Gut 2001;49:743–745
`
`743
`
`Leading article
`
`The putative role of inflammation in the irritable bowel
`syndrome
`
`The irritable bowel syndrome (IBS) may be defined as a
`painful chronic abdominal symptom complex which is
`usually associated with altered bowel habit, and for which
`there is no discernible underlying structural abnormality. It
`is generally accepted that symptoms are generated by
`abnormalities of gut function, including altered sensory
`perception, abnormal motility and,
`in some patients,
`abnormalities of epithelial function. Behavioural factors
`are important, particularly in the reporting of symptoms.
`What is lacking is an understanding of the pathogenetic
`mechanisms that alter gut function. IBS is a heterogeneous
`condition, not only in its clinical presentation and
`pathophysiology, but also in terms of its pathogenesis.
`While both central and peripheral factors have been impli-
`cated in the pathogenesis of IBS, this article will restrict
`itself
`to an evaluation of
`the evidence supporting
`inflammation as a basis for altered gut function in IBS.
`In considering the role of inflammation in IBS, one is
`prompted to make a comparison with asthma. Like IBS,
`asthma was once considered a psychosomatic disorder,
`particularly in non-atopic children. For more than 50 years
`the treatment of asthma focused on the pharmacological
`correction of abnormal end organ physiology (that is,
`airways hyperresponsiveness), an approach that is similar
`to current therapeutic approaches to IBS, and which are
`aimed at modulating motor activity or sensory perception.
`The subsequent discovery of inflammatory cells in the
`normally sterile broncheoalveolar
`lavage led to the
`recognition of asthma as an inflammatory condition. There
`are two reasons why a similar shift in thinking in IBS will be
`diYcult. Firstly, the gut is normally in a state of controlled
`inflammation and the challenge of identifying a subtle
`increase in inflammatory cell number or composition is not
`to be underestimated. Secondly, IBS is intuitively more
`heterogeneous than asthma, and inflammation is unlikely
`to be a factor in all cases. Nevertheless, there is emerging
`evidence for a role of inflammation in the pathogenesis of a
`least a subset of IBS patients.
`From a clinical point of view, there are two scenarios that
`prompt consideration of a role for inflammation in the
`pathogenesis of IBS. The first is the development of IBS in
`patients following gastroenteritis (post-infective IBS (PI-
`IBS)). This occurs in 7–31% of patients with gastroenteri-
`tis from a variety of microbial agents1–3 including parasites.4
`Some studies have shown a persistent increase in the cellu-
`larity of the lamina propria and mucosa or an increase in
`lymphocytes in the colon of
`these patients.5 6 Taken
`together, these findings suggest that the inflammatory
`response to infection, rather than the infective agent itself,
`
`is the important factor in induction of altered colonic
`physiology and generation of IBS symptoms.7 The second
`scenario is that of IBS-like symptoms that occur with a
`higher than expected frequency in patients in remission
`from inflammatory bowel disease (IBD), particularly
`ulcerative colitis.8 It is likely that the inflammatory process
`during acute exacerbation of IBD induces sensory-motor
`changes in the colon that have been shown to persist during
`remission9 and which may be a basis for generation of IBS-
`like symptoms.
`The observations made in these patient groups are sup-
`ported by studies in animal models of
`infection and
`inflammation. It is well recognised that an inflammatory
`response, which is largely restricted to the intestinal
`mucosa, may cause profound changes in the function of
`smooth muscle,10 enteric nerves,11 and interstitial cells of
`Cajal.12 Some of these changes also occur at remote
`non-inflamed sites,13 producing extensive disturbances in
`gut physiology. These studies also demonstrate that the
`changes in gut physiology result from specific components
`of the inflammatory response, including T lymphocytes10
`and macrophages,11 rather than simply the presence of the
`infective agent. Of particular relevance to the above
`described clinical scenarios are demonstrations of persist-
`ence of altered physiology after recovery from infection and
`resolution of the mucosal inflammatory response.14–17 In
`studies of primary nematode infection in the mouse,
`successful expulsion of the parasite and resolution of the
`inflammatory response was accompanied by dysfunction of
`intestinal muscle and enteric nerves14 for 4–6 weeks. In
`addition, there was evidence of increased substance P lev-
`els and altered sensory perception following balloon
`distension of the colon 4–6 weeks post-infection.15 16 While
`T cells are required for the initiation of the changes in
`muscle contractility during the acute infection, the changes
`that persist post-infection are maintained by cyclooxygen-
`ase 2 derived prostaglandin E2 production by resident cells,
`including smooth muscle.17 Since the persistent changes in
`muscle function could be reversed by a short course of
`corticosteroid, administered after recovery from infection,
`they reflect a low grade inflammatory process in the mus-
`cularis externa.
