Irritable Bowel Syndrome Message Boards | Inflammatory Bowel Disease

The Clinical Epidemiology of Inflammatory Bowel Disease

Bret A. Lashner, MD

Introduction
Several important advances regarding the clinical epidemiology of inflammatory bowel disease (IBD) were presented during this year's Digestive Disease Week (DDW) meeting. Among the advanced imaging techniques examined, computed tomography (CT) enterography, chromoendoscopy, and magnetic resonance (MR) colography appear to be the leading technologies, whereas wireless capsule endoscopy appears to be less useful than previously believed. Additionally, genetic linkages in IBD are being discovered or confirmed at a very rapid rate, as highlighted in key discussions during these meeting proceedings. Investigators are also elucidating the natural history of IBD from large, meticulously maintained databases to confirm incidence and surgery rates, associations with other diseases, and risk of complications, such as pouchitis or cancer. As further evident from the focus of key sessions at this year's meeting, cancer surveillance in IBD remains a hotly debated topic with somewhat conflicting studies to sort through.

This clinical overview discusses some of the more key DDW sessions documenting these advances.

Advanced Imaging in IBD
There is mounting evidence that chromoendoscopy is a preferred imaging technique for cancer surveillance in ulcerative colitis. This technique could be improved even further with the addition of confocal laser microscopy. In a randomized clinical trial involving 153 patients with long-standing ulcerative colitis, 80 patients underwent conventional colonoscopic surveillance and 73 underwent chromoendoscopy with confocal endomicroscopy for detection of lesions suspicious for neoplasia.[1] Significantly more neoplastic lesions were found in the chromoendoscopy group (19 vs 4; P = .0007). Compared with conventional histology, confocal endomicroscopy had a sensitivity of 95% and a specificity of 98% for identifying neoplastic lesions Therefore, the study authors concluded that chromoendoscopy, as compared with conventional endoscopy, was able to identify lesions likely to be neoplastic, and that confocal laser microscopy could confirm neoplasia in these lesions in vivo.

Wireless capsule endoscopy is used in clinical practice to diagnose Crohn's disease or as a tool to assess extent and severity of disease. In a study by Esrailian and colleagues[2] presented during these meeting proceedings, 41 experts in IBD were asked to judge the appropriateness of wireless capsule endoscopy in 5 case scenarios. The overwhelming majority of experts (> 83% for each case) deemed wireless capsule technology to be "inappropriate" in cases of (1) suspected Crohn's disease; (2) newly diagnosed Crohn's disease; (3) new perianal fistulas; (4) steroid-refractory stricture in Crohn's disease; and (5) postoperative fibrostenotic Crohn's disease. At the present time, experts seem to agree that wireless capsule endoscopy is not helpful in the diagnosis or management of patients with Crohn's disease. Children may be at higher risk than adults for complications from wireless capsule endoscopy. Indeed, a retrospective review by Moy and colleagues[3] found a 22.5% risk for complications among 32 studies in 31 children. Three patients had capsules that did not pass the pylorus by 8 hours (2 patients needed endoscopic removal) and 4 had capsules that did not pass through the small bowel (3 required surgical removal or bowel resection and 1 required steroid treatment). Thus, it is doubtful that the potential benefits of wireless capsule endoscopy justify the risk in pediatric patients.

The utility of CT enterography was evaluated in 51 patients with Crohn's disease of the small bowel to determine whether the additional information provided by this modality changed clinical management (eg, steroid use choices).[4] Although CT enterography correlated poorly with other radiologic and clinical findings, it did change management in 34 (67%) of the patients. On the basis of the additional findings on CT enterography, steroids were added in the management of 14 patients, and 20 patients had steroid therapy reduced or eliminated. Therefore, such application of technology appears to be promising.

Solem and colleagues[5] compared the sensitivity, specificity, and accuracy of CT enterography, wireless capsule endoscopy, small bowel x-ray, and ileoscopy during colonoscopy in the diagnosis of small bowel Crohn's disease. Forty-two patients with suspected or known Crohn's disease were offered all 4 tests sequentially. CT enterography and ileocolonoscopy had the highest accuracy (86% and 85%, respectively). Small bowel x-ray had an accuracy of 79% due to a relatively low sensitivity (65%), and wireless capsule endoscopy had a low accuracy (67%) due to a poor specificity (53%). On the basis of these results, CT enterography appears likely to improve our current approach to diagnosing Crohn's disease.

