "BACKGROUND There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. METHODS Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. RESULTS Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. CONCLUSIONS Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.", "author" : [ { "dropping-particle" : "", "family" : "Desbonnet", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Gerard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Traplin", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Sullivan", "given" : "Orla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crispie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "Rachel D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cotter", "given" : "Paul D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "165-73", "publisher" : "Elsevier Inc.", "title" : "Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Light-dark boxAnxiety, anxiety behaviourSupplementary Table 5b: Behavioural tests and descriptive terms relative to depressionPublicationBehavioural testDescriptionsBravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Forced swim testDepression, depression-related behaviourPark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Tail suspension testDepression, depression-like behaviour; behavioural depressionIn addition to scoring the occurrences of descriptive terms, we also assessed the context in which they were used. We found several instances of inappropriate descriptive terms. With respect to the open field test, for example, Hsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013) write that: “Open field exploration involves mapping an animal’s movement in an open arena to measure locomotion and anxiety (Bourin et al., 2007)”, and Bravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011) report that “L. rhamnosus (JB-1)-fed mice were less anxious”. Similarly for depression, Park et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013) state that “The induction of chronic depression alters motor activity and the microbial pro?le in the colon”, and Jiang et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.03.016", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "25882912", "abstract" : "Studies using animal models have shown that depression affects the stability of the microbiota, but the actual structure and composition in patients with major depressive disorder (MDD) are not well understood. Here, we analyzed fecal samples from 46 patients with depression (29 active-MDD and 17 responded-MDD) and 30 healthy controls (HCs). High-throughput pyrosequencing showed that, according to the Shannon index, increased fecal bacterial \u03b1-diversity was found in the active-MDD (A-MDD) vs. the HC group but not in the responded-MDD (R-MDD) vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria strongly increased in level, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups compared with the HC group. Despite profound interindividual variability, levels of several predominant genera were significantly different between the MDD and HC groups. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium. A negative correlation was observed between Faecalibacterium and the severity of depressive symptoms. These findings enable a better understanding of changes in the fecal microbiota composition in such patients, showing either a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacterial genera. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and depression and to evaluate the suitability of the microbiome as a biomarker.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Haiyin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Zongxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Hongjin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Zhanping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Wenxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Zhonglin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shi", "given" : "Jianfei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lanjuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruan", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "186-94", "publisher" : "Elsevier Inc.", "title" : "Altered fecal microbiota composition in patients with major depressive disorder.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015) note that “Studies using animal models have shown that depression affects the stability of the microbiota”. Thus, even though all studies in our sample do use “anxiety-like” and “depression-like” descriptive terms when describing findings obtained in animal behavioural tests, several of them also employ anxiety and depression in an inappropriate way, namely to describe anthropomorphically phenomena derived from rodent models. Supplementary Table 6: Independent variables tested, plus statistical methods used in the 25 most cited MGB papers. Bold font in the statistical-test cells indicates seemingly inappropriate use of statistical tests in view of the experimental design. PublicationIndependent variablesStatistical test Diaz Heijtz et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1010529108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21282636", "abstract" : "Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.", "author" : [ { "dropping-particle" : "", "family" : "Diaz Heijtz", "given" : "Rochellys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Shugui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anuar", "given" : "Farhana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qian", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f6rkholm", "given" : "Britta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samuelsson", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibberd", "given" : "Martin L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forssberg", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettersson", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "2", "15" ] ] }, "page" : "3047-52", "title" : "Normal gut microbiota modulates brain development and behavior.