University of Manchester



Progress with Treating the Microbial Dysbiosis Associated with Irritable Bowel SyndromePearson, J.S. *Whorwell, P.J. ***Neurogastroenterology Unit, University Hospital of South Manchester, M23 9LT**Centre for Digestive Diseases, University of Manchester, M23 9LTCorresponding Author:James PearsonJames.Pearson@manchester.ac.uk0161 291 4177Neurogastroenterology Unit, University Hospital of South Manchester, M23 9LTPurpose of ReviewMicrobial dysbiosis is receiving increasing attention as possibly being important in the pathophysiology of irritable bowel syndrome (IBS). This review will summarise the most recent literature addressing attempts to explore and target the microbiome in patients with IBS.Recent FindingsManipulation of the intestinal microbiota in IBS is receiving increasing attention. Traditionally, dietary manipulation has been utilised. There is now evidence that a low FODMAP diet has not only been able to improve symptoms, but may have an effect on the gut microbiota. Probiotics are a safe and attractive option for the manipulation of the microbiota. There have been a number of well-designed trials examining the efficacy of certain strains of bacteria, and even yeasts are receiving attention. The role of antibiotics remains controversial and it seems likely that their use should currently be limited to those individuals with small intestinal bacterial overgrowth (SIBO). Interest in the role of faecal microbiota transplantation (FMT) for the treatment of a number of gastrointestinal conditions has intensified and IBS is no exception. SummaryThe manipulation of the microbial dysbiosis is gaining momentum. However, further research is required in order to identify the most appropriate treatment option for the individual patient.Key WordsIrritable Bowel Syndrome, Dysbiosis, Probiotics, Antibiotics, Faecal Microbiota TransplantationIntroductionThe functional gastrointestinal disorders encompass a number of conditions where there are abnormalities with the functionality of the gastrointestinal tract rather than the structure. Irritable bowel syndrome (IBS) is one of the most common of these disorders and affects between 10 to 15 % of the population. IBS is characterised by abdominal pain in combination with an unpredictable bowel habit and consequently is often stratified arbitrarily into the predominant bowel habit leading to three main sub-types. IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D) and IBS with bowel habits alternating between the two, referred to as IBS with a mixed bowel habit (IBS-M). The pathophysiology is poorly understood but it has been suggested that autonomic dysfunction, visceral hypersensitivity, low grade inflammation and dysbiosis all play a role. There is increasing clinical evidence that symptoms of IBS can develop following a gastrointestinal infection, possibly as a result of a disturbance of the gut microbiota [1]. In particular, this has been described following Campylobacter Jejuni and Clostridium Difficile infections as well as viral gastroenteritis, but it is likely that it can be triggered by any type of gastrointestinal infection [2,3,4]. Additionally, symptoms have been described following antibiotic therapy in approximately 30 % of patients with IBS, especially when there is prolonged exposure [5]. Paradoxically, certain antibiotics have also been shown to improve IBS symptoms. For instance, rifaximin, is a broad-spectrum, non-absorbed antibiotic, which has demonstrated sustained efficacy in patients with non-constipation type IBS in the TARGET trial series [6]. The use of rifaxamin was originally based on the hypothesis that some patients with IBS appear to have small bowel bacterial overgrowth (SIBO). However, the role of SIBO in IBS is somewhat controversial as it remains unclear whether it leads to the problem in the first place or results from the dysmotility associated with IBS. Furthermore, the breath testing techniques used to identify SIBO can be unreliable, especially when small intestinal transit is rapid. In addition, the different substrates that can be used to identify SIBO can lead to differing results [7].Interest has intensified as a result of accumulating evidence suggesting that the microbiome in patients with IBS may not be “normal” when compared to that of healthy controls, often referred to as dysbiosis. Microbial analyses have provided qualitative and quantitative differences in the gut microbiota between healthy subjects and those with IBS [8]. However, alterations in the gut microbiota have also been noted between healthy populations, making the comparison of results between studies in patients with IBS difficult to interpret [9]. A recent ROME foundation report summarises the current evidence for dysbiosis in IBS [10]. It is clear that there are a variety of complex internal and external factors involved in determining the final composition of the gut microbiota in any particular individual whether