On the pathogenesis of the irritable bowel syndrome : The irritable bowel or the irritable patient ?

The traditional perspective of irritable bowel syndrome (IBS) as a 
behavioural problem has tended to downplay the role of gastrointestinal dysfunction. 
Contrary to predictions based on the traditional philosophy, a recent 
study has shown that IBS patients have increased pain tolerance compared to 
healthy subjects. This profile of pain tolerance is similar to that seen in chronic 
organic disease of the gut (eg, Crohn's disease), raising the possibility that IBS 
patients may experience pain resulting from gastrointestinal dysfunction. The 
recent finding of increased airway responsiveness to inhaled methacholine in 
certain IBS patients provides an objective and quantifiable measurement of tissue 
dysfunction in that syndrome, and focuses attention on possible mechanisms 
underlying the altered responsiveness of hollow organs in patients with IBS; these 
mechanisms are discussed.

T HE ISSUE OF WHETHER THE IRRITABLE bowel syndrome ( IBS) reflects a primary disorder of the brain or the gut has plagued gastroenterologists, psychologists and psychia trists for yea rs.An editorial published in The Lancet in 1984 crystallized the controversy by stati ng: "At one end of the spectrum is the belief that the prim ary disorder is almost entirely psychiatric: the patients a rc anxious, dependent, hysterical or otherwise deranged, and their symptoms are largely imaginary.or at the very least grossly exaggerated . . .At the other end of the scale is the notion that the irritable bowel sy ndrome is an organic disorder of gut function" (1 ).The controversy hinges on the idea that IBS must be an exclusive <lisordcr of the brain or gu t, and the no-La pathogenese du syndrome du colon irritable : Colon OU patient irritable ?RESUME: A cause de la perspective traditionnelle qui consiste a voir le syndrome du colon irritable ([BS-SGI) com me un probleme de comportement avant tout, on a eu tendance a accorder une importance moindre a la comprehension des causes du dysfonctionnement gastrointestinal clans cette affection.Or, contrairement aux previsions conformes a cette philosophic, une etude recente demontrc que !es patients souffrant de SGl manifestent une tolerance accrue a la douleur, compares aux sujets en bonne sante.Ce profil de tolerance a la douleur est semblable a celui que !'on observe clans le cas d'autres maladies organiques chroniques de l'intestin (maladie de Crohn, par exemple); ii serait done possible que !es patients atteints de SGI souffrent bien de douleurs resultant d 'une dysfonction gastrointestinale.Des resultats recents montrent, chez certains de ces patients, une facultc de reponse accrue des voies aeriennes aux inhalations de methacholinefournissant une mesure objective et quantifiable de la dysfonction des tissus dans ce syndrome et attirant !'attention sur !es mecanismes qui sont peut-etre a !'oeuvre clans la faculte de reponse altcrce des organes creux chez ces patients; ces mecanismes sont examines.tion that !BS represents a single pathogcnetic process.Since it is unlikely that either of these views is correct, one may claim that the controversy is, to some extent, artificial.

