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Digestive Disease Week 2000Day 3 - May 23, 2000 Irritable Bowel Syndrome: A Postinfectious and Inflammatory Disorder?Nicholas J. Talley, MD, PhD The pathophysiology of the functional gastrointestinal disorders remains obscure, but there is increasing evidence that, in at least a subset of patients, infection and inflammation may play key roles.[1] After an episode of severe gastroenteritis requiring hospitalization, it has been observed that approximately 1 in 4 patients has long-standing irritable bowel syndrome (IBS)-like symptoms on follow-up 6 months later.[2,3] A topic forum was therefore devoted to infection and inflammation in functional bowel disease. A number of other key abstracts were also presented on this topic, and a review of the new data and the clinical implications will be highlighted. Can Infection Change Gut Sensory Perception?It is established that patients with IBS usually have visceral hypersensitivity, particularly in the colon, although pan-gut involvement has been documented. A key question is whether infection can directly alter colonic sensory pathways. A useful model developed in mice involves infection with the parasite Trichomonas spiralis, which results in neuromuscular abnormalities in both the colon and small bowel that persist despite healing of the initial injury and loss of the organism.[1] Dr. Yukang Mao and colleagues from McMaster University in Hamilton, Ontario, Canada, examined the acute and chronic effects of T spiralis on colonic sensory function by measuring the dorsal root ganglion single-unit discharges in adult male NIH Swiss mice.[4] The investigators placed a latex balloon in the colon distally following the introduction of T spiralis. There was jejunal enteritis at 6 days postinfection, which returned to normal in 28 days. There were no T spiralis remaining in the bowel after 3 weeks. The investigators found postinfection hyperalgesic sensory response following distension of the colon that persisted despite healing of the acute inflammation. Furthermore, the authors were able to show that the induced response was blocked by a neurokinin (NK)-1 receptor antagonist (SR140333). The results confirm that postinfection inflammation can alter visceral sensitivity and imply that NK-1 antagonists may be therapeutically useful in this situation. There is increasing interest in NK receptor antagonists as visceral analgesics,[5] and these drugs are currently being tested in IBS. Is There Evidence of Increased Inflammation in IBS?Direct evidence of an active inflammatory component in IBS remains to be confirmed. Earlier reports suggested that there is a small, albeit significant, quantitative increase of colonic inflammatory cells in patients with IBS as well as an increase in terminal ileal mast cells.[1,6] More direct evidence has become available during this year's DDW. Dr. Maria A O'Sullivan and colleagues from Dublin, Ireland, aimed to determine whether there is evidence of increased inducible nitric oxide (NO) synthase (iNOS) and nitrotyrosine (NT) in IBS.[7] Nitric oxide is known to have a number of effects on gastrointestinal function, and increased infiltration of mast cells could potentially be effectors of nitric oxide generation. They studied 11 patients with IBS, 4 normal controls, and 3 with inactive inflammatory bowel disease of the colon. Biopsies from the colon were stained for iNOS and NT by applying validated immunohistochemistry and quantified image analysis techniques. Of interest, compared with the controls, both iNOS and NT were significantly increased in IBS at all colonic sites except the rectum. Not surprising, those with inactive colitis had more iNOS than IBS, although this was not significant. The other observation of interest was that iNOS was colocalized with B and T cells in IBS. The results imply that B cells and T cells are activated, and via nitric oxide release may be mediators of functional changes in IBS. An important poster from Dr. Hans Tornblom and colleagues[8] from the University of Lund in Malmo, Sweden, reported direct evidence of inflammation in IBS. They examined 6 patients with documented, severe IBS. These patients fulfilled the Rome criteria and had normal antro-duodenal manometry, implying they were not misdiagnosed cases of chronic idiopathic intestinal pseudo-obstruction. At laparoscopy, full-thickness biopsies from the proximal jejunum were obtained. In all 6 patients, inflammatory infiltration of lymphocytes in the myenteric plexus was observed. These lymphocytes were situated in peri- and intraganglionic locations. The authors also noted hypertrophy of the longitudinal muscle layer in 4 patients and abnormalities in the interstitial cells of the Cajal (the pacemakers of the gut) in 5 patients. These results are provocative. The major concern remains misdiagnosis of pseudo-obstruction. Furthermore, it is unclear whether these results can be generalized to all IBS patients. At the distinguished abstract plenary session on Monday, Dr. Joyce Chan and colleagues, from Manchester, United Kingdom, reported further provocative evidence supporting a direct role for inflammation in IBS.[9] In ulcerative colitis, it has been reported that lower amounts of the anti-inflammatory cytokine interleukin (IL)-10 is produced and this is associated with a reduced frequency of the -1082*G allele. The authors therefore postulated that in IBS there would be a reduced frequency of the IL-10 allele as is observed in ulcerative colitis. This hypothesis was tested by extracting DNA from the peripheral blood leukocytes of 140 IBS patients. The genotypes for IL-10 as well as other inflammatory cytokines were determined using standardized techniques. Of great interest, the IL-10 -1082*G allele was significantly reduced in IBS patients compared with healthy controls. Similarly, the TGF-beta high producer (+915*G allele) was reduced in IBS vs controls. The authors speculate that high production of anti-inflammatory cytokines may protect against IBS, but those who are genetically predisposed to lower amounts may be more likely to develop the condition. As there is other evidence supporting a genetic predisposition in IBS,[10] these results are exciting. Moreover, the findings may lead to the development of testable disease markers in IBS. Post-Campylobacter Enteritis and IBSGwee and colleagues have previously established a relationship between Campylobacter enteritis and the subsequent risk of IBS.