MR colonography, without colonic cleansing, has been proposed for use in the pediatric IBD patient. In a study by Falconieri and colleagues,[6] 22 pediatric patients (14 with ulcerative colitis, 2 with Crohn's disease, and 6 normal [controls]) underwent unprepped MR colonography to compare the findings with colonoscopy. Twelve of the 14 patients with ulcerative colitis had thickened bowel wall (abnormal MR colonography) that correlated with the extent of disease. The sensitivity and specificity of this test was 81% and 85%, respectively. Thus, on the basis of these findings, MR colonography, with no radiation exposure and no preparation, has certain advantages over other forms of testing for investigation of colonic involvement in pediatric IBD.

Genetic Susceptibility in IBD
Some patients with chronic pouchitis may have undiagnosed Crohn's disease. Pouchitis is a common complication after ileal pouch-anal anastomosis for ulcerative colitis, and innate immune responses targeted against enteric bacteria have a role in its pathogenesis. Meier and colleagues[7] conducted a retrospective study of 97 patients with ileal pouch-anal anastomoses to determine whether genetic polymorphisms in the innate immune receptor toll-like receptor 4 and the IBD susceptibility gene NOD2/CARD15 were associated with pouchitis. The L1007fsinsC mutation in CARD15 was found to be associated with chronic pouchitis -- all patients who harbored this mutation developed pouchitis. No patient with intermittent pouchitis or no pouchitis was found to harbor this mutation. Additionally, the toll-like receptor 4 polymorphisms, a common defect in innate immunity dysfunction, were not associated with pouchitis. The study authors concluded that patients with chronic pouchitis had genetic polymorphisms similar to those found in patients with Crohn's disease, whereas in those without pouchitis, the frequency of these polymorphisms was similar to that reported in ulcerative colitis patients and the general population. Thus, CARD15 mutations, particularly the L1007fsinsC polymorphism, may predispose to the development of chronic pouchitis following ileal pouch-anal anastomosis for ulcerative colitis.

There is a purported linkage with IBD on chromosome 10 near the DLG5 gene (codes for an important scaffolding protein). Cummings and colleagues[8] conducted a case-control study to examine the contribution of variants in this gene to disease heterogeneity in IBD. The study authors compared 699 IBD patients with 360 controls; no associations with DLG5 polymorphisms were found, even when patients were stratified according to CARD15 polymorphisms. In another cohort involving 981 IBD patients and 305 controls, the OCTN (carnitine/organic cation transporter) gene cluster on chromosome 5 (the IBD5 locus) was found to be associated with fistulizing Crohn's disease (odds ratio [OR]: 1.47, 95% confidence interval [CI] 1.03-2.11).[9] No associations with IBD (ie, a particular phenotype) were found for the DLG5 gene.

Studying phenotypic homogeneous subgroups of IBD patients may increase the likelihood of finding genotype-phenotype correlations. In a study involving 867 IBD-affected relative pairs, linkage was found for CARD15 (IBD1 locus) and ileal Crohn's disease (lod score [measure of degree of linkage] = 2.56; P = .035), the IBD2 locus and extensive ulcerative colitis (lod = 3.27; P < .001), Crohn's disease in non-Jewish patients and IBD3 (lod = 2.93 for colonic disease, lod = 2.97 for perianal disease), and evidence for linkage on IBD5 was seen in non-Jewish patients with colonic disease (lod =2.85).[10] Very few of these associations could have been identified without examining homogeneous subgroups.

Blood samples were collected from 595 patients with IBD and 627 controls followed for more than 10 years in the European Cooperative IBD study. Data from this cohort are unique in that they can facilitate the investigation of whether genetic or immune markers influence longitudinal changes in disease phenotypes. Riis and colleagues[11] studied mutations in CARD15 and ASCA (anti-Saccharomyces cerevisiae) with regard to longitudinal changes in disease phenotype among IBD patients The immune marker ASCA and CARD15 were found to be associated with a change in behavior over time from inflammatory to stricturing or fistulizing Crohn's disease (OR: 3.2; 95% CI: 1.2-8.8). Indeed, both genetic factors and abnormal immune responses to bacterial stimuli are believed to play a role in the pathogenesis underlying Crohn's disease. Recently, an association between Crohn's disease and CARD8 located in the IBD6 region (19p13) has been reported. In a study of 354 patients with Crohn's disease and 225 matched controls, the combination of CARD8 mutations in the IBD6 region on chromosome 19 and anti-OmpC (antibody to a protein expressed by Escherichia coli) was found to be synergistically associated with fistulizing Crohn's disease.[12] The study authors theorized that a mutation in the CARD8 protein could lead to a dysregulated immune response that when coupled with an aberrant immune response to commensal bacteria (anti-OmpC mutation) could lead to an aggressive, transmural inflammatory disease.