IRRITABLE MlND?
The trad itio nal and hitherto dominant view of !BS has been that it represen ts a primary be havioural problem , and chat if indeed there is any gastroi n testinal dysfunc tion, the gut is involved as an 'innocent bystander'.This view 1s supported by both scientific data and sentiment.
The main body o f evid ence in support of a primary behavioural basis for lBS comes from studies that demonstrate an abnormal behavioural profile in the IBS patient population, and from studies reporting improvement in IBS symptoms following psychotherapy o r the use of psychorropic drugs (Table I).As a group, !BS patients generall y appear to be psycho logically fragile; this is borne o ut in fo rmal psychometric assessments.There is a higher than expected prevalence of ).However, it should be remembered that these studies were performed largely on patients in tertiary referral centres which attract the mo re chronic and refractory patients.Pe rhaps it is no t surprising that this group should exhi bit signs of anxiety o r depressio n ; little is known of the psychometric profile of !BS patients early in the course of their illness.
There is evidence from controlled trials that antidepressants (6)(7)(8)(9)(10).psychotherapy ( 11) and hypnotherapy ( 12) may improve gastro intestinal symptom s in certain !BS patients, b u t the applicability of these treatment strategies to the !BS patient population as a whole is questionable.ln clinical practice, one is conscious of the overtly anxious or d epressed IBS patient in whom such m easures are appropriate, but there are also many !BS patients with severe sym ptoms who a re psychologically robust and in whom these therapeutic strategies are like ly to be ineffe ctive and perhaps offensive.These obse rvatio ns underscore the suspicion that the clinical en tity •ms• may be the expressio n of several quite dissimilar pathogcne tic processes, some of which impact directly on the gut and others which do so via the central nervous system .
The paucity of non psychotropic therapies of proven efficacy for the gastrointestinal symptoms in ms may be misconstrued as evidence in favour of a primarily behavioural etiology.However, there exist several ocher reasons why a drug migh t exhibit poorly dcmonstra• ble efficacy aga in st these symptoms (Table 2).The first and most obvious reason is that traditional methods for evalu ating drug efficacy are inappropri• ate for a condi tion chat is heterogeneous not only in its clinical presen tation, but most likely in its pathogenesis.Methods fo r evaluating drug efficacy require patie nt homoge nei ty, a relatively low placebo effect and a predictable and stable course of the disease over time.They do not cake into account the conside ra ble he teroge neity of the patient population, the very high placebo race, or the spontaneous relapses and remissions that cha racterize !BS.This subject has recently been reviewed in depth ( 13).

TABLE2
Reasons for limited proven efficacy of gastrointestinal drugs in IBS Inappropriate study design Incomplete understanding of basis for gastrointestinal symptoms Limited understanding of drug action and the pharmacology of gut motility Actual absence of efficacy Another reason for the failure to demonstra te drug efficacy aga inst gastrointesti nal symptoms in !BS ts the limited understanding o f the mechanisms underlying these symptoms.Although there are considerable data ill ustra ti ng motility d isturbances throughou t the gut in IBS patients, the relationship between symptoms and abnormal motor patterns is inco mpletely understood.This is perhaps most pronou nced in relation to abd o minal pain; it is likely better understood in the case of constipation and diarrhea.A further problem rests with the complexities of the pharmacology of gastrointestinal m otility ( 14 ).These issues are serio us ones in chat they may not only mislead one into believing that poten• tially useful drugs have no place in the treatment of IBS. but may also prompt one to dismiss the notion that gastrointestinal dysfu nction exists as a basis for sym p toms in IBS.
A different a rgument that mitigates in favour of a primary behavioural abnormality in !BS is the demonstration chat symptoms simi lar to those reported by as much as 14% of the population i 15, 16).This finding, taken in conjunction with a report of a greater prevalence of learned illness behaviour in !BS patients compared to those with peptic ulcer disease ( 17), suggests that IBS patients are intolerant of 'normal' gastrointestinal sensations and use this experience to seek attention.Since pain is the symptom that has been shown to be the most common reason for !BS patients to seek attention, one might surmise that such patients select themselves from the general population by virtue of poor pain tolerance.If one assumes, for a moment, that gut function is normal in !BS, then previous reports of incolerance to balloon distension of the rectum in !BS patients this notion ( 18).However, the results of a recent study seriously weaken this argument.
Pain perception and reporting were examined in !BS patients using electrocutaneous stimulation over the dorsum of the hand (Figure I) ( 19).Results were compared to those obtained in healthy controls and in a group of patients with chronic abdominal pain due to Crohn 's disease.Both !BS and Crohn's disease patients had significantly (P= O.O 16) higher pain thresholds than normal~.and these thresholds were similar in the IBS and Crohn's disease groups.In addition.touch thresholds were higher in these groups compared to the controls, and were significantly higher in the !BS patients than in those with Crohn's disease.These results indicate that !BS patients are less sensitive to low intensity nonpainful stimuli (touch) and have a higher threshold for painful stimuli than normal subjects.The results suggest that !BS patients do not select themselves from the general population by virtue of a generalized reduction in pain tolerance.It follows chat reports of pain by !BS patients should not be disregarded as a manifestation of learned illness behaviour.
Since the ability to tolerate higher lev- Irritable.bowelsyndrome els of pain is usually associated with painful chronic conditions (20-22) and can be induced in animals subjected to pain ( 23 ), the results suggest that IBS patients experience chronic pain on the basis of gastrointestinal dysfunction.