they are healthy or not. Additionally, there have been reports of low-grade inflammation present in the biopsies of the gastrointestinal tract in patients with IBS [11]. Whether this inflammation is the result of a previous gastrointestinal infection, or in some way linked to dysbiosis, remains to be determined.As a result of all this mounting evidence that abnormalities of the microbiome could be important in the pathophysiology of IBS, targeting it from a therapeutic point of view has become very topical.The Change in Management of Patients with IBSTraditionally, the symptoms of IBS are treated rather than the underlying cause. Consequently, laxatives or anti-diarrhoeal medications are given to patients depending on the nature of their bowel habit in combination with antispasmodics and antidepressants as necessary. However, there has been a paradigm shift in the management of patients with IBS in recent years, with research focussing on treating the underlying pathophysiology of IBS. As dysbiosis has been implicated as a possible mechanism, manipulation of the gut microbiota has become an attractive therapeutic target.Manipulation of the Gut MicrobiotaThere have been attempts to modify the human microbiota using dietary manipulation or the utilisation of probiotics, prebiotics, antibiotics, as well as more novel options. This review will summarise the most recent literature pertinent to the management of patients with IBS.DietA low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet has become a popular intervention in patients with IBS and has been reported to reduce gastrointestinal symptomatology in approximately 75 % of patients. A recent study examining potential changes in the gut microbiota in patients with IBS, on a low FODMAP diet, demonstrated a reduction in bacterial diversity and abundance in those on the diet [12]. The cross-over nature of the trial allowed an examination of changes in the microbiota between a “normal” Australian diet and a low FODMAP diet. Interestingly, the lower diversity and abundance of bacteria found in this study, would traditionally be considered as an unfavourable outcome in certain gastrointestinal conditions. Consequently, the authors concluded that asymptomatic individuals should avoid a low FODMAP diet. Additionally, FODMAP restriction should be tailored individually to a level that leads to adequate symptom relief and that long term restriction should probably be avoided. Inevitably, FODMAP restriction leads to a low dietary fibre intake and it has been suggested that rye bread, which is low in FODMAP’s, may be a way to increase dietary fibre in those individuals who are reluctant to relax the diet [13]. Evidence continues to accumulate that a low FODMAP diet is beneficial in IBS, but it remains unclear whether it is the microbial changes associated with this diet that lead to symptom improvement. Other mechanisms by which FODMAP restriction might improve symptoms include an effect on histamine or short chain fatty acids. Low grade mucosal inflammation has been implicated in the pathophysiology of IBS. Histamine is an important inflammatory mediator and levels of this neurotransmitter have been shown to decrease following a low FODMAP diet [14*]. In addition, the authors profiled the gut microbiota and reported an increase in Actinobacteria richness and diversity in the FODMAP restriction group. A further study demonstrated a reduction in the number of short chain fatty acids following FODMAP restriction [15]. These are produced following fermentation of dietary fibre, and are suggested to decrease transit time, an observation which was supported by higher levels found in patients with IBS-D. PrebioticsPrebiotics are broadly defined as non-digestible food ingredients which beneficially affect the host by selectively stimulating the growth of a limited number of colonic bacteria. Consequently, it is not surprising that their therapeutic potential in IBS has been explored. However, some prebiotics resemble FODMAPS and this has to be taken into consideration. An investigation into partially hydrolysed guar gum, which is known to increase the number of Bifidobacterium, Lactobacilli spp and short chain fatty acids, found significant improvements in bloating following treatment. However, there were no significant differences found in pain scores, stool frequency, or general quality of life following treatment [16].A recent study evaluated the potential effects of a short-chain fructooligosaccharide (scFOS) in IBS patients with visceral hypersensitivity [17*]. The authors found that scFOS improved anxiety but only resulted in a reduction in visceral hypersensitivity in the constipation subgroup. Additionally, a faecal microbiota analysis demonstrated an increase in the number of Bifidobacteria following treatment when compared to those participants in the placebo arm.ProbioticsManipulation of the gut microbiota by probiotics in patients with IBS has been assessed in