The objectives are to briefly review the ‘classical’ (old) pathophysiology and mechanisms1 in irritable bowel syndrome (IBS), to address the current understanding2 of the role of inflammation in IBS (borrowed), and to evaluate the potential of novel mechanisms: serotonin, genetics and intraluminal factors. The pivotal mechanisms involved in the pathophysiology of IBS are altered psychosocial function, motility and hypersensitivity. The psychosocial aspects are well reviewed elsewhere1 and, in summary, they are important determinants of the emotional response to visceral stimulation, influence the time of presentation to physicians and severity of disease, and may potentially be treated with antidepressants and other behavioural approaches. Important motor dysfunctions also have been summarized elsewhere3 and include prominent symptoms and colonic contractions after feeding in diarrhoea-predominant irritable bowel syndrome (D-IBS)4,5 and poor colonic response in constipation-predominant irritable bowel syndrome (C-IBS) or functional constipation associated with slow transit.6 Disturbances of transit profiles reflect the predominant bowel dysfunction,7–9 and gas transit is also demonstrable experimentally and is related to bloating sensation.10,11 Associated evacuation disorder (e.g. puborectalis spasm) may result in an overlap with symptoms of C-IBS.12,13 Epidemiological studies document overlap with upper functional disease, specifically dyspepsia or upper abdominal pain, which occurred in 80% of IBS patients in one study.14 Overlap of IBS with celiac disease may merely reflect the concurrence of two relatively common disorders in the same person and the limited symptomatic manifestations of diverse gut disorders. Clearly, screening for celiac disease is important in susceptible populations, although recent population-based studies suggest that serological screening does not identify significant numbers of celiac disease patients among people with IBS and dyspepsia in a community with a predominant Northern European extraction.15 Visceral hypersensitivity and hyperalgesia are well documented in IBS,16–21 and the rectal sensory threshold for pain of 32 mmHg has relatively high sensitivity and specificity for identifying hypersensitivity. The increased activation of the limbic or emotional motor system in IBS patients during rectal distension has been confirmed in several studies.22,23 There are several lines of evidence to address this question. First, epidemiological studies suggest an association between inflammation following prior infection and the persistence of IBS symptoms. This literature is well reviewed elsewhere.1 The interdependence of prior infection and psychological status has also been consistently documented,1 and this may question the role of persistent inflammation as an independent risk factor. Alternatively, the data are interpreted as evidence of the importance of psychoneuroimmune interactions; it is then unclear whether the inflammation is a key common final pathway to non-specific psychological influence on gut function, and the prior infection potentially unrelated other than as an initiator of the cascade of events. However, a summary of the epidemiology data also shows that the prevalence of postinfectious IBS (p1-IBS) is no more prevalent than IBS in the general population. A second approach is to review the quantitative differences in the inflammation and their association with symptoms. Several studies have documented increased numbers of CD3, CD25 or mast cells in ileal, colonic or rectal biopsies,24–31 but the differences for lymphocyte counts between controls and IBS are small, with predominant overlaps in the counts between the two conditions; a few outliers seem to be exceptions, and it is unclear whether these higher immune cell counts have functional significance, e.g. influence sensitivity or permeability. Differences in mast cell numbers27–31 appear to be more substantial and consistent, and there is now evidence that there are functional correlates in the significant association between mast cells in close proximity to nerves and severity and frequency of abdominal pain.31 Nevertheless, it is significant that only one of five markers of mast cell morphology was associated with IBS, the sample size was small, and the correlation is influenced by the fact that three of 13 IBS patients had no pain (questioning whether they indeed had IBS using current criteria). The third line of evidence to be examined is the response of IBS to anti-inflammatory treatment. A controlled trial has shown that, among carefully selected patients with postinfectious IBS, prednisone 30 mg b.i.d. was not significantly better than placebo and that, while placebo resulted in the customary, significant 30% change in median symptom score relative to baseline, no change in score was noted in the prednisone treatment group.32 In this section, the following themes will be reviewed: IBS as a ‘serotonin