IRRITABLE BOWEL?
There is an emerging literature which demonstrates that sensory perception within the gut is altered in !BS patients, suggesting that the bowel may be truly 'irritable' Although the emphasis ha~ been placed on an altered motor function in !BS, it is likely that the exaggerated motor responses observed in !BS may reflect, at leas t 111 part, altered sensory input.
Earlier studies reporting intolerance to balloon distension of the rectum in !BS patients ( 17) support the notion that there is altered sensory input from the gut, particularly if one accepts char these patients are able co tolerate larger amounts of pain than normal subjects ( 19).The demonstration of abnormal vagal activity in !BS patients (24) may also reflect this, particularly as the majority of the vagal fibres are afferent.Recently reported studies provide further evidence of irritability' in the gastrointestinal tract of !BS patients.
One study extended previous work by showing that intolerance to balloon distension is evident in the stomach of patients with idiopathic functional dyspepsia.which may represent a subgroup of the lBS population (25).Another study examined the ability of various luminal stimuli to induce pain and/or colonic mocor responses in !BS patients and controls.The luminal stimuli consisted of balloon distension, infusion of 15 mM deoxycholic acid (DCA) and of a mixture of short chain fatty acids (SCFA) (70 mM acetic acid and 50 mM lactic acid) delivered in random order and interspersed with saline infusion (26).DCA infusion reproduced the familiar pain in seven of eight !BS patients but in only one of five controls.SCFA infusion produced similar responses in five of seven IBS patients but in none of the five controls.The threshold for pain induced by balloon distension of the distal colon was lower in !BS patients compared to the control threshold (75.7 versus 17 1 ml, P<0.00 I).Although the motor responses to the acid infusions were larger in IBS patients compared to the controls, the differences were not significant.These results suggest that there is a n increased sensitivity of afferent nerves responding to mechanical or chemical stimu lation in the gut of lBS patients, which contrasts sharply with the demonstration of increased pai n thresholds outside the gut in IBS patients.The implication is that the gastrointestinal tract is indeed abnormal in !BS patients.