in well over 30 randomised controlled trials. There are many different probiotic preparations with varying formulations, some containing single organisms, others multiple organisms. Meta analyses have demonstrated a positive effect for patients with IBS, although the use of this type of analysis for probiotics trials should be treated with some caution [18]. This is because probiotic preparations can exhibit a wide range of activities depending on the organisms they contain. Consequently, it is really only appropriate to undertake a meta-analysis of trials of probiotic preparations containing the same organisms or group of organisms. A recent meta-analysis has adopted this approach [19]. More recent trials of probiotics in IBS have been of better quality that some of the earlier studies. These have provided a more robust examination of any potential role for probiotics in the management of IBS. A trial investigating Bacillus coagulans MTCC 5856 found improvements in IBS symptoms including abdominal pain, diarrhoea, and bloating in patients with the diarrhoeal form of the condition [20]. Although an investigation into the use of Escherichia coli Nissle 1917 failed to improve symptoms in an IBS population as a whole, differening responses were found when patients were sub-grouped according to their bowel habit [21]. Two further trials, one investigating the effect of Lactobacillus casei Shirota and the other investigating a multiple strain containing Lactobacillus acidophilus, L. rhamnosus, Bifidobacterium breve, B. actis, B. longum, and Streptococcus thermophiles, have been reported [22, 23]. Both of these studies failed to show any significant effect and this highlights the issues that not all probiotics may be effective in a particular condition. In addition to bacteria, the gut microbiota contains a variety of other organisms such as viruses, particularly in the form of phages, fungi and yeasts. However, there is little information on their role in IBS, although a multi-centre investigation into Saccharomyces cerevisiae failed to demonstrate any significant improvements in IBS symptoms when compared to placebo [24]. However, a planned subgroup analysis of the study participants demonstrated a significant improvement in symptoms in those with the constipation form of IBS. The authors have suggested that the product increases the amount of short chain fatty acids in the small intestine, accelerating gastrointestinal transit, and thus increasing the number of bowel movements and reducing constipation.It seems reasonable to conclude that probiotics have a positive effect in patients with IBS but different preparations may not be as effective as others. In addition, the benefits may take time to accumulate and they are probably best suited to the milder forms of the condition. In the future, it may be possible to develop “designer” probiotics, containing organisms that are known to have an impact on symptoms rather than the current, “trial and error” approach to their use.AntibioticsThe debate about the potential role of antibiotics in the treatment of IBS continues. In addition to the previously mentioned TRAGET trials, the TARGET III trial investigated the long term use of rifaximin in patients with IBS [25*]. The authors found that 64 % of initial responders to a two week course of rifaxamin developed recurrence of IBS symptoms during the 18 week follow up period. Further re-treatment with rifaximin demonstrated similar response rates as in the initial trials. However, there are still some reservations about the repeated use of rifaxamin and whether responses will be maintained after multiple courses of treatment. The possibility of microbial resistance and Clostridium Difficile infection also needs to be taken into account when considering continuing retreatment. Additionally, the reported therapeutic gain of rifaximin over placebo is only 9 % and it would be useful to identify those patients who may derive the most benefit from this treatment option. As rifaxmin is potentially targeted towards the small bowel, it could be argued that those patients with SIBO should be specifically selected for treatment until we have more data on the mechanism of action of this antibiotic [26]. This approach is supported by a study investigating those with SIBO diagnosed by culturing intestinal aspirates [27]. Following treatment with norfloxacin, a significant proportion of those who were initially diagnosed as SIBO positive, no longer fulfilled the ROME III criteria for IBS, when compared to those treated with placebo. Additional evidence from a retrospective cohort analysis suggests that patients with IBS could be selected for treatment with antibiotics following lactulose breath testing dependant on the levels of hydrogen and methane produced [26]. A study evaluating the use of rifaximin in IBS patients who were negative for SIBO appeared to show an increased colonic transit time in those without constipation which