Natural History of IBD
Autoimmune manifestations are reported to be associated with both Crohn's disease and ulcerative colitis. In this context, Bernstein and colleagues[13] assessed the coincident occurrence of IBD and other autoimmune disorders using population-based data from Manitoba. Odds ratios significantly greater than 1 were found for asthma, bronchitis, and psoriasis with Crohn's disease, and for asthma, bronchitis, psoriasis, multiple sclerosis, and chronic renal disease with ulcerative colitis. Asthma was the most common autoimmune disorder found to be coincident with IBD. Thyroiditis and neuropathy were not more common in patients with IBD compared with controls. In a related investigation, Tang and colleagues[14] conducted a retrospective study using the University of Manitoba IBD database to examine fistula formation in patients with Crohn's disease. They found that 19.2% of the Crohn's disease population had fistulas. If perianal fistulas were present, the risk of having a concomitant luminal fistula was found to be significantly increased (OR: 4.45; 95% CI: 2.92-6.76). Therefore, the presence of perianal fistulas should prompt an examination for luminal fistulous disease. In another study reported during these meeting proceedings, Bernstein and colleagues[15] assessed the burden of IBD using population-based data from 5 provinces in Canada. Incidence rates for Crohn's disease per 100,000 ranged between 12.2 and 22.5, and for ulcerative colitis ranged between 8.6 and 21.2. Prevalence of disease per 100,000 persons ranged between 231 and 325 for Crohn's disease, and between 182 and 255 for ulcerative colitis. For all IBD, the female:male ratio ranged from 1.14 to 1.29. Thus, overall, the prevalence of IBD in Canada was found to be 491/100,000 persons; that is, 0.5% of the population has IBD.

Is there an association between early postoperative pouch histology and development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis? To predict the development of acute or chronic pouchitis, investigators from Toronto took biopsies from the pouch of patients soon after surgery and evaluated 109 patients for a mean of 11.5 years.[16] Early inflammation was found to be a predictor of chronic pouchitis (hazard ratio 7.4; 95% CI: 2.14-24.2). The investigators suggested that such patients should be considered for early prophylactic therapy to prevent development of chronic pouchitis. Early histology did not predict the occurrence of acute pouchitis.

What is the colectomy risk in ulcerative colitis after 10 years? The European Cohort IBD group studied 784 patients with ulcerative colitis for a minimum of 10 years to evaluate colectomy rates.[17] They found that only 7.6% of patients had colectomies. It is interesting to note that northern European countries had much higher colectomy rates than southern European countries. Despite the fact that no information on extent of disease was presented, the purported colectomy rate of 20% to 30% in patients with ulcerative colitis is likely to be a gross overestimate.

Cancer Surveillance in IBD
Are older patients with late-onset IBD at risk for colorectal cancer and do they require frequent colonoscopic surveillance? Investigators from the Hines VA Hospital in Hines, Illinois, followed 114 older ulcerative colitis patients with late-onset disease and compared outcomes with a comparable group of 6829 non-IBD controls.[18] The annual incidence of cancer in the ulcerative colitis group was 0.14% compared with 0.11% in controls (P = not significant). On the basis of these findings, the investigators suggested that older patients with late-onset ulcerative colitis should undergo surveillance at the same intervals suggested for those with sporadic disease.

The long-term safety of infliximab, an anti-tumor necrosis factor-alpha monoclonal antibody, is currently under investigation. In a case-control study, Biancone and colleagues[19] evaluated the development of neoplasia in 392 patients with Crohn's disease treated with infliximab compared with matched controls. Nine patients treated with infliximab and 6 controls developed neoplasia (OR: 1.51; P = .60). Among those patients in the infliximab-treated group who developed neoplasia, there was 1 cholangiocarcinoma, 3 breast cancers, 2 skin cancers, 1 laryngeal cancer, and 2 anal canal cancers. Among the controls who developed neoplasia, there was 1 ileal adenocarcinoma, 2 skin cancers, 1 lymphoma, 1 cecal adenocarcinoma, and 1 breast cancer. Thus, the results of this study suggest that infliximab did not significantly increase the risk of neoplasia.

Recent reports have suggested that dysplasia and colorectal cancer may be endoscopically visible in many patients with IBD. Rubin and colleagues[20] conducted a retrospective review of a large registry of patients with ulcerative colitis who underwent surveillance examinations over a 10-year period; 1339 examinations were performed in 622 patients. Sixty-four dysplastic lesions were found in 44 patients during this study interval; 35 of 56 (62.5%) dysplastic lesions were visible to the endoscopist, and 7 of 8 (87.5%) cancers were visible. Visible lesions included polyps or masses, strictures, or irregular mucosa. The sensitivity of visibly (ie, by endoscopy) identifying neoplastic lesions was 79.5%. Chromoendoscopy is likely to increase this sensitivity rate much further by making even more lesions visible.