GASTROINTESTINAL DYSFUNCTION IN IBS
Altered motor function: Previous discussions regarding the nature of gastrointe tinal dysfunction in IBS have tended to focus on motor abnormalities, and there has even been on the existence of a primary disorder of smooth muscle in the gut in lBS (27).This was prompted in part by demonstrations of altered myoelectric activity reco rded in vivo from the unstimulated colon of IBS patients, and in particular the suggestion that there may be an altered slow wave freq~ncy with a higher incidence of 3 cycles/min activity in IBS (28-30).
Since slow waves arc generated by oscillations in membrane potential, changes in slow wave frequency m,iy be regarded as manifestations of a fundamental alteration in smooth muscle cell (31 ).However, this finding has not p roven to be robust and several other workers have failed to demonstrate it (32-33 ).
This has as much to d o with the difficu lties in obtai ning and processing electrical signals from the human colon (34) as it docs with the inherent complexity and variability of the electrophysio logic control of colonic motility (35).The question of whether there is a primary abno rmality in smooth muscle cell function in !BS remains open, bur it is this author's opinion that if such an abnorm ality ex ists, it does so only in a subpopulation of patients; as already mentio ned, IBS is likely to reflect more than one pachogenetic process.
In spite of the uncertainty regarding a primary ro le for smooth muscle dysfunction in !BS, there is little doubt that stimulated motor activ ity is abnormal in !BS.Several studies have shown that motor responses to nutrients (36,37).co drugs (38).to hormo nes (39) and to bile acids (40) are exaggerated in IBS patients versus controls.Since some of these stimuli were delivered via the gut lumen, the exaggerated motor response may reflect, in part, an altered sensory input.However, in certain instances, stimuli such as cho lecyscokinin and parasympathomimetic drugs were d elivered parenterally and would be presumed to act on the m otor apparatus directly.The extent to which these responses reflect changes in enteric (efferent) nerves or smooth muscle cells re ma ins to be determined.Altered epithelial function: Altered gastrointestinal function in IBS is not restricted to the neuromuscular tissues.A study from De nmark has shown that the intestinal epithelium &om patients with diarrhea-predominant IBS exhibits net secretory characteris tics co mpared to controls when challenged with bile acids ( 41 ).ln addition, the re is a study in which patients with IBS and a specific food intolerance produced more prostaglandin E, in the gut lumen when challenged in a double blind manner (42).Although the so urce of the prostaglandins could not be identified , it was most like ly produced by the e pithelium and is unlikely to have originated in the deep muscular layers of the gut wall.

IRRITABLE BODY?
The prevalence of extragastrointestinal symptoms in IBS patients (43,44) has p rompted the investigation o f dysfunction in hollow organs outside the gut in lBS patients.Abnormal urodynamics have been recorded in patients with constipalion due to colon ic inertia ( 45) and in other lBS patients ( 46).Others have reported significantly lower blood pressures in a group of IBS patients compared to controls (47)(48)(49).Some of these data have been interpreted as providing evid ence of altered smooth muscle function (46,47,49).However, vascu lar and urinary bladder responses may re-Acct hormonal and neural as well as muscular factors, and data obtained from such studies are difficult to quantitate accurately.
To purs ue this issue further, and to overcome some of the obstacles fou nd in previous stud ies, airway responsiveness was recently examined in JBS patients.In humans, the measurement of the volume of air expi red in I s under maximal effort follow ing methacholine or histamine inhalation (FEV,) is a reliable method of assessing b ronchial air• way calibre and reactivity (50)(51)(52).The response to in haled mcthacholine is generally considered to reflect an interaction with muscarinic receptors on airway smooth muscle (51).!BS patients were found to be significantly more sensitive to the bronchoco ns tricting effects of methacholine than a group of hcalthv subjects o r those with organic diseases of the gastrointestina l tract ( 54 ).Significantly larger changes in FEV, were reco rded in !BS patients and occurred fo llowi ng the admi nistration of significantly smaller amounts of methacholine than was requi red in other groups.The cha nges in FEV, were not, however, of the magnitude observed in asthmatic patients, and none of the !BS patients studied were atopic.
What a re the im p lications of these results?First, they provide bona fide evidence of altered smooth muscle function outside the gut in !BS patients.The alteration in smooth muscle function may be primary secondary to altered innervation of the muscle or, as in asthma, the consequence of an inflammatory process in the ai rways.Second, these results raise the spectre of a convcnieni screeni ng test fo r JBS patients, although it must be emphasized that the results were obtained in a highly selected JBS group and it is not known whether the fi ndings can be extrapolated to the IBS population at large.Finally, the results prompt comparisons between !BS and asthma.

IBS AS 'THE ASTHMA
OF THE GUT' Could IBS, o r subgroups of JBS, patients reflect the same spectru m of pathop hysiological processes that are believed to produce asthma?Why not?There are broad similarities between the digestive and respiratory tracts, and several striking similarities between the two conditions (Table 3).
Let us reca ll that asthma was conside red in itially to be a largely psychogenic