was accompanied by an increase in overall bacterial diversity [28*]. This unexpected finding, of an increase in bacterial diversity, following the administration of a broad-spectrum antibiotic, deserves further research if confirmed.The role of antibiotics in the treatment of IBS remains controversial. However, in those patients who provide a positive breath test, antibiotic therapy, with a course of rifaxamin may be of benefit.SymbioticsA symbiotic is a combination of a probiotic and a prebiotic with the intention that the two components might be synergistic. There have been very few good quality studies of the use of symbiotics in IBS. However, there has been a recent trial of a probiotic containing four different bacteria and a prebiotic consisting of 90 % inulin and 10 % oligofructose. The comparator was a placebo containing just the inulin and oligofructose prebiotic. There was no improvement in symptoms but interestingly, a similar change in microbial profile was seen in both the active and placebo groups which suggests that the prebiotic was accounting for this effect on the microbiota [29]. Faecal Microbiota Transplantation (FMT)FMT has been practiced in an uncontrolled manner for many years and often been treated with derision. However, since the publication of a pivotal trial utilising FMT for recurrent Clostridium difficile infection, which demonstrated superior efficacy above conventional treatment, interest in the utilisation for FMT in other gastrointestinal conditions, including IBS, has intensified. To date, there have been no randomised, well-designed, controlled trials of this approach in IBS. There have been case reports suggesting the use of FMT is beneficial in treating refractory IBS [30]. Holvoet et al, report the use of FMT in a case series of 12 patients with IBS-D, with 75 % reaching the primary end point of “adequate relief of global IBS symptoms and bloating” at 12 weeks post FMT [31*]. Additionally, subjects reported improvements in abdominal pain, bloating, flatulence and overall quality of life. Those subjects who were available at one-year follow-up continued to experience sustained symptom relief. The possible management of gastrointestinal conditions, other than Clostridium difficile, by FMT needs far more research. There are many questions to be answered over the safety of donor material, as well as the dose and best route of administration of the material to the recipient. It is possible that FMT may find its niche in a particular subset of patients with IBS; such as those with very severe forms of the condition.ConclusionThe targeting of intestinal dysbiosis in patients with IBS is gaining momentum. There has been an increase in the number of well-designed, randomised, controlled trials evaluating the efficacy of a number of different therapeutic options. These have largely been promising, although further work is required in order to identify the best choice of treatment for a particular patient.Key PointsTargeting of the intestinal dysbiosis in IBS is gaining momentum.Recently, more well-designed studies have been conducted and have provided encouraging results.Further work is required before we are able to provide personalised treatments in individual patients.References1.Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med. 1962;31:307-22.2.Marshall JK, Thabane M, Borgaonkar MR, James C. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol. 2007;5(4):457-60. Epub 2007/02/10.3.Marshall JK, Thabane M, Garg AX, et al. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology. 2006;131(2):445-50; quiz 660.4.Spiller RC. Infection, immune function, and functional gut disorders. Clin Gastroenterol Hepatol. 2004;2(6):445-55.5.Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol. 2002;97(1):104-8.6.Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364(1):22-32.7.Simren M, Stotzer PO. Use and abuse of hydrogen breath tests. Gut. 2006;55(3):297-303.8.Shukla R, Ghoshal U, Dhole TN, Ghoshal UC. Fecal Microbiota in Patients with Irritable Bowel Syndrome Compared with Healthy Controls Using Real-Time Polymerase Chain Reaction: An Evidence of Dysbiosis. Digestive Diseases and Sciences. 2015;60(10):2953-62.9.De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. P Natl Acad Sci USA. 2010;107(33):14691-6.10.Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-76..11.Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002;123(6):1972-9.12.Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93-100.13.Laatikainen R, Koskenpato J, Hongisto SM, et al. Randomised clinical trial: low-FODMAP rye bread vs. regular rye bread to relieve the symptoms of irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44(5):460-70. 14.*McIntosh K, Reed DE, Schneider T, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 2016. Epub 2016/03/16.A restricted FODMAP diet improves symptoms in patients with IBS. This article explores a possible mechanism by which the diet might affect inflammation.15.Valeur J, Roseth AG, Knudsen T, et al. Fecal Fermentation in Irritable Bowel Syndrome: Influence of Dietary Restriction of Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols. Digestion. 