Digestive and Liver Disease
Volume 41, Issue 12 , Pages 850-853, December 2009

The putative role of the intestinal microbiota in the irritable bowel syndrome☆

The Farncombe Digestive Health Research Institute, The Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Received 22 July 2009; accepted 30 July 2009. published online 09 September 2009.

Article Outline

Abstract 

The irritable bowel syndrome (IBS) is a chronic abdominal symptom complex that is heterogeneous in terms of its clinical presentation and underlying pathophysiology and pathogenesis. It is now established that enteric infection can trigger the syndrome in at least a subset of patients. In addition, there is growing evidence of low grade inflammation and immune activation in the distal bowel of some IBS patients. These observations now prompt the question as to what maintains gut dysfunction in these patients. The intestinal microbiota influences a broad array of host organs that include the gut and the brain, and is an important determinant of normal function in these systems. Disruption of the delicate balance between the host and its intestinal microbiota (termed dysbiosis) results in changes in the mucosal immune system that range from overt inflammation as seen in Crohn's Disease, to low grade inflammation without tissue injury, as seen in a subset of IBS patients. Under experimental conditions, disruption of the microbiota also produces changes in gut sensory-motor function and immune activity. Thus, dysbiosis induced by infection, dietary change or drugs such as antibiotics could produce low grade inflammation and chronic gut dysfunction, reminiscent of that seen in IBS. Fluctuations in gut physiology destabilize the habitat of commensal bacteria and provide a basis for chronic dysbiosis. Recent observations in animal models that changes in gut flora influence behavior provide a basis for a novel unifying hypothesis that accommodates both gut dysfunction and behavioral changes that characterize many IBS patients. This hypothesis states that dysbiosis exists in at least a subset of IBS patients, as a result of infection, dietary change or drugs and contributes to gut inflammatory and functional change in addition to psychiatric co-morbidity.

Keywords: Bacteria, Flora, Functional GI disorders, Gastroenteritis, Inflammation, Motility, Pain

 

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1. Introduction 

The irritable bowel syndrome is an important clinical problem. It is accompanied by a poor quality of life [1], substantial psychological co-morbidity [2] and even suicidal behavior in those with severe symptoms [3]. IBS imparts a huge economic burden on society [4], [5], [6] due to in part to excessive investigation and therapies of limited efficacy [7]. This in turn reflects our limited understanding of the underlying pathogenesis and pathophysiology.

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2. Evolving concepts of functional GI disorders 

Historically, IBS was considered a psychosomatic disorder with the emphasis placed on behavioral issues [8], [9] and in which the gut was involved as a secondary organ via the brain–gut axis. Therapy was directed at correcting behavior or towards attenuation of specific gastrointestinal symptoms such as pain or changes in bowel habit. The one symptom that has escaped any useful therapeutic approach is bloating – one of the most common manifestations of IBS. The initial suspicion that infection might trigger chronic GI symptoms similar to IBS in the 1950s and 60s [10], [11] prompted prospective studies that demonstrated the development of IBS in up to 30% of individuals recovering from acute gastroenteritis [12]. This entity became known as post-infective IBS (PI-IBS). In that series of studies, the importance of both behavioral and biological factors in determining the development of PI-IBS was recognized [13], [14] and was confirmed by others. Using the pro-inflammatory cytokine interleukin-1β as a marker in colonic biopsies in patients during and after acute gastroenteritis, it was found that those who developed PI-IBS inefficiently down-regulated the inflammatory response to the infection, and exhibited elevation of the marker at least 3 months post-infection [15]. This observation prompted the hypothesis that at least a subset of IBS patients, including those with a history of acute gastroenteritis, have low grade mucosal inflammation as a basis for chronic gut dysfunction and the expression of GI symptoms [16], [17] and this was supported at the time by an emerging body of evidence from animal studies showing that low grade inflammation in the mucosal compartment of the gut could alter function in the underlying neuromuscular tissues [18]. An animal model provided proof of the concepts that acute transient infection may induce long term gut dysfunction [19], [20] that this was maintained by inflammatory mediators [21] and driven by factors in the gut lumen luminal factors [22]. The later demonstration that specific probiotics therapy could reverse post-infective gut dysfunction in this model raised the question regarding the potential role of commensal microbes in maintaining functional changes in the gut [22]. A large body of evidence subsequently emerged to support the presence of immune activation and low grade inflammation in subsets of IBS patients with or without a history of gastroenteritis. The lines of evidence included the demonstration of increased numbers of inflammatory cells in the colon or terminal ileum [23], [24] as well as in the myenteric plexus [25] of IBS patients, the close positioning of immune cells and enteric nerves [26], increased mediator production by these cells [24] and demonstration of the potent biological effects of the supernatant from freshly taken mucosal biopsies from IBS patients on sensory and epithelial function [26], [27].