disease’ and the role of serotonin transporter the role of genetics and IBS, and the concept of the ‘irritated bowel’. Aficionados have claimed that IBS is a disorder of serotonin. This is partly influenced by the recent evidence that modulation of serotonergic mechanisms significantly impacts the manifestations of IBS. In some respects, this is also a borrowed concept since serotonin is a key player in the secretion and dysmotility of the carcinoid syndrome,33 in which 5-HT3 antagonists reduce the colonic response to feeding34, diarrhoea and the need for rescue antidiarrhoeal agents.35 There are other more direct lines of evidence to address the potential role of serotonin. First, plasma 5-HT levels are elevated in patients with IBS.36,37 Postmeal symptoms can be prominent in IBS patients,37,38 and Houghton attempted to correlate postprandial symptoms and increase in plasma 5-HT.37 However, it appears that the peak in plasma 5-HT levels does not match with the time (first 60–90 min) when patients typically experience pain, diarrhoea and urgency in IBS.39 Second, enteroendocrine cells in rectal biopsies of PI-IBS patients24,25,27 show significantly increased numbers of 5-HT containing cells; these quantitative differences were more impressive in one study24 than a subsequent study from Spiller's group,25 and overlap with numbers in disease control groups, or non-PI-IBS suggests that prior infection may not be a key factor. A third line of evidence that comprehensively assessed several factors involved in the control of 5-HT in IBS involved mucosal biopsies from IBS, healthy and disease controls (ulcerative colitis). Thus, Coates et al.40 showed that the number of enteroendoerine E cells containing 5-HT was normal, in contrast to other studies,25–27 and the release of 5-HT from mucosal biopsies under baseline conditions or in response to stimulation was normal. However, the mucosal content of the 5-HT re-uptake protein, SERT, was reduced as shown by SERT mRNA content and immunohistochemistry. These changes paralleled the findings in non-severe ulcerative colitis, and it is unlikely that the diarrhoea itself may have induced the changes since results were similar in D-IBS and C-IBS. The mechanisms causing these changes and their functional importance remain the subject of continued research. Certainly, differences in SERT function appear to influence the response to therapy in IBS41 and further studies are awaited. Fourth, serotonergic agents are effective in the treatment of multiple symptoms of IBS, including 5-HT3 antagonists42 and 5-HT4 agonists.43 Three lines of evidence suggest there may be a role for genetics, but the data are certainly not conclusive at present. First, familial aggregation studies suggest that family members of IBS patients are more likely to suffer from IBS than their spouse controls.44,45 Second, twin studies also document a difference between risk of IBS in monozygotic relative to dizygotic twins;46,47 however, the fact that mothers of mono- and dizygotic twins have similar prevalence of IBS suggests that heredity and social learning or other environmental factors interact as risk factors in development of IBS. Third, genetic epidemiology studies start to provide some evidence of a genetic association in IBS. However, these data are to be viewed as preliminary and the pitfalls of such association studies, which may be underpowered, should be kept in mind in reviewing these data. Fewer IBS patients have high IL-10 producer (G/G) genotype than controls.48 The potential functional significance is that these patients do not down-regulate inflammation, which may be a factor in the development of IBS. Holtmann et al. have shown that a polymorphism in the gene for the G protein involved in mediating the effects of several neurotransmitters and hormones, GNβ3 C825T genotype, is significantly associated with the report of dyspepsia and to a lesser extent in IBS patients presenting to a clinic in Germany.49 Adrenergic and serotonergic genotypes were investigated in 276 IBS patients and 120 community controls. A 44 bp deletion in the gene for the promoter for SERT (SERT-P) has been previously shown to influence the function of the SERT protein produced. Thus, the wild type l/l polymorphism results in normal function, whereas the presence of the short allele (s/l or s/s) results in impaired function.50 In 90 C-IBS patients of 274 IBS patients and 120 controls, Kim et al.51 showed a significant association with α2A adrenoceptor polymorphism, and the combination of the α2 adrenoceptor and SERT-P polymorphism was associated with high somatic scores in patients with lower functional gastrointestinal disorders (FGIDs). SERT-P alone was not a risk factor for D-IBS in the Mayo Clinic study,51 and a summary of studies to date suggests there is no significant association with IBS or its subtypes51–54 in studies from North America and Korea. A positive association with D-IBS in Turkey55 needs to be viewed