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Microbiota status (GF vs SPF)Repeated measures ANOVA (phenotype between, time within)One-way ANOVAHsiao et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2013.11.024", "ISBN" : "0092-8674", "ISSN" : "1097-4172", "PMID" : "24315484", "abstract" : "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "author" : [ { "dropping-particle" : "", "family" : "Hsiao", "given" : "Elaine Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McBride", "given" : "Sara W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsien", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharon", "given" : "Gil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyde", "given" : "Embriette R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCue", "given" : "Tyler", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codelli", "given" : "Julian A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chow", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reisman", "given" : "Sarah E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "Paul H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazmanian", "given" : "Sarkis K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "12", "19" ] ] }, "page" : "1451-63", "publisher" : "Elsevier Inc.", "title" : "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "type" : "article-journal", "volume" : "155" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Maternal immune activation;B. fragilis treatment Student’s t-test, one way ANOVA, two-way repeated measure ANOVA (PPI, CD4+ stim) Bravo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1102999108", "ISBN" : "1102999108", "ISSN" : "1091-6490", "PMID" : "21876150", "abstract" : "There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(A\u03b12) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(A\u03b12) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.", "author" : [ { "dropping-particle" : "", "family" : "Bravo", "given" : "Javier A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsythe", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Chew", "given" : "Marianne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Escaravage", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savignac", "given" : "H\u00e9l\u00e8ne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2011", "9", "20" ] ] }, "page" : "16050-5", "title" : "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.", "type" : "article-journal", "volume" : "108" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Ingestion of Lactobacillus;VagotomyStudent’s t-test, two-way ANOVASudo et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1113/jphysiol.2004.063388", "ISBN" : "1469-7793", "ISSN" : "0022-3751", "PMID" : "15133062", "abstract" : "Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.", "author" : [ { "dropping-particle" : "", "family" : "Sudo", "given" : "Nobuyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chida", "given" : "Yoichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aiba", "given" : "Yuji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sonoda", "given" : "Junko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oyama", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Xiao-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kubo", "given" : "Chiharu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koga", "given" : "Yasuhiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of physiology", "id" : "ITEM-1", "issue" : "Pt 1", "issued" : { "date-parts" : [ [ "2004", "7", "1" ] ] }, "page" : "263-75", "title" : "Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.", "type" : "article-journal", "volume" : "558" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2004)", "plainTextFormattedCitation" : "(2004)", "previouslyFormattedCitation" : "(2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2004)Microbiota status (GF, SPF and gnotobiotic);Stress (restraint, ether);Reconstitution with bacteriaFactorial analysis of varianceBercik et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2011.04.052", "ISBN" : "1528-0012 (Electronic)\\r0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "21683077", "abstract" : "BACKGROUND & AIMS Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.", "author" : [ { "dropping-particle" : "", "family" : "Bercik", "given" : "Premysl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denou", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Josh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Wendy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jury", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yikang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macri", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "Elena F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "Stephen M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "8" ] ] }, "page" : "599-609, 609.e1-3", "title" : "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.", "type" : "article-journal", "volume" : "141" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Microbiota status (antibiotic);Recolonization;Nerve transectionAnalysis of varianceO’Mahony et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2008.06.026", "ISBN" : "1873-2402; 0006-3223", "ISSN" : "1873-2402", "PMID" : "18723164", "abstract" : "BACKGROUND Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.", "author" : [ { "dropping-particle" : "", "family" : "O'Mahony", "given" : "SM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Codling", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ceolho", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "2", "1" ] ] }, "page" : "263-7", "publisher" : "Society of Biological Psychiatry", "title" : "Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.", "type" : "article-journal", "volume" : "65" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2009)", "plainTextFormattedCitation" : "(2009)", "previouslyFormattedCitation" : "(2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2009)Early life stress(Open field, but all animals)(Colorectal distension, but all animals)Student’s t-test, two-way ANOVA (CRD, open field)Neufeld et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4161/cib.4.4.15702", "ISBN" : "1942-0889 (Electronic)", "ISSN" : "1942-0889", "PMID" : "21966581", "abstract" : "The acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of many immune and metabolic systems integral to health and well-being. Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.1 Accordingly, we sought to investigate if there were other changes of brain function such as behavioral alterations in germ free (GF) mice, and if so, to compare these to behavior of mice with normal gut microbiota. Our recent paper showed reduced anxietylike behavior in the elevated plus maze (EPM) in adult GF mice when compared to conventionally reared specific pathogen-free (SPF) mice.2 Here, we present data collected when we next colonized the adult GF mice with SPF feces thereby introducing normal gut microbiota, and then reassessed anxiety-like behavior. Interestingly, the anxiolytic behavioral phenotype observed in GF mice persisted after colonization with SPF intestinal microbiota. These data show that gut-brain interactions are important to CNS development of stress systems and that a critical window may exist after which reconstitution of microbiota and the immune system does not normalize the behavioral phenotype.