The question remains as to the factors that maintain low grade inflammation and chronic gut dysfunction in these patients. Several observations prompt consideration of the intestinal microbiota as a putative driver of these changes. First, increases in intestinal permeability had been demonstrated in diarrhea predominant IBS patients and particularly those with PI-IBS [28], [29]. Second, changes in fermentation profiles had been observed using breath or stool samples from IBS patients, suggesting quantitative or qualitative changes in the metabolic activity of the microbiota in selected IBS patients [30], [31], although the issue of bacterial overgrowth in IBS remains controversial. Third, molecular based studies have revealed differences in the profile of the microbiota between selected IBS patients and controls [32], [33], [34]. These findings are important in establishing a new conceptual model of IBS based discussed below.

2.1. The intestinal microbiota 

The gut contains a vast and complex microbial ecosystem, comprising mainly bacteria and of which most are strict anaerobes. Commensal bacteria instruct the immune and physiological systems throughout life and are responsible for the presence of inflammatory and immune cells in the healthy gut – so-called “physiological” or “controlled” inflammation. The microbiota serve the host by protecting against pathogens, harvesting nutrient from our diet, metabolizing certain drugs and carcinogens, and influencing the absorption and distribution of body fat [35], [36]. The influence of intestinal microbiota extends beyond the gut, and includes pain perception in the skin [37], and fat deposition in the liver (for reviews see [38], [39]). Breakdown of this mutualistic relationship, or dysbiosis [40], results in perturbation of host function, and, in some cases, the expression of overt and serious diseases such as inflammatory bowel disease and Clostridium difficile colitis [41], [42].

2.2. Evidence of dysbiosis in IBS 

Indirect supporting evidence of dysbiosis in IBS arises from the demonstration of abnormal breath hydrogen and methane profiles in IBS patients, suggesting changes in bacterial fermentation [30], [31]. In addition, there are reports that symptomatic improvement occurs in some of these patients following dietary change [43], [44]. Recently, studies using 16s-rDNA based PCR-DGGE have shown changes in the microbiota in IBS patients, including a prominent reduction in Lactobacillus species, greater temporal instability of intestinal microbiota and a reduction in Clostridia species in constipation predominant IBS [32], [33]. A study also identified temporal instability of the microbiota but unfortunately the changes in bacterial profile were not correlated with symptom expression [34]. Thus, there is evidence that dysbiosis exists in at least a subset of IBS patients and prompts examination of the impact of intestinal microbiota on enteric neuromuscular function.

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3. Evidence that the intestinal microbiota (including probiotics bacteria) influence enteric neuromuscular function 

3.1. Effect on motility 

Longstanding observations indicate that the caecum and colon of germ-free animals is distended in comparison with colonized animals and that there are changes in the enteric nervous system [44] suggesting that motility is altered. The absence of commensal bacteria also changes myoelectrical activity in the gut, and this is reversed on colonization [45]. A study using supernatant of the probiotic Escherichia coli Nissle 1917 showed that soluble factors from this bacterium enhance colonic contractility by direct stimulation of smooth muscle cells but the underlying mechanisms remain to be determined [46]. In another study, exposure of human colonic muscle cells to Lactobacillus rhamnosus GG (LGG) resulted in a significant impairment of acetylcholine-stimulated contraction and the effect was dose- and time-dependent [47].

3.2. Effect on visceral pain 

A recent study examined the effects of live, heat killed, or gamma irradiated Lactobacillus reuteri on cardio-autonomic response and single fibre unit discharge in dorsal root ganglia to colorectal distension in healthy Sprague–Dawley rats housed under conventional conditions. Treatment with live, heat killed, or gamma irradiated bacteria as well as their products (conditioned medium) prevented the pain response and both viable and non-viable bacteria significantly decreased dorsal root ganglion single unit activity to distension [48]. No effects were seen on somatic pain which is interesting in light of the postulated role of intestinal bacteria in the generation of inflammatory pain responses in the skin [37]. In a further study, the feeding of Lactobacillus reuteri (LR) or vehicle control to rats increased excitability, the number of action potentials per depolarizing pulse, decreased calcium dependent potassium channel (IK (Ca)) opening and decreased the slow after-hyperpolarization (sAHP) selectively in sensory AH neurons. Thus, LR targets an ion channel in enteric sensory nerves through which it affects visceral pain perception [49].

3.3. Evidence that perturbation of the microbiota influences enteric neuro-motor function motility and pain 

The above section demonstrated that commensal microbes are able to influence sensory-motor function in the gut. If dysbiosis is to be considered as a basis for gastrointestinal dysfunction in IBS, then it is necessary to examine whether perturbation of an established microbiota has impact on sensory-motor function. There are two experimental strategies that can be brought to bear; these involve perturbing the microbiota by diet or antibiotics. In one study, rats were fed a diet supplemented with chicory inulin, Lactobacillus rhamnosus and Bifidobacterium lactis and intestinal myoelectrical activity was measured. The symbiotic diet increased the number of bifidobacteria and reduced the number of enterobacteria in the jejunum, ileum, caecum and colon. It also increased the number of total anaerobes and lactobacilli in the caecum and colon [50]. Treatment with these synbiotics increased frequency of phase III of the Migrating Motor Complex (MMC), increasing the propagation velocity of phase III, the frequency of response potentials of the propagated phase III of the MMC and significantly decreased the duration of phase II of the MMC, but did not change the duration of phase I and phase III. Thus, perturbation of the microbiota by diet alters gut motility.