[2] The risk of IBS appears to be increased in those with psychological distress.[3] The exact role of bacterial virulence and the risk of IBS remains unknown. Dr. Thornley and coworkers from Nottingham, England, studied the effect of specific bacterial toxins and their relationship to outcome following Campylobacter enteritis.[11] They evaluated 188 patients who had clinically isolated Campylobacter species. Seventeen (9%) patients at 6 months met the Rome I criteria for IBS. The toxigenic effects of HEP-2, VERO, and CHO-K1 toxins were obtained by testing epithelial cell monolayers; the toxigenic effects were measured at 12 and 24 hours in duplicate. They observed that persistently altered bowel habit was more common in subjects with HEP-2 toxin positive infections, compared with those who were negative for this toxin, but this was not significant. There was no association with the CHO or VERO toxins. These results imply that bacterial factors are less important than presumably other largely unidentified host factors in the pathogenesis of postinfectious IBS. As there is increasing interest in potentially targeting those who develop acute bacterial gastroenteritis with prophylactic therapy to try and prevent the development of IBS (eg, with local steroids), these observations are potentially of major clinical relevance if confirmed. It is well established that patients with IBS have more psychiatric and psychological disturbances than non-IBS controls, although this may be explained at least in part by a healthcare-seeking bias (those presenting in tertiary care centers are more likely to have psychological disturbances that drive them to seek this level of care). Dr. Simeran and colleagues from Gothenburg, Sweden, investigated the relationship between psychological factors and IBS by studying patients with ulcerative colitis in remission.[12] It is known that IBS-like symptoms are more common in patients with IBS in remission (about one third) than in controls. The reasons for this relationship remain unclear. However, in view of the postinflammatory IBS hypothesis, this is a fruitful group of patients to study. The investigators evaluated 43 patients with ulcerative colitis and 40 with Crohn's disease in remission. IBS-like symptoms were reported in 33% of ulcerative colitis patients and 59% of Crohn's disease patients; results were similar in men and women. Those with IBS-like symptoms (compared with those who did not have IBS-like symptoms) had more anxiety and depression as well as lower psychological well-being, based on standardized psychological self-rating scales. The authors speculated that previous inflammation can result in persisting gut dysfunction, and psychological factors are important in mediating symptom persistence. However, it is also possible that distressing, persistent gut symptoms may alter psychological function and result in the association observed. Further studies of patients with inflammatory bowel disease in remission are indicated; these studies will need to include appropriate controls and preferably assess psychological status before and after disease onset (which will represent a challenge). ConclusionsThe results of these new studies are exciting. There appears to be increasing evidence that IBS and probably other functional gastrointestinal disorders are, at least in a subset, due to structural disease. Host and bacterial factors may both be important. The development of new disease markers appears likely from the novel work in progress. This in turn should lead to characterization of more homogenous groups of patients and the development of better-targeted therapeutic approaches (perhaps NK-1 antagonists). Clinicians should watch this space! References1. Collins SM, Valiance B, Barbara G, Borgaonkar M. Putative inflammatory and immunological mechanisms in functional bowel disorders. Baillieres Best Pract Res Clin Gastroenterol. 1999:13:429-436. 2. Gwee KA, Leong YL, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44:400-406. 3. Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet. 1996;347:150-153. 4. Mao Y, Wang L, Chen Y, Blennerhassete PA, Collins SM, Tougas G. Hyperalgesic colonic sensory afferent pathways following T spiralis enteritis: involvement of NK receptors. Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 3838. 5. Julia V, Morteau O, Bueno L. Involvement of neurokinin 1 and 2 receptors in viscerosensitive response to rectal distension in rats. Gastroenterology. 1994;107:94-102. 6. Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig Dis Sci. 1993;38:1590-1595. 7. O'Sullivan MA, Clayton N, Wong T, Bountra C, Buckley MM, O'Morain CA. Increase iNOS and nitrotyosine expression in irritable bowel syndrome (IBS). Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 3840. 8. Tornblom H, Lindberg G, Nyberg B, Veress B. Histopathological findings injejunum of patients with severe irritable bowel syndrome. Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 3840. 9. Chan J, Gonsalkorale M, Perrey C, et al. IL-10 and TGF-beta genotypes in irritable bowel syndrome: evidence to support a inflammatory component? Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 1191. 10. Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol. 1998;93:1311-1317. 11. Thornley JP, Brough J, Wright T, Neal KR, Jenkins D, Spiller RC. Bacterial toxins influence long term bowel dysfunction following Campylobacter enteritis. Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 3841. 12. Simren M, Axeisson J, Abrahamsson H, Svediund J, Bjsrnsson ES. Symptoms of irritable bowel syndrome in inflammatory bowel disease in remission and relationship to psychological factors. Program and abstracts of Digestive Disease Week; May 21-24, 2000; San Diego, California. Abstract 3842.
 
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