2016;94(1):50-6. 16.Niv E, Halak A, Tiommny E, et al. Randomized clinical study: Partially hydrolyzed guar gum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome. Nutr Metab. 2016;13.17.*Azpiroz F, Dubray C, Bernalier-Donadille A, et al. Effects of scFOS on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: a randomized, double blind, placebo controlled study. Neurogastroenterol Motil. 2016. By showing that this particular prebiotic leads to a change in the microbiota, and also improves anxiety, this paper supports the view that the gut microbiota interacts with the central nervous system.18.Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61; 62.19.Eales J, Gibson PR, Whorwell PJ, et al. Systematic review and meta-analysis: the effects of fermented milk with Bifidobacterium lactis CNCM I-2494 and lactic acid bacteria on gastrointestinal discomfort in the general adult population. Therap Adv Gastroenterol. 2016;In Press.20.Majeed M, Nagabhushanam K, Natarajan S, et al. Bacillus coagulans MTCC 5856 supplementation in the management of diarrhea predominant Irritable Bowel Syndrome: a double blind randomized placebo controlled pilot clinical study. Nutrition journal. 2016;15:21. 21.Faghihi AH, Agah S, Masoudi M, et al. Efficacy of Probiotic Escherichia coli Nissle 1917 in Patients with Irritable Bowel Syndrome: a Double Blind Placebo-controlled Randomized Trial. Acta medica Indonesiana. 2015;47(3):201-8. 22.Thijssen AY, Clemens CH, Vankerckhoven V, et al. Efficacy of Lactobacillus casei Shirota for patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2016;28(1):8-14. 23.Yoon H, Park YS, Lee DH, et al. Effect of administering a multi-species probiotic mixture on the changes in fecal microbiota and symptoms of irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Biochem Nutr. 2015;57(2):129-34. 24.Spiller R, Pelerin F, Decherf AC, Maudet C, Housez B, Cazaubiel M, et al. Randomized double blind placebo-controlled trial of Saccharomyces cerevisiae CNCM I-3856 in irritable bowel syndrome: improvement in abdominal pain and bloating in those with predominant constipation. United Eur Gastroent. 2016;4(3):353-62.25.*Lembo A, Pimentel M, Rao SS, et al. Repeat Treatment With Rifaximin is Safe and Effective in Patients With Diarrhea-predominant Irritable Bowel Syndrome. Gastroenterology. 2016. Epub 2016/08/17.There seems no doubt that some IBS patients respond to rifaxamin. However, the use of antibiotics in a condition which is often life-long raises questions about safety. This study at least shows that at least one retreatment is effective and no associated with any significant adverse events.26.Kasir R, Zakko S, Zakko P, et al. Predicting a Response to Antibiotics in Patients with the Irritable Bowel Syndrome. Digestive Diseases and Sciences. 2016;61(3):846-51.27.*Ghoshal UC, Srivastava D, Misra A, Ghoshal U. A proof-of-concept study showing antibiotics to be more effective in irritable bowel syndrome with than without small-intestinal bacterial overgrowth: a randomized, double-blind, placebo-controlled trial. Eur J Gastroen Hepat. 2016;28(3):281-9.With questions hanging over the use of antibiotics in IBS, it seems reasonable to target those who have small intestinal bacterial overgrowth (SIBO) until further machanistic data is forthcoming.28.*Acosta A, Camilleri M, Shin A, et al. Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome. Clinical and translational gastroenterology. 2016;7:e173. Epub 2016/05/27.This study shows that rifaximin appears to have more effects than those which would be predicted if it was just a straighforward antibiotics.29.Bogovic Matijasic B, Obermajer T, Lipoglavsek L, et al. Effects of synbiotic fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis ssp. lactis BB-12 on the fecal microbiota of adults with irritable bowel syndrome: A randomized double-blind, placebo-controlled trial. Journal of dairy science. 2016;99(7):5008-21. 30.Zoller V, Laguna AL, Prazeres Da Costa O, et al.[Fecal microbiota transfer (FMT) in a patient with refractory irritable bowel syndrome]. Dtsch Med Wochenschr. 2015;140(16):1232-6. 31.*Holvoet T, Joossens M, Wang J, et al. Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. Gut. 2016. Epub 2016/08/12.Tantalising results but we need to know a lot more about the potential of faecal microbiota transplantation (FMT) in IBS.Conflicts of InterestP Whorwell has acted as a consultant for, or received research grant support from, the following pharmaceutical companies in the last 5 years: Almirall Pharma, Boehringer–Ingelheim, Chr. Hansen, Danone Research, Ironwood Pharmaceuticals, Salix, Shire UK, Sucampo Pharmaceuticals and Allergan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. ................
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