A study in mice used oral antibiotics to perturb the intestinal microbiota, resulting in changes to visceral pain responses using viscero-motor responses [51]. Antibiotic therapy substantially reduced lactobacilli and decreased bacteroides and enterococci. This was accompanied by a small but significant increase in MPO activity in the gut wall which was not associated with tissue damage. Antibiotic therapy increased substance P in the myenteric plexus and increased the viscero-motor response to colonic distension. These results indicate that perturbation of a previously stable microbiota influence sensory function and visceral perception. In this particular case, the shift in microbiota produced a small increment in “physiological” inflammation. That is, a small increase in the inflammatory cell presence in the gut but insufficient to cause tissue damage – reminiscent of the low grade inflammation seen in subsets of IBS patients. As the changes in MPO, substance P and viscero-motor responses could be restored with either lactobacillus or dexamethasone treatment, the changes in sensory physiology in this model were induced by changes in the composition of the microbiota and were mediated by the consequent increment in physiological inflammation [51]. This model therefore links the intestinal dysbiosis, low grade gut inflammation and visceral pain perception in a new conceptual model of IBS.

3.4. The interdependence of gut sensory-motor functions and the intestinal microbiota. 

From these observations, it is evident that changes in the microbiota influences sensory-motor function in the gut. It has also been shown that disruption of normal GI physiology results in changes in the composition of the microbiota [52]. Thus, there is a critical interdependence between the composition and stability of the microbiota and sensory-motor function in the gut. Stability of intestinal physiology maintains the habitat for microbiota and changes in physiology, as seen in IBS and motility disorders such as scleroderma [53] results in shifts in the bacterial composition of the gut and a vicious cycle is developed. Alternatively, factors that influence the microbiota, such as diet, infection and antibiotics, will produce changes in gut sensory-motor activity and disturb the habitat of the pre-existing flora. Changes in gut physiology in turn generate instability of the flora (as has been seen in IBS) and may promote a modified microbiota. Thus, a new construct for gut dysfunction in IBS may be developed around dysbiosis and is illustrated in Fig. 1. Factors known to produce perturbation of the flora, including acute infection dietary factors or antibiotic usage are risk factors for IBS [54], [55], [56]. While changes in the microbiota following infection or antibiotics are transient in otherwise normal subjects, we propose that in IBS patients, the underlying instability of gut physiology and the presence of low grade inflammation promote an unstable habitat for commensal bacteria and promote long term dysbiosis as a basis for gut dysfunction in this chronic relapsing condition.

  • View full-size image.
  • Fig. 1. 

    Conceptual framework for the role of the microbiota in IBS. Established risk factors for IBS are known to alter the bacterial composition of the gut. Experimental evidence cited in this paper indicates that perturbation of the microbiota can result in low grade inflammation and perturb gut function [51]. In addition, changes in the bacterial composition of the gut lead to altered behavior [59]. Taken together, we propose that these responses could contribute to both gastrointestinal dysfunction and the psychiatric co-morbidity that occurs in IBS patients.

3.5. Psychiatric co-morbidity in IBS; putative role of the microbiota 

There are several lines of evidence indicating that the bacteria composition of the gut influences behavior. First, recognition of antibiotics and laxatives as first line treatment for hepatic encephalopathy reminds us that gut microbes can influence behavior, albeit under pathological conditions. Second, changes in fermentation profiles have been observed in patients with depression and the latter has been improved following removal of certain carbohydrates from the diet [43], [44]. Third, studies in germ-free mice reveal changes in the hypothalamic pituitary response to stress and changes in brain-derived neurotrophic factor (BDNF) that could be corrected by selective bacterial colonization of the gut [57]. Finally, emerging evidence indicates that perturbation of the microbiota by dietary modification [58] or antibiotics influences behavior – for review see [59]. Based on these observations, it is possible to include dysbiosis in a comprehensive model of IBS that accommodates the psychiatric co-morbidity that occurs in up to 60% of patients. In this conceptual model, dysbiosis arises for the reasons outlined above and in Fig. 1, and may not only drive gastrointestinal dysfunction, but may also contribute to the behavioral profiles of IBS patients [8], [9].

Our understanding of how the microbiota interact with the host in the maintenance of health and in the expression of G.I. and other system diseases is in its infancy. As we become more adept at characterizing the microbiota, and in understanding the degree of variability and diversity that exists within healthy individuals over time, we can proceed to investigate correlations between microbiota profiles and symptom expression in chronic relapsing disorders such as IBS. Clinical observations of this type will provide the basis for future mechanistic investigation of how selected commensal bacteria alter GI function. The lesson learned from the role of Helicobacter pylori in peptic ulcer disease is a reminder of the plausibility of a role for commensally bacteria in chronic lower GI conditions that are currently considered to be “idiopathic”.

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☆ Dr Collins receives a grant in aid from Nestle Research Foundation and from The Canadian Institutes of Health Research.

PII: S1590-8658(09)00329-6

doi:10.1016/j.dld.2009.07.023

Digestive and Liver Disease
Volume 41, Issue 12 , Pages 850-853, December 2009

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