• Eamonn M M Quigley
  • Aamir Ghafoor Khan


Irritable bowel syndrome (IBS) is one of the mostcommon of all medical disorders, whether surveyed inthe community, in a primary care practice or at aspecialist gastroenterology referral centre.1,2 Itsprevalence has long been appreciated in the West; whatis new is a recent accumulation of evidence to indicatethat IBS is also highly prevalent in the East and even indeveloping nations like Pakistan.3,4 These same studieshave also revealed some interesting differences indemographics and mode of presentation between Eastand West. Thus, female predominance, a hallmark of IBSin Europe and North America, is not as striking in theEast and may not even exist in certain countries, wheremale IBS subjects may be in the majority. Furthermore,symptom patterns may vary, with lower abdominal painand a preoccupation with bowel habit being the foremostpattern in the West, whereas upper abdominal symptomsare common in the East where sufferers also seem lessexercised about bowel dysfunction. The latter reminds usof the importance of overlap with another functionaldisorder, functional or non-ulcer dyspepsia (FD). Some,indeed, would refer to evidence such as this to emphasisethe degree of overlap between these conditions andwould question whether FD, a disorder which has provendifficult to define clinically, is really a distinct entity butrather a part of the spectrum of IBS, a much moreaccepted clinical entity.5While research continues, in a variety of areas,on the pathophysiology of IBS, work on a possibleinflammatory component to IBS is currently attracting thegreatest attention. Three principal strands of evidence havebeen explored: the role of enteric infection in initiating IBS(post-infectious IBS, or PI-IBS), the possibility thatalterations, be they quantitative or qualitative, in the entericflora might be relevant to the genesis of symptoms in IBSand, finally, the suggestion that low-grade inflammationand immune activation may be a fundamental abnormalityin IBS. With regard to the former, there is now anoverwhelming body of epidemiological and clinical data tosupport the concept of PI-IBS, an entity that clinicianshave recognised for decades.6 Though the risk ofdeveloping PI-IBS following an episode of bacterialgastroenteritis is low, afflicted patients may endureprolonged and significant IBS-type symptoms and mayexhibit an associated persistent inflammatory response inthe rectal mucosa. Over the years a number of studies havesuggested that the colonic (or, more correctly, the faecalflora) flora may demonstrate quantitative changes in IBS;studies on the faecal flora in IBS have, however, providedvariable results, one of the few consistent findings being anapparent suppression of the population of bifidobacteraia.Given the limitations of faecal sampling as a reflection ofthe colonic flora and of current culture techniques, per se,more study is required on this issue. Very recent studies,using molecular techniques, have, not only begun to revealthe true diversity of the intestinal microbiota, but havebegun to establish, on a firmer footing, differencesbetween IBS and control subjects.7 Even morecontroversial has been the suggestion that a significantproportion of the IBS population harbour bacterialovergrowth in their small intestines and that they canexpect a significant symptomatic response to course ofantibiotics.8 Critics of this hypothesis have drawn attentionto the poor specificity of the test (the lactulose breathhydrogen test) used to diagnose bacterial overgrowth inthese studies, to the non-specificity of gastrointestinalsymptoms, in general, and to the far from spectacularresponse to antibiotic therapy.9,10 Furthermore, others havefailed to reproduce this finding. This is an important issue,as the prospect of long-term, or even repeated, courses ofantibiotics to subjects with a disorder as chronic andrelapsing as IBS, is a cause for some considerable concern.The inflammatory concept, in contrast, continues to gathermomentum. It began with the demonstration, in biopsymaterial from the rectum, colon and ileum, of evidence ofincreased numbers of a variety of cells (lymphocytes, mastcells) known to participate in an inflammatory responseand to produce cytokines and other biologically activesubstances that could modulate enteric nerve and musclefunction.11 Since then, others have gone on to demonstrateelevated levels of pro-inflammatory cytokines in theperipheral blood of IBS patients and have even suggestedthat some IBS patients may be genetically predisposed todevelop a low-grade, but sustained, inflammatory responseto certain stimuli, including those that may originate in thelumen itself.12-14 In this way, a luminal stimulus couldinitiate a local inflammatory response in the colon or smallintestine and, through the local or systemic release ofcytokines, generate the motor (“spasm”), sensory (visceralhypersensitivity and hyperalgesia) and mucosal responsesthat typify IBS. It is also feasible, based on evidence fromanimal models as well as from man, to reconcile these“inflammatory” findings with more central {aberrantcerebral activation and disturbances in the hypothalamicpituitary-adrenal (HPA) axis} and even systemicdisturbances (fatigue, fibromyalgia) associated with IBS.Whether these linkages between inflammation and otherphysiological perturbations represent mere associations or,indeed, even epiphenomena, or are truly causal remains tobe determined. For now, these findings have raised thepossibility that a targeted anti-inflammatory approach mayameliorate symptoms or even cure IBS is tantalizing one;evidence with a probiotic (Bifdobacterium infantis infantis35624) with potent anti-inflammatory properties suggeststhat journeys down this therapeutic avenue may proveproductive.12J Ayub Med Coll Abbottabad 2009;21(1)2 now, the management of IBS continues topose significant challenges for the patient and the clinician,alike. The importance of the physician-patient interactioncannot be over-emphasised: it is critical that the physicianrecognise the patient’s symptoms, their impact on theirdaily lives and any associated psychosocial dimensions.With regard to the evaluation of the patient presenting withIBS-type symptoms we have recently witnessed a seachange in attitude. The concept of IBS as a diagnosis ofexclusion (or even of exhaustion), arrived at only when arange of biochemical, radiological and endoscopic testshad eliminated other ‘pathologies’, has now been castaside: in the right context and in the absence of symptomsor signs suggestive of other diseases, a positive diagnosisis, not only possible, but recommended.15,16 This approacheliminates the need for the application of expensive,invasive and, almost certainly worthless, investigations, toall IBS patients. Given the heterogeneity of symptoms andmodes of presentation in IBS it should come as no surprisethat management strategies can seldom be generalised butrequire considerable nuance and even individualization.What may assist a patient with frequent bowel movementsor even diarrhoea may significantly impair the patient withconstipation in association with IBS. The concept oftailored therapy based on predominant stool frequencycame to the fore with the development of IBS-targetedtherapies that either accelerated (tegaserod) or inhibited(alosetron and cilansetron) gut transit. All of these agentswere designed to modulate serotonergic (5-hydroxytryptamine, 5-HT) activity in the enteric nervoussystem. The universal adoption of these agents has beenlimited by regulatory issues (none of these agents has beenapproved for use in the European Union) and, in the caseof the 5-HT3antagonists, by the spectre of ischemic colitis.Tegaserod, in turn, was withdrawn because of rare cardiaceffects. The regulatory travails of all of these compounds,on both sides of the Atlantic, have revealed the challengesthat face those that attempt to introduce, test and bring tomarket, new therapies in IBS.17 It is, after all, aheterogeneous disorder of uncertain cause for which wehave no validated biomarker and which is associated witha placebo response that averages 40% in clinical trials.Furthermore, IBS is regarded, by regulatory bodies, as avery benign disorder; as such adverse events of anymagnitude or severity will not be tolerated. Most recently,Food and Drug Administration in the US has imposed amoratorium on new IBS studies pending definition,validation and acceptance of an appropriate primaryoutcome endpoint. These misgivings notwithstanding,research continues on a variety of chemical entities thatmay impact on IBS, be they located on sensory neurons,on gut smooth muscle, the central nervous system, in theintestinal lumen or inflammatory cells.


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