`that IBD may predispose to IBS is
`The concept
`supported by recent work in animals. Changes in colonic
`smooth muscle contraction have been observed in animals
`
`Abbreviations used in this paper: IBS, irritable bowel syndrome;
`PI-IBS, post-infective IBS; IBD, inflammatory bowel disease; IL,
`interleukin; TGF-♢, transforming growth factor ♢.
`
`Leading articles express the views of the author and not those of the editor and the editorial board
`
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`
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`

`744
`
`Collins, Piche, Rampal
`
`recovering from hapten induced colitis; muscle hypercon-
`tractility emerged at 21 days post-colitis and was initiated
`by T cells.18 Other studies using models of experimental
`colitis have shown an increase in serotonin containing
`enterochromaYn cells19 but it is not known whether these
`persist after resolution of the inflammatory response, as has
`been observed in patients with PI-IBS.6
`Animal studies provide clear demonstrations of the
`abilities of immune or inflammatory cells to infiltrate and
`alter function in the deeper neuromuscular layers.10 11 The
`limited data from humans suggest that a similar process
`may occur in some IBS patients. These studies were
`performed on full thickness biopsies or surgical specimens,
`and are therefore restricted to patients with severe
`functional disturbances. Full thickness surgical specimens
`from the colon of patients with “spastic colitis” revealed
`mast cell infiltration of the myenteric plexus and muscula-
`ris externa.20 Recently, laparoscopic assisted biopsies from
`patients with severe IBS revealed a prominent lymphocytic
`infiltration of the myenteric plexus.21 The extent to which
`these findings apply to milder forms of IBS is not known.
`In the majority of studies on IBS, histological examina-
`tion has been restricted to the mucosa and lamina propria
`but have nevertheless demonstrated an inflammatory pres-
`ence in some cases. Increases in mast cell number have
`been demonstrated in the colon or terminal ileum of IBS
`patients.22 23 Other studies have identified lymphocytes and
`other cell types6 24 or simply an increased cellularity of the
`lamina propria.25 Interestingly, in several of these studies
`the changes were more marked in the ileum or right colon,
`and the rectum often tended to be normal. In a recent
`report, Barbara et al in Bologna identified a 30% increase
`in cellularity, including mast cells, in the colonic mucosa of
`IBS patients compared with controls, using quantitative
`microscopy. In addition they found, using electron micros-
`copy, that there was a closer anatomical proximity between
`nerve trunks and lymphocytes or mast cells, suggesting
`neuroimmune interactions in the pathogenesis of IBS.26
`There is limited insight into the presence of inflamma-
`tory mediators in IBS. A previous study on IBS patients
`with specific food intolerances suggested increased prosta-
`glandin production on double blind food challenge.27
`Studies on unselected IBS patients have demonstrated
`increased inducible nitric oxide synthase and nitrotyrosine
`expression which was associated with lymphocyte activa-
`interleukin (IL)-1♢
`tion24 and increased expression of
`mRNA in mucosal biopsies.28 While no mechanistic
`interpretation can be placed on these findings, they suggest
`an inflammatory presence in the IBS patients studied.