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "Nancy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Communicative & integrative biology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2011", "7" ] ] }, "page" : "492-4", "title" : "Effects of intestinal microbiota on anxiety-like behavior.", "type" : "article-journal", "volume" : "4" }, "suppress-author" : 1, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/j.1365-2982.2010.01620.x", "ISBN" : "1365-2982 (Electronic)\\n1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "21054680", "abstract" : "BACKGROUND There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.", "author" : [ { "dropping-particle" : "", "family" : "Neufeld", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kang", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienenstock", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "255-64, e119", "title" : "Reduced anxiety-like behavior and central neurochemical change in germ-free mice.", "type" : "article-journal", "volume" : "23" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011a, 2011b)", "plainTextFormattedCitation" : "(2011a, 2011b)", "previouslyFormattedCitation" : "(2011a, 2011b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011a, 2011b)Microbiota status (GF vs SPF; colonized GF vs SPF)Student’s t-test, two-way ANOVA (OF, EPM)Tillisch et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.gastro.2013.02.043", "ISBN" : "1528-0012 (Electronic)\\n0016-5085 (Linking)", "ISSN" : "1528-0012", "PMID" : "23474283", "abstract" : "BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.", "author" : [ { "dropping-particle" : "", "family" : "Tillisch", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labus", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kilpatrick", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Zhiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stains", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ebrat", "given" : "Bahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guyonnet", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legrain-Raspaud", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trotin", "given" : "Beatrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naliboff", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Emeran A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "1394-401, 1401.e1-4", "publisher" : "Elsevier Inc.", "title" : "Consumption of fermented milk product with probiotic modulates brain activity.", "type" : "article-journal", "volume" : "144" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Consumption of probioticsT testMessaoudi et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1017/S0007114510004319", "ISBN" : "1475-2662; 0007-1145", "ISSN" : "1475-2662", "PMID" : "20974015", "abstract" : "In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0\u00b705) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0\u00b705; somatisation, P < 0\u00b705; depression, P < 0\u00b705; and anger-hostility, P < 0\u00b705), the HADS (HADS global score, P < 0\u00b705; and HADS-anxiety, P < 0\u00b706), and by the CCL (problem solving, P < 0\u00b705) and the UFC level (P < 0\u00b705). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.", "author" : [ { "dropping-particle" : "", "family" : "Messaoudi", "given" : "Micha\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lalonde", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Violle", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Javelot", "given" : "Herv\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desor", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nejdi", "given" : "Amine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisson", "given" : "Jean-Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rougeot", "given" : "Catherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichelin", "given" : "Matthieu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Murielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazaubiel", "given" : "Jean-Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The British journal of nutrition", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "755-64", "title" : "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.", "type" : "article-journal", "volume" : "105" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Consumption of probiotics;Diazepam(Conditioned defensive burying, but all animals) Kruskal-Wallis rank sum test, Mann-Whitney U test, Wilcoxon testBailey et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2010.10.023", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "21040780", "abstract" : "The bodies of most animals are populated by highly complex and genetically diverse communities of microorganisms. The majority of these microbes reside within the intestines in largely stable but dynamically interactive climax communities that positively interact with their host. Studies from this laboratory have shown that stressor exposure impacts the stability of the microbiota and leads to bacterial translocation. The biological importance of these alterations, however, is not well understood. To determine whether the microbiome contributes to stressor-induced immunoenhancement, mice were exposed to a social stressor called social disruption (SDR), that increases circulating cytokines and primes the innate immune system for enhanced reactivity. Bacterial populations in the cecum were characterized using bacterial tag-encoded FLX amplicon pyrosequencing. Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines.", "author" : [ { "dropping-particle" : "", "family" : "Bailey", "given" : "Michael T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowd", "given" : "Scot E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Galley", "given" : "Jeffrey D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hufnagle", "given" : "Amy R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "Rebecca G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyte", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "397-407", "publisher" : "Elsevier Inc.", "title" : "Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Social disruption stress;AntibioticTwo-way ANOVAClarke et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.77", "ISBN" : "1476-5578 (Electronic)\\n1359-4184 (Linking)", "ISSN" : "1476-5578", "PMID" : "22688187", "abstract" : "Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenham", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scully", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "R. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanahan", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "T. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "J. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "6" ] ] }, "page" : "666-73", "title" : "The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.", "type" : "article-journal", "volume" : "18" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Microbiota status (GF, conventional and colonized GF);Novelty stressSexOne-, two- and three-way ANOVAGareau et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2009.202515", "ISBN" : "1468-3288 (Electronic)\\r0017-5749 (Linking)", "ISSN" : "1468-3288", "PMID" : "20966022", "abstract" : "BACKGROUND The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.", "author" : [ { "dropping-particle" : "", "family" : "Gareau", "given" : "M\u00e9lanie G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wine", "given" : "Eytan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues", "given" : "David M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Joon Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whary", "given" : "Mark T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philpott", "given" : "Dana J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macqueen", "given" : "Glenda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherman", "given" : "Philip M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3" ] ] }, "page" : "307-17", "title" : "Bacterial infection causes stress-induced memory dysfunction in mice.", "type" : "article-journal", "volume" : "60" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2011)", "plainTextFormattedCitation" : "(2011)", "previouslyFormattedCitation" : "(2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2011)Infection (Citrobacter rodentium);Water avoidance stress;Probiotic treatment;Microbiota status (GF vs conventional) Student t-test, one-, two-way ANOVA, Mann-Whitney testAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2012.03.024", "ISBN" : "1873-3360; 0306-4530", "ISSN" : "1873-3360", "PMID" : "22541937", "abstract" : "BACKGROUND AND AIMS Intestinal barrier impairment is incriminated in the pathophysiology of intestinal gut disorders associated with psychiatric comorbidity. Increased intestinal permeability associated with upload of lipopolysaccharides (LPS) translocation induces depressive symptoms. Gut microbiota and probiotics alter behavior and brain neurochemistry. Since Lactobacillus farciminis suppresses stress-induced hyperpermeability, we examined whether (i) L. farciminis affects the HPA axis stress response, (ii) stress induces changes in LPS translocation and central cytokine expression which may be reversed by L. farciminis, (iii) the prevention of \"leaky\" gut and LPS upload are involved in these effects. METHODS At the end of the following treatments female rats were submitted to a partial restraint stress (PRS) or sham-PRS: (i) oral administration of L. farciminis during 2 weeks, (ii) intraperitoneal administration of ML-7 (a specific myosin light chain kinase inhibitor), (iii) antibiotic administration in drinking water during 12 days. After PRS or sham-PRS session, we evaluated LPS levels in portal blood, plasma corticosterone and adrenocorticotropic hormone (ACTH) levels, hypothalamic corticotropin releasing factor (CRF) and pro-inflammatory cytokine mRNA expression, and colonic paracellular permeability (CPP). RESULTS PRS increased plasma ACTH and corticosterone; hypothalamic CRF and pro-inflammatory cytokine expression; CPP and portal blood concentration of LPS. L. farciminis and ML-7 suppressed stress-induced hyperpermeability, endotoxemia and prevented HPA axis stress response and neuroinflammation. Antibiotic reduction of luminal LPS concentration prevented HPA axis stress response and increased hypothalamic expression of pro-inflammatory cytokines. CONCLUSION The attenuation of the HPA axis response to stress by L. farciminis depends upon the prevention of intestinal barrier impairment and decrease of circulating LPS levels.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durand", "given" : "Henri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "Christel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaumaz", "given" : "Gilles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eutamene", "given" : "H\u00e9l\u00e8ne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrier", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fioramonti", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bueno", "given" : "Lionel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "Vassilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2012", "11" ] ] }, "page" : "1885-95", "title" : "Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2012)", "plainTextFormattedCitation" : "(2012)", "previouslyFormattedCitation" : "(2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2012)Partial restraint stress;L. farciminis treatment;Myosin light chain kinase inhibitor;Antibiotic treatmentStudent’s t-testBajaj et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0060042", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23565181", "abstract" : "UNLABELLED Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. METHODS Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. RESULTS There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. CONCLUSIONS Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. TRIAL REGISTRATION NCT01069133.", "author" : [ { "dropping-particle" : "", "family" : "Bajaj", "given" : "Jasmohan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heuman", "given" : "Douglas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanyal", "given" : "Arun J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hylemon", "given" : "Phillip B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sterling", "given" : "Richard K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stravitz", "given" : "R. Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuchs", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridlon", "given" : "Jason M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daita", "given" : "Kalyani", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monteith", "given" : "Pamela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noble", "given" : "Nicole A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "White", "given" : "Melanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Andmorgan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sikaroodi", "given" : "Masoumeh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rangwala", "given" : "Huzefa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillevet", "given" : "Patrick M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e60042", "title" : "Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.", "type" : "article-journal", "volume" : "8" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Rifaximin treatment;Time (before and after treatment)Student t-test, principal coordinate analysis (PCA), Wilcoxon matched-pair signed rank testsJiang et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.03.016", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "25882912", "abstract" : "Studies using animal models have shown that depression affects the stability of the microbiota, but the actual structure and composition in patients with major depressive disorder (MDD) are not well understood. Here, we analyzed fecal samples from 46 patients with depression (29 active-MDD and 17 responded-MDD) and 30 healthy controls (HCs). High-throughput pyrosequencing showed that, according to the Shannon index, increased fecal bacterial \u03b1-diversity was found in the active-MDD (A-MDD) vs. the HC group but not in the responded-MDD (R-MDD) vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria strongly increased in level, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups compared with the HC group. Despite profound interindividual variability, levels of several predominant genera were significantly different between the MDD and HC groups. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium. A negative correlation was observed between Faecalibacterium and the severity of depressive symptoms. These findings enable a better understanding of changes in the fecal microbiota composition in such patients, showing either a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacterial genera. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and depression and to evaluate the suitability of the microbiome as a biomarker.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Haiyin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Zongxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Hongjin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Zhanping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Wenxin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Zhonglin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shi", "given" : "Jianfei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lanjuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruan", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "186-94", "publisher" : "Elsevier Inc.", "title" : "Altered fecal microbiota composition in patients with major depressive disorder.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Depression (active MDD, respond MDD, healthy controlKruskal-Wallis rank sum testLeclercq et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1415174111", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "25288760", "abstract" : "Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.", "author" : [ { "dropping-particle" : "", "family" : "Leclercq", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matamoros", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cani", "given" : "Patrice D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neyrinck", "given" : "Audrey M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jamar", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St\u00e4rkel", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windey", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tremaroli", "given" : "Valentina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbeke", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timary", "given" : "Philippe", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delzenne", "given" : "Nathalie M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences USA", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2014", "10", "21" ] ] }, "page" : "E4485-93", "title" : "Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.", "type" : "article-journal", "volume" : "111" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Alcohol dependent detoxification before and after;Intestinal permeability (high, low)Parametric ANOVA, Kruskal-Wallis, Wilcoxon or paired Student t-testsde Theije et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2013.12.005", "ISBN" : "0889-1591", "ISSN" : "1090-2139", "PMID" : "24333160", "abstract" : "Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.", "author" : [ { "dropping-particle" : "", "family" : "Theije", "given" : "Caroline G", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wopereis", "given" : "Harm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramadan", "given" : "Mohamed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eijndthoven", "given" : "Tiemen", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambert", "given" : "Jolanda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knol", "given" : "Jan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garssen", "given" : "Johan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kraneveld", "given" : "Aletta D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oozeer", "given" : "Raish", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "3" ] ] }, "page" : "197-206", "publisher" : "Elsevier Inc.", "title" : "Altered gut microbiota and activity in a murine model of autism spectrum disorders.", "type" : "article-journal", "volume" : "37" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Valproic acid injection during gestation;SexKruskal-Wallis rank sum test, Mann-Whitney U testSteenbergen et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.003", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25862297", "abstract" : "BACKGROUND Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sellaro", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemert", "given" : "Saskia", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Jos A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colzato", "given" : "Lorenza S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "258-64", "publisher" : "Elsevier Inc.", "title" : "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Probiotic consumption (multispecies preparation vs placebo);Time (before) Repeated measures ANOVA (treatment between, time within), Bayesian probabilitiesBruce-Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.biopsych.2014.07.012", "ISBN" : "1873-2402 (Electronic)\\r0006-3223 (Linking)", "ISSN" : "1873-2402", "PMID" : "25173628", "abstract" : "BACKGROUND The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. METHODS Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses. RESULTS The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in \u03b1- and \u03b2-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis. CONCLUSIONS Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.", "author" : [ { "dropping-particle" : "", "family" : "Bruce-Keller", "given" : "Annadora J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salbaum", "given" : "J. Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Meng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanchard", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Christopher M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berthoud", "given" : "Hans-Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "4", "1" ] ] }, "page" : "607-15", "publisher" : "Elsevier", "title" : "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.", "type" : "article-journal", "volume" : "77" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Microbiota transfer (high fat or control diet-fed donors)Student t-test, repeated measures two-way ANOVA (body weight, fear conditioning)Crumeyrolle-Arias et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2014.01.014", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "24636517", "abstract" : "BACKGROUND AND AIMS Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stress-sensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. METHODS Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we examined the behavior responses of rats to social interaction and open-field tests. Serum corticosterone concentrations, CRF mRNA expression levels in the hypothalamus, glucocorticoid receptor (GR) mRNA expression levels in the hippocampus, and monoamine concentrations in the frontal cortex, hippocampus and striatum were compared in rats that were either exposed to the open-field stress or not. RESULTS GF rats spent less time sniffing an unknown partner than SPF rats in the social interaction test, and displayed a lower number of visits to the aversive central area, and an increase in latency time, time spent in the corners and number of defecations in the open-field test. In response to the open-field stress, serum corticosterone concentrations were 2.8-fold higher in GF than in SPF rats. Compared to that of SPF rats, GF rats showed elevated CRF mRNA expression in the hypothalamus and reduced GR mRNA expression in the hippocampus. GF rats also had a lower dopaminergic turnover rate in the frontal cortex, hippocampus and striatum than SPF rats. CONCLUSIONS In stress-sensitive F344 rats, absence of the gut microbiota exacerbates the neuroendocrine and behavioral responses to acute stress and the results coexist with alterations of the dopaminergic turnover rate in brain upper structures that are known to regulate reactivity to stress and anxiety-like behavior.", "author" : [ { "dropping-particle" : "", "family" : "Crumeyrolle-Arias", "given" : "Mich\u00e8le", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jaglin", "given" : "Mathilde", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Aur\u00e9lia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vancassel", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardona", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daug\u00e9", "given" : "Val\u00e9rie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naudon", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rabot", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "207-17", "title" : "Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.", "type" : "article-journal", "volume" : "42" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Microbiota status (GF vs SPF);Novelty stress (open field or not)Student’s t-test, two-way repeated measures ANOVA (microbial status between, time on sniffing within), Mann-Whitney and KruskalOhland et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.psyneuen.2013.02.008", "ISBN" : "1873-3360 (Electronic)\\r0306-4530 (Linking)", "ISSN" : "1873-3360", "PMID" : "23566632", "abstract" : "Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10(-/-)) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%)\u00b1Lactobacillus helveticus ROO52 (10(9)cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10(-/-) mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype- and diet-dependent. Anxiety-like behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WT and IL-10(-/-)mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.", "author" : [ { "dropping-particle" : "", "family" : "Ohland", "given" : "Christina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kish", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Haley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thiesen", "given" : "Aducio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hotte", "given" : "Naomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pankiv", "given" : "Evelina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madsen", "given" : "Karen L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychoneuroendocrinology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1738-47", "publisher" : "Elsevier Ltd", "title" : "Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.", "type" : "article-journal", "volume" : "38" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Genotype (WT vs IL-10 KO);Diet (standard chow vs Western);Lactobacillus helveticus gavageStudent’s one-way ANOVAPark et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12153", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "23773726", "abstract" : "BACKGROUND Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. METHODS Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles. KEY RESULTS Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon. CONCLUSIONS & INFERENCES The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.", "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blennerhassett", "given" : "P. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghia", "given" : "J. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verdu", "given" : "E. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bercik", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collins", "given" : "S. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "733-e575", "title" : "Altered colonic function and microbiota profile in a mouse model of chronic depression.", "type" : "article-journal", "volume" : "25" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2013)", "plainTextFormattedCitation" : "(2013)", "previouslyFormattedCitation" : "(2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2013)Olfactory bulbectomy;Intracerebroventricular injection (CRH vs vehicle)(Water avoidance stress, but all animals) Student’s t-testAit-Belgnaoui et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/nmo.12295", "ISBN" : "1365-2982 (Electronic)\\r1350-1925 (Linking)", "ISSN" : "1365-2982", "PMID" : "24372793", "abstract" : "BACKGROUND A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(\u00ae) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(\u00ae) pretreated mice submitted to chronic psychological stress. METHODS Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were used to assess brain activity. In addition, gut permeability and tight junction (TJ) proteins levels were also determinated. KEY RESULTS We observed that a pretreatment with the probiotic formulation attenuated HPA axis and ANS activities in response to WAS, and reduced cFos expression in different brain areas but Lactobacillus salivarius (a negative control) treatment was ineffective on these parameters. Moreover, probiotic pretreatment prevented the WAS-induced decrease hippocampal neurogenesis and expression changes in hypothalamic genes involved in synaptic plasticity. These central effects were associated with restoration of TJ barrier integrity in stressed mice. CONCLUSIONS & INFERENCES These data suggest that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by a pretreatment with the Probio'Stick(\u00ae) formulation, suggesting that probiotics modulate neuroregulatory factors and various signaling pathways in the central nervous system involved in stress response.", "author" : [ { "dropping-particle" : "", "family" : "Ait-Belgnaoui", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colom", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braniste", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramalho", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marrot", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cartier", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houdeau", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theodorou", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tompkins", "given" : "T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurogastroenterology and motility", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "510-20", "title" : "Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.", "type" : "article-journal", "volume" : "26" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2014)", "plainTextFormattedCitation" : "(2014)", "previouslyFormattedCitation" : "(2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2014)Probiotic administration (Lactobacillus helveticus R0052 & Bi?dobacterium longum R0175, L. salivrius, placebo);Chronic water avoidance stressOne-way ANOVADesbonnet et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbi.2015.04.004", "ISBN" : "1090-2139 (Electronic)\\r0889-1591 (Linking)", "ISSN" : "1090-2139", "PMID" : "25866195", "abstract" : "BACKGROUND There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. METHODS Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. RESULTS Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. CONCLUSIONS Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.", "author" : [ { "dropping-particle" : "", "family" : "Desbonnet", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Gerard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Traplin", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Sullivan", "given" : "Orla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crispie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moloney", "given" : "Rachel D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cotter", "given" : "Paul D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dinan", "given" : "Timothy G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cryan", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain, behavior, and immunity", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "8" ] ] }, "page" : "165-73", "publisher" : "Elsevier Inc.", "title" : "Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.", "type" : "article-journal", "volume" : "48" }, "suppress-author" : 1, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2015)", "plainTextFormattedCitation" : "(2015)", "previouslyFormattedCitation" : "(2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2015)Microbiota status (antibiotic)Restraint stressStudent t-test, factorial and repeated measures ANOVA (antibiotic and stress between, time within)7. Microbiota patents and probioticsWe used the European Patent Office’s search tool to find all patents written in English containing the words “microbiome OR microbiota” in the title, abstract or the full text. This search found 2096 patents, which we downloaded and analysed. There is inflationary growth in the number of patents awarded since mid-2016 (Fig. S1).Figure S1. Histogram of the number of microbiota-related patents published in the last ten years.The majority of microbiota patents in the EPO database are filed from the US, and the contribution of the next most prolific country, France, is one-tenth that of US (Fig. S2A). Patent applicants vary from food companies and for-profit biotech companies to academic research institutions (Fig. S2). Elwha LCC, the second most prolific patent applicant, is a holding company with a large but latent patent portfolio. Its business model involves acquiring patents and never attempting to commercialize them, but instead using them to file lawsuits against institutions using those inventions.Figure S2. Microbiota patents applicants A) Country of origin of the microbiota related patents’ applicants. B) The most prolific patent applicants.As might be expected, the most popular class of microbiota patents is the category labelled C12Q1/68: “Measuring or testing processes involving enzymes, nucleic acids or microorganisms”. The next largest proportion of patents involves administration or preparation of probiotics (class A61K3 and its subclasses). 8. Microbiota gut brain in general press and online sourcesWe used Factiva () to search for mass media articles about MGB research. The search was performed on July 4th, 2018 with the term: “(microbiome OR microbiota) AND ((brain AND (cogn* OR (behavio* AND (mood OR stress)))) OR gut brain axis)”. The search scoured English-language major news and business sources, and resulted in 310 articles. Among those articles, the most mentioned companies include University College Cork and Synthetic Biologics. The most prolific source was the Daily Mail with 46 articles, followed by The Times (UK) with 25 articles. US sources include Dow Jones Newswires and The New York Times (Fig. S3).Figure S3. Most mentioned Subjects, Industries, Sources, Companies and Regions in the 310 general press articles pertaining to “microbiota gut brain” found through a Factiva search.Supplementary Material Table 8: Selected quotes from online sites (in order of appearance in a list generated from a Google search for ‘gut brain microbiome’). 