Therapeutic Advances in Gastroenterology
Review
Do patients with functional gastrointestinal disorders have an altered gut flora? Eamonn M.M. Quigley
Ther Adv Gastroenterol (2009) 2(Suppl 1) S23–S30 DOI: 10.1177/ 1756283X09335636 ! The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract: The description of the de novo development of irritable bowel syndrome (IBS) following an episode of bacterial gastroenteritis (postinfectious IBS) illustrated the potential for a luminal factor (a bacterial pathogen) to cause this common gastrointestinal ailment. As a consequence of these and other observations as well as results of experiments involving animal models, the enteric flora and the immune response that it generates in the host have, somewhat surprisingly, come centre-stage in IBS research with their potential to induce the pathophysiological changes that are associated with IBS. While evidence for immune dysfunction both in the mucosa and systemically continues to accumulate, methodological limitations have hampered a full delineation of the nature of the microbiota in IBS. The latter is eagerly awaited and may yet provide a firm rationale for the use of certain probiotics and antibiotics in IBS, whose benefits have now been described with some consistency. Keywords: irritable bowel syndrome, gastroenteritis, probiotics
Introduction Functional gastrointestinal disorders (FGIDs) are common, of uncertain cause and clinically challenging. Though many persons in the community suffer occasionally or intermittently from FGID-type symptoms, few seek medical attention. Those that do may experience significant impairment to their quality of life as well as incur significant socioeconomic and financial costs. For all of these reasons, significant efforts are now being exerted towards the identification of the cause(s) of FGIDs. Irritable bowel syndrome (IBS), perhaps the best characterized of the FGIDs, has been the subject of considerable and quite diverse research efforts in recent years and this disorder will, therefore, be the focus of this review. Over the decades, various theories have been advanced to explain the pathogenesis of symptoms in the IBS patient, including dysmotility, visceral hypersensitivity and effects of the psyche. The concept of the gut–brain axis, emphasizing the interactivity at sensory, motor and neuroendocrine levels between the brain and the gut has provided a useful paradigm to encompass these diverse factors. Most recently, as illustrated in Figure 1, this axis has
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been extended by some to include interaction between the gut flora (or microbiota), the immune system (both mucosal and systemic), the gut and the brain (the gut–brain–immune– microbial axis). In this scenario, interactions between the flora (be it normal or disturbed) and the mucosal immune system (gut-, or mucosa-associated lymphoid tissue, GALT or MALT) lead to the release of peptides and other neuroactive substances which generate, both locally and systemically, the neuromuscular events that typify IBS and generate the patient’s symptoms. The advancement of this concept in IBS occurs at a time when considerable emphasis and research effort is being expended with considerable success at understanding the role of the microbiota in health and disease [Guarner and Malagelada, 2003] and in unlocking its therapeutic potential [O’Hara and Shanahan, 2007].
Correspondence to: Eamonn M.M. Quigley Alimentary Pharmabiotic Centre, Department of Medicine, University College Cork, Cork, Ireland
[email protected]
What is the evidence to support such an apparently wild foray into territory previously unexplored or undreamt of in relation to IBS? The evidence comes from a number of sources: postinfectious IBS, data describing various immunological phenomena in IBS (which could be provoked or sustained by microbial stimuli),
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Therapeutic Advances in Gastroenterology 2 (Supplement 1) Altered microbiota
Bacteria, bacterial components, metabolites, products
Immune activation
Stress infection ?
Mast cell activation
Figure 1. A schematic representation of how the flora (microbiota), the intestinal epithelium, various components of the immune response (mast cells and lymphocytes) may interact to lead to neural activation and subsequent local and/or systemic responses.