`A recent preliminary report has suggested that some IBS
`patients may be genetically susceptible to inflammatory
`conditions. The study examined 140 unselected IBS
`patients for the frequency of alleles that encode the high
`production of the counter inflammatory cytokines IL-10
`(−1082*G/A) and transforming growth factor ♢ (TGF-♢)
`(+915*G). They found that the frequency of the IL-10
`high producer (−1082*G) allele and the TGF-♢ high pro-
`ducer allele were both significantly reduced in IBS patients
`compared with healthy controls.29 As these cytokines are
`anti-inflammatory, low secretors may be less eYcient in
`downregulating responses to inflammatory stimuli such as
`enteric infection. It is possible that such an abnormality
`could determine which patients develop IBS following gas-
`troenteritis. This is supported by the demonstration of
`higher IL-1♢ mRNA expression in the colon of patients
`with PI-IBS compared with those who recovered fully from
`the infection.28 The notion that patients with PI-IBS are
`more prone to inflammatory conditions is indirectly
`supported by the observation that patients with a more
`
`Enteric infection1–3 or Recent exacerbation of IBD 8 9
`
`Genetic
`predisposition 28
`
`Behavioural
`factors and stress1
`
`Increased intestinal
`permeability 6 30
`
`Low grade
`inflammation 6
`
`14 17
`
`Persistent
`sensory-motor
`dysfunction7 9
`
`IBS
`Figure 1 Schematic representation of the relationship between
`inflammation and the irritable bowel syndrome (IBS). Citations represent
`evidence, from basic or clinical research, that support the proposed model.
`IBD, inflammatory bowel disease.
`
`the
`
`risk for
`
`protracted acute illness are at higher
`development of PI-IBS.3
`Stress and behavioural factors have also been shown to
`influence the development of IBS after gastroenteritis.
`While behavioural
`factors are clearly important
`in
`symptom reporting in IBS, it is also possible that the
`development of PI-IBS reflects a convergence of behav-
`ioural and inflammatory components. For example, prior
`stress has been shown to enhance the response to an
`inflammatory stimulus in animals30 and to increase intesti-
`nal permeability.31 These factors,
`in the presence or
`absence of a genetically determined susceptibility, could
`lead to a protracted inflammatory response to enteric
`infection and induce PI-IBS (see fig 1). The increased per-
`meability of the intestine recently described in patients
`with PI-IBS6 might provide a mechanism for maintenance
`of the condition by exposing the gut to luminal antigen and
`activating the mucosal immune system, as reflected by
`demonstration of increased numbers of lymphocytes in
`colonic biopsies from these patients.6
`In conclusion, animal studies have shown that mild
`inflammatory stimuli can perturb the sensory-motor
`system of the gut and that under certain conditions these
`functional perturbations may persist after resolution of the
`inflammatory response. This process may underlie the
`development of IBS in patients recovering from acute gas-
`troenteritis or a relapse of IBD. Genetic as well as
`behavioural factors may influence susceptibility to inflam-
`matory signals and play a role in the development of IBS in
`these situations. The extent
`to which inflammation
`contributes to the pathogenesis of the remainder of the IBS
`population remains unclear but there are morphological
`data implicating immune activation in the myenteric plexus
`of patients with severe IBS. Future research should seek to
`identify markers of inflammatory based IBS, particularly in
`PI-IBS patients, and explore new therapeutic options
`aimed at suppressing the ongoing low grade inflammatory/
`immune response.
`
`S M COLLINS
`T PICHE
`P RAMPAL
`
`McMaster University, Hamilton, Ontario, Canada and
`Federation des Maladies de l’Appareil Digestif,
`Centre Hospitalier Universitaire de Nice,
`Faculte de Medecine, Universitaire de Nice, Nice, France
`
`www.gutjnl.com
`
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`

`

`Inflammation in IBS
`
`745
`
`Correspondence to: Professor S Collins, Federation des Maladies de l’Appareil
`Digestif, Centre Hospitalier Universitaire de Nice, Hopital de L’Archet 2, 151
`Route de Saint-Antoine de Ginestiere, BP 3079, 06202 Nice Cedex 3, France.
`scollins@mcmaster.ca
`
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`2 McKendrick MW, Read NW. Irritable bowel syndrome—post salmonella
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`
`www.gutjnl.com
`
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