50 hits were examined, scholarly articles discarded, and quotes extracted from the first 10 remaining sites. ‘The microbiome-gut-brain axis also has the potential to fortify mental toughness in both sport and life’Psychology Today Blog‘Recent findings between the gut microbiota and the brain suggest that our microbiota can deeply influence our health, brain and potentially even our behaviour. The microbiota has been associated with several neurological conditions and it could be playing a role in your migraine condition’MigrainePal‘It is of course not surprising that gut microbiota profiling is not included as part of the routine clinical practice … Most psychiatric patients have digestive disorders, where 99% of all cognitive disorders start, so why are they being treated with Psychotropic drugs [and not diet?]’Dr John Bergman‘Down in your large intestine live trillions and trillions of helpful bacteria and other microscopic creatures, collectively known as your gut microbiome. These critters help digest your food, keep you in good health, and — according to new research — influence your thoughts’Nine Digital Coach‘It seems that our minds are, in some part, controlled by the bacteria in our bowels’Medical News Today‘Gut flora influence various brain functions, affecting your thoughts, emotions, and memory’Dr Lam Coaching‘What we eat or take can also weaken our microbiome. Pharmaceuticals such as anti-biotics, the oral contraceptive pill, antidepressants all wipe out our beneficial bacteria. Foods such as coffee, alcohol, refined sugar, Artificial and GMO Foods also disrupt the balance’Griffith Consulting‘Research suggests that up to 90% of health conditions be [sic] linked to the microbiome and the gut. Find out which top foods to avoid in your diet and which to increase in order to create a healthy gut-brain connection. Learn all of the other ways, including supplementation, which can protect the microbiome. Your gut-brain axis also affects your memory, concentration and focus’Institute of Holistic Nutrition‘This study suggests that reduced microbiome diversity may be related to weight gain in women taking atypical antipsychotics. Atypicals are in widespread use in the US. Given the other benefits of probiotic supplementation, it would be a winning proposition to add probiotics for those taking atypical antipsychotics’Janet Settle Integrative Psychiatry‘The lack of diversity in the microbial population, and the integrity of the intestinal wall – which is maintained with a healthy, flourishing microbiome – may influence negative symptoms and disease such as depression, anxiety, autism and Parkinson’s disease. Gut bacteria may also impact teen behavior, and appears to influence levels of mood modulating neurotransmitters, such as dopamine, GABA, histamine, acetylcholine and serotonin. What is interesting, is diet seems to have powerful sway over the state of balance (symbiosis), or imbalance (dysbiosis) of the microbiota, and therefore our mental and brain health’That Sugar Film‘When your gut microbiome is balanced, you stay healthy, you are in a good mood and you have a lot of energy. When your gut microbiome is out of balance, you are setting yourself up for a host of health issues, including weight gain, diabetes, brain fog, and cancer … The good new[s] is that you can change your gut microbiome. You see, the average lifespan of a bacterium in your microbiome is 20 minutes! So you have the opportunity every time you eat to begin to change the population of your gut microbiome. This is good news because it means that rather than having to subscribe to theories, such as the Paleo diet, which assumes our genes evolve so slowly that we all need to eat like cavemen, we can begin to change our gut microbiome (and thus it’s [sic] genes) one meal at a time, and even achieve a healthy gut very quickly’Dr NorthrupSupplementary Material Table 9: Most popular news articles about MGB shared on Twitter in November and early December 2017. We made an advanced Twitter search with the phrase: “gut brain microbiota OR bacteria OR micro OR bact OR bug since:2017-11-01” on December 17, 2017. A representative quote for each article is presented in the table. Articles are ordered by decreasing popularity.‘If the research holds up … it may one day be possible to prevent the development of the malformations in susceptible newborns by manipulating their microbiome – perhaps with a simple fecal transplant.’The New York TimesA Baffling Brain Defect Is Linked to Gut Bacteria, Scientists Say10.06.2017‘these microbes have eons of experience modifying our brains, they are likely to be more precise and subtle than current pharmacological approaches, which could mean fewer side effects.’The AtlanticWhen Gut Bacteria Change Brain Function24.06.2015‘Right now, we don't know enough to justify the claims made for probiotic supplements. The marketing is leagues ahead of the evidence, and we’d do well to view these claims with skepticism.’ForbesScience Is Showing How Gut Bacteria Affect The Brain, But Don't Bother Taking Probiotics Yet27.08.2017‘A three-way relationship between the brain, gut and stress hormone cortisol appears to influence how 'messages' are communicated in the body, which may result in autistic symptoms’Daily MailIs gut bacteria linked to autism? Pathogens in the stomach alter the brain's development and may increase the risk of condition25.08.2017‘researchers listed 10 different ways that the microbiome may contribute to the development of Alzheimer’s disease, including fungal and bacterial infections in the intestinal tract and increased permeability of the blood-brain barrier.’Huffington PostTargeting Gut Bacteria May Be The Key To Preventing Alzheimer’s21.02.2017‘Could it be a similar case to that of the human genome – another great hope in predicting disease and personalised preventative medicine, but which becomes more impenetrably complex the more we learn about it?’The GuardianIs your gut microbiome the key to health and happiness?6.11.2017‘It's far too soon to know whether the probiotic has any effect, but [a study participant] suspects it might.’National Public RadioGut Bacteria Might Guide The Workings Of Our Minds18.11.2017‘According to influential neurologist from the US, Dr David Perlmutter, there is some good news about the treatment of brain disorders in the future.’Australian Broadcasting Corporation, All in the MindThe second brain17.01.2016‘1. 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