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direct evidence of quantitative and/or qualitative abnormalities in the small intestinal and colonic flora in IBS and therapeutic trials of antibiotics and probiotics in IBS. The latter will be dealt with elsewhere in this issue [Whorwell, 2009] and will not be discussed further in this paper. Let us start with a clinical scenario that has, perhaps, most clearly illustrated the role of the flora and immune responses in a functional disorder: postinfectious IBS (PI-IBS).
and those who suffer from anxiety or depression being at greatest risk [Thabane et al. 2007]. These symptoms are not transient; in a Scandinavian study in which 12% of their subjects had IBS within 3 months of gastroenteritis, 9% still had symptoms 5 years later [Tornblom et al. 2007]. Neal and colleagues documented similar recovery rates for postinfectious and non-postinfectious IBS in a 6-year follow-up study [Neal et al. 2002].
Postinfectious IBS We are now beginning to see real data to directly support the concept of PI-IBS [Spiller, 2003]. First reported by McKendrick and Read [1994] the occurrence of IBS following episodes of bacteriologically confirmed gastroenteritis has now been documented in several studies [Tornblom et al. 2007; Spence and MossMorris, 2007; Ruigomez et al. 2007; Thabane et al. 2007; Marshall et al. 2006; Mearin et al. 2005; Dunlop et al. 2003; Spiller et al. 2000; Garcia Rodriguez and Ruigomez, 1999; Gwee et al. 1999,1996; Neal et al. 1997]. Thabane and colleagues concluded that the overall risk for the development of IBS was increased six-fold following an episode of bacterial gastroenteritis with younger subjects, those who have prolonged fever during the episode of gastroenteritis
One study went on to establish a direct link between prior exposure to an infectious agent, persisting low-grade inflammation and IBS [Gwee et al. 1999]. In this study, an increase in the number of chronic inflammatory cells in the rectal mucosa was seen only among those exposed patients who had developed IBS. Others have demonstrated a persisting increase in rectal mucosal enteroendocrine cells, T-lymphocytes and gut permeability in patients with postdysenteric IBS [Dunlop et al. 2003; Spiller et al. 2000]. These observations are important as they indicate a relationship between perturbations of the microbiota, mucosal inflammation and IBS, a hypothesis that is amply supported by data from studies in experimental animal models. The development of IBS has recently been linked with non-GI infections [McKeown et al. 2006], again perhaps
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EMM Quigley
Disturbed flora Susceptible host Inflammatory response Myo-neural dysfunction
SYMPTOMS Figure 2. What we have learned from postinfectious irritable bowel syndrome (IBS). Exposure to pathogenic organisms in susceptible individuals leads to a sustained, albeit low-grade, inflammatory response which triggers, through the release of inflammatory mediators and other molecules, the myo-neural phenomena that can generate IBS-type symptoms.
invoking a role for a systemic inflammatory response in the mediation of symptoms. A number of parasites, such as Dientamoeba fragilis, Blastocystis hominis and Giardia have been associated with the development of chronic gastrointestinal symptoms which may mimic IBS [Stark et al. 2007; Grazioli et al. 2006]; whether parasitic infections can trigger IBS, per se, is unknown. Very recently, an outbreak of viral gastroenteritis was associated with the new onset of an IBS-type syndrome in 24% of affected subjects when interviewed 3 months later; subsequent follow-up suggested that postviral IBS was more transient than its bacterial counterpart [Marshall et al. 2007]. Postinfectious IBS may explain only a minority of cases of IBS (1–6.7% in one recent study [Borgaonkar et al. 2006]) but it does represent a clear link between exposure to an environmental agent, inflammation and IBS in predisposed individuals (Figure 2).
Inflammation and IBS Direct and compelling evidence for a role for mucosal inflammation in IBS was first provided by Chadwick and colleagues among 77 IBS
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patients: 31 demonstrated microscopic inflammation and eight fulfilled criteria for lymphocytic colitis. However, among the group with ‘normal’ histology, immunohistology revealed increased intraepithelial lymphocytes as well as an increase in CD3þ and CD25þ cells in the lamina propria; all therefore showed evidence of immune activation [Chadwick et al. 2002]. Subsequent studies have provided further evidence of T-lymphocyte [Holmen et al. 2007; Ohman et al. 2005] and mast cell activation [Barbara et al. 2007, 2004; Cenac et al. 2007, Guilarte et al. 2007] in the mucosa in IBS; others have demonstrated an extension of inflammation into the myo-neural compartments [Tornblom et al. 2002] and others still cytokine profiles in peripheral blood mononuclear cells [Liebregts et al. 2007; O’Mahony et al. 2005] and serum [Dinan et al. 2006] compatible with a proinflammatory state. It is attractive to suggest that these immunological changes could result from exposure to an exogenous (such as bacterial) antigen challenge [Collins, 2002; Spiller, 2002]. That IBS patients may be predisposed to an albeit contained inflammatory response to luminal triggers is, indeed, supported by the finding of polymorphisms in genes that encode for the production of anti-inflammatory cytokines among IBS patients [van der Veek et al. 2005; Gonsalkorale et al. 2003] and by the very recent description of high titers of antiflagellin antibodies in serum derived from IBS patients [Schoepfer et al. 2008; Ivison and Steiner, 2008; Kirsch and Riddell, 2006]. While the idea that IBS patients may truly harbor inflammatory changes in the colonic mucosa is increasingly gaining credence, many important questions remain to be answered and it is clear that this is going to be an area of active investigation for some time to come.
Qualitative or quantitative changes in the enteric flora (microbiota) For some time, various studies have suggested the presence of qualitative changes in the colonic flora in IBS patients; a relative decrease in the population of bifidobacteria being the most consistent finding [Dear et al. 2005; Malinen et al. 2005; Matto et al. 2005; Si et al. 2004; King et al. 1998; Bradley et al. 1987]. It should be noted, however, that these findings have not always been reproduced and the methods employed have been subject to question. Nevertheless, qualitative changes in the colonic
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Therapeutic Advances in Gastroenterology 2 (Supplement 1) flora, be they primary or secondary, could lead to the proliferation of species that produce more gas [Dear et al. 2005; King et al. 1998] and shortchain fatty acids and are more avid in the deconjugation of bile acids. With regard to the former the displacement of gas-forming species could result in local changes in gas production, a development which may be poorly tolerated by IBS subjects who seem to have difficulties with the transport of gas along the intestine and to be overly sensitive to gas-induced distension. The latter could, in turn, lead to clinically significant changes in water and electrolyte transport in the colon and affect colonic motility and/or sensitivity. Similarly, a repopulation of the flora with the deficient commensal could restore homeostasis. Attractive as this concept may be, it belies the challenges posed by attempts at a comprehensive description of the flora in IBS, or in any condition. Several factors limit the interpretability of prior studies, including the unrepresentative nature of the fecal flora, a failure to describe those bacterial populations that may be adherent to the mucosal surface and, above all, the recognition that a very significant proportion of the colonic microbiota cannot be identified by conventional
culture methods. Molecular methods are now being applied to this complex issue and have, indeed, confirmed that IBS patients, regardless of sub-type, do exhibit a fecal flora that is clearly different from control subjects [Kassinen et al. 2007; Maukonen et al. 2006; Matto et al. 2005; Malinen et al. 2005]. The precise nature of these differences and their potential to disturb mucosal or myoneural function, in the gut wall, or induce local or systemic immune responses, remains to be defined. In our own laboratory, we recently investigated the diversity of the dominant microbiota in the fecal material from both IBS patients and healthy controls. In addition we examined mucosal biopsies of nine IBS patients and compared them to their own faecal microbiota. Bacterial DNA was extracted from fecal samples and biopsies, visualized by agarose gel electrophoresis and quantified using spectrophotometry. IBS and healthy fecal samples were compared by DGGE of the V1–V3 region of the 16S rRNA gene. From the analysis of the DGGE profiles for both IBS and healthy subjects we found that the gut microbiota was highly variable but that this variability was far less in biopsies than in faeces among the IBS patients (Figure 3). Statistical comparisons of
Biopsy 1
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Figure 3. Comparisons of molecular profile of colonic microflora from irritable bowel syndrome (IBS) subjects comparing, on the left, samples obtained from mucosal biopsies to those, on the right, obtained from feces. Note, considerably less variability in biopsies compared to fecal samples. Each lane represents a single subject.
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EMM Quigley the fecal analyses indicated that controls exhibited greater variability than the IBS patients. More recently, the role of the gut flora in IBS has been taken a stage further with the suggestion that some IBS patients may harbor quantitative changes in the indigenous flora in the small intestine: small intestinal bacterial overgrowth (SIBO) [Cuoco and Salvagnini, 2006; McCallum et al. 2005; Nucera et al. 2005; Pimentel et al. 2003, 2000]. The occurrence of SIBO has been associated with abnormalities in small intestinal motor function [Pimentel et al. 2002] and its eradication with symptomatic relief [Weinstock et al. 2008a, 2008b; Majewski and McCallum, 2007; Esposito et al. 2007; Cuoco and Salvagnini, 2006; Pimentel et al. 2003, 2000]. These striking results have been the target of much criticism on several grounds [Vanner, 2008b; Quigley, 2007; Cuoco et al. 2001; Jones et al. 2001; Mishkin et al. 2001; Riordan et al. 2001; Hasler, 2003]. First, IBS symptoms are nonspecific and may be mimicked by SIBO, regardless of etiology; patient selection is therefore an issue. Second, the hydrogen breath test, which has been the test most widely used to make the diagnosis of SIBO in this context, is subject to considerable error, especially in relation to altered small bowel transit [Vanner, 2008a; Simre´n and Stotzer, 2006] and third, others have failed to confirm these finding [Bratten et al. 2008; Posserud et al. 2006; Walters and Vanner, 2005; Parisi et al. 2003].
Efficacy of antibiotics in IBS The principal evidence for a role for antibiotics in IBS comes from studies among the aforementioned IBS patients with associated SIBO [Majewski and McCallum, 2007; Esposito et al. 2007; Cuoco and Salvagnini, 2006; Pimentel et al. 2003, 2000]. In a subsequent study that did not document bacterial overgrowth, Pimentel and colleagues treated IBS patients with the poorly absorbed antibiotic rifaximin [Pimentel et al. 2006]. Some IBS patients, at least, demonstrated a prolonged response (up to 10 weeks) to a short course of this antibiotic. However, as pointed out in an accompanying editorial, there are several limitations to this study which reduce its impact [Drossman, 2006]. In a recently reported multicenter phase II study, 388 diarrhea-associated IBS subjects were randomized to either rifaximin in a dose of 550 mg twice a day or placebo for 14 days, followed by another 14 days on placebo
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alone and then 12 weeks follow-up. During treatment, at 4 weeks and at 12 weeks, those randomized to rifaximin had a modest 8–13% therapeutic gain for adequate relief of global IBS symptoms and a rather disappointing 4–8% gain for relief of bloating [Lembo et al. 2008; Ringel et al. 2008]. However, the eradication of SIBO, as proposed by these authors, may not be the sole explanation for these responses, which could also be explained on the basis of a suppression of fermenting bacteria in the colon, as suggested by Dear et al. [2005] and supported by the recent report from Sharara et al. [2006]. Finally, one must remain reluctant, pending long-term studies, to recommend a prolonged course of antibiotic therapy to any population regardless of the safety profile of a given antibiotic.
Conclusions Somewhat surprisingly the enteric flora and the immune response that it generates have come centre-stage in IBS research with their potential to induce the pathophysiological changes that are associated with IBS being most vividly illustrated by postinfectious IBS. While evidence for immune dysfunction both in the mucosa and systemically continues to accumulate, methodological limitations have hampered a full delineation of the nature of the microbiota in IBS. The latter is eagerly awaited and may yet provide a firm rationale for the use of probiotics and antibiotics in IBS.
Conflict of interest statement None declared.
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