with caution, given the ethnic differences in the genetic distribution of the polymorphism and the small sample studied (n = 18). In summary, the reduced mucosal SERT in C-IBS and D-IBS observed by Coates et al.40 does not appear to be genetically determined, based on reports in the literature to date. In this section, the ‘old’ concept of the irritated bowel will be addressed because recent data suggest that changes in the intraluminal milieu may result in symptoms which may be restored by treatments directed to the intraluminal factors. There is overlap in symptoms between idiopathic bile acid catharsis, or rapid ideal transit that results in failure of bile acid absorption. Merrick et al.56 used bile salt retention to demonstrate that patients with functional diarrhoea that may or may not be associated with pain may have evidence of bile acid malabsorption. Patients with IBS show higher intestinal secretion in response to perfused bile acids in the ileum, relative to controls.57 Malaguti et al. showed that retarding transit with loperamide reduces the risk of bile salt loss.58 It is not surprising therefore that bile salt binding with cholestyramine may be effective in the treatment of IBS with diarrhoea. Perfusion of the mammalian or human colon with di-α hydroxybile acids such as chenodeoxycholic acid or short chain fatty acids (SCFAs) results in high amplitude propagated contractions or rapid transit in healthy colon.59–63 Studies have not been conducted in IBS patients. However, the relatively low concentrations of bile acid (1 mmol L−1) required to induce highly propulsive propagated sequences suggest that relatively modest levels of malabsorption may be sufficient to perturb colonic motility. The concentrations of long chain fatty acids (e.g. oleic acid) needed to accelerate colon transit are relatively high, but certainly would be in the range associated with moderate fat malabsorption.59 Such colonic concentrations of longer chain fatty acids are unlikely to be achieved in patients with IBS, although formal studies with long and short chain fatty acids are required. Does a change in intraluminal milieu or bacterial ecology in the intestine improve bowel function and symptoms in IBS? Small studies suggest that probiotics or antibiotics aimed at changing bacterial counts may indeed alter symptoms, although the mechanism is still unclear. Nobaek et al. showed that alteration of intestinal microflora by feeding probiotics was associated with reduction in abdominal bloating and pain in patients with IBS.64 Similarly, Kim et al. showed that, in patients with IBS, the combination probiotic, VSL no. 3, resulted in improvement of the symptom of bloating, but no other symptoms or global relief or change in small bowel or colonic transit were observed relative to placebo treatment.65 Quigley et al. have preliminarily reported that there is benefit with bifidobacteria, not with lactobacillus containing probiotics.66 Finally, change in the bacterial ecology with the non-absorbable antibiotic, neomycin, results in short-term improvement in the composite score for IBS and bowel dysfunction.67 These effects were observed in a 7-day trial; interestingly, patients whose lactulose-hydrogen breath test normalized had greater improvement than those with no response in breath hydrogen. The authors’ interpretation is that this represents an effect on bacterial overgrowth in the small bowel in IBS. While this interpretation may be questioned and longer-term studies and outcomes of treatment with bacterial modification need to be evaluated, these data are consistent with the concept that it is time to revisit the role of the intestinal milieu and the effects of bacteria and endogenous factors such as bile acids and fatty acids in the mechanisms and treatment of IBS. While there is increasing evidence that IBS represents an enteric neurological disorder that alters bowel sensation, secretion, and motility, it is important to continue to study inflammation and the potential for intraluminal factors resulting in dysregulation of those functions. Central mechanisms may enhance visceral sensation or the interpretation of ascending visceral signals as unpleasant because of the disturbances in the limbic system which is involved in the affective response to pain. At this time, the role of genetics is uncertain. These data suggest that therapies should continue to be directed at these pathophysiological mechanisms in the gut and central control; however, it is conceivable that further understanding of the bowel ecology in health and disease may open new avenues for treatment of IBS. The author is supported by grants RO1-DK54681, RO1-DK67071 and K24-DK02638 from the National Institutes of Health. The excellent secretarial support of Mrs Cindy Stanislav is gratefully acknowledged.
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Michael Camilleri (2005) studied this question.
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