At present, it remains unclear why some patients with IBD have an increased risk of colorectal neoplasia. Jess and colleagues[21] conducted a nested case-control study to investigate risk factors for colorectal neoplasia in 2 large population-based IBD cohorts; 52 patients with ulcerative colitis and neoplasia were compared with a matched set of controls. Significant risk factors for neoplasia included primary sclerosing cholangitis (OR: 8.7), active disease (OR: 3.1), continuously active disease for more than 1 year (OR: 4.0), sulfasalazine use (OR: 1.13), mesalamine use (OR: 1.22), and a higher cumulative dose of steroids (OR: 1.05). These study findings did not support the accumulating evidence that mesalamine may have chemopreventive effects for neoplasia.

Results of population-based studies have demonstrated a slightly increased mortality rate for patients with Crohn's disease over the last 40 years. Wolters and colleagues[22] presented the results of a study assessing mortality risk in a European cohort of Crohn's disease patients 10 years post diagnosis. In this European cooperative study of 371 incident cases of Crohn's disease followed for at least a decade, there were 37 deaths (SMR [standardized mortality ratio] 1.72; 95% CI: 1.21-2.38). There were 8 deaths from gastrointestinal malignancies vs only 0.86 expected (SMR 8.14; 95% CI: 3.26-16.78). In this cohort, patients with Crohn's disease had an increased mortality risk, especially from gastrointestinal malignancies.

Recent reports have suggested a high risk for progression to high-grade dysplasia or cancer among IBD patients with flat low-grade dysplasia; this has led to more aggressive surgical intervention. Jess and colleagues[23] reported the results of a study to assess the true long-term outcome of colorectal dysplasia in a population-based IBD cohort. Among 691 incident ulcerative colitis cases followed in a cancer surveillance program, there were 9 with dysplasia in flat mucosa, 1 with a dysplasia-associated lesion or mass (DALM), and 23 with adenoma-like masses (ALMs). In patients with ALMs, 3 had recurrent adenomas, 3 developed flat low-grade dysplasia, 2 developed DALMs, and 1 developed multifocal Dukes' C adenocarcinoma. Although these findings did not confirm the previously reported risk for progression in flat dysplastic lesions, they did document ALMs as worrisome lesions in patients with ulcerative colitis.

Conclusion
On the basis of data presented during this year's DDW meeting, and as discussed above, the clinical care of IBD patients may evolve and change. Although findings suggest that CT enterography and MR colography will be used more often to diagnose IBD and its complications; wireless capsule endoscopy has not yet found its place in the care of these patients. Chromoendoscopy is sure to improve outcomes from cancer in IBD, but much additional study is needed regarding treatment recommendations for lesions found with such testing. Last, as investigators continue to identify and confirm genes associated with IBD, the closer clinicians are to finding the cause and cure of IBD.

References
Kiesslich R, Goetz M, Schneider C, et al. Confocal endomicroscopy as a novel method to diagnose colitis-associated neoplasm in ulcerative colitis: A prospective randomized trial. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 483]
Esrailian E, Targownik EL, Spiegel BM, et al. Is wireless capsule endoscopy appropriate for the diagnosis and management of Crohn's disease? A survey of North American Inflammatory Bowel Disease experts. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 484]
Moy L, Levine J. Wireless capsule endoscopy in the pediatric age group: Experience and complications. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 485]
Higgins PD, Caoili E, Zimmermann M, et al. CT enterography adds information to clinical management in small bowel Crohn's disease. Gastroenterology. 2005;128(suppl 2):A73-A74. [Abstract 487]
Solem CA, Loftus EV, Fletcher JG, et al. Small bowel imaging in Crohn's disease: A prospective, blinded, 4-way comparison trial. Gastroenterology. 2005;128(suppl 2):A74 [Abstract 488]
Falconieri P, Laghi A, Paolantonio P, et al. Un-prepped MR colonography in pediatric patients with inflammatory bowel disease. Gastroenterology. 2005;128(suppl 2):A-49. [Abstract 342]
Meier C, Aisenberg J, Legnant P, et al. Innate immune receptor polymorphisms in pouchitis: Is NOD2/CARD15 a susceptibility factor? Gastroenterology. 2005;128(suppl 2):A-112. [Abstract 726]
Cummings JRF, Kerrlinger KR, Ahmad T, Jewell DP. Genotype-phenotype analyses of the IBD susceptibility gene DLG5. Gastroenterology. 2005;128(suppl 2):A-112. [Abstract 727]
Vermeire S, Pierik M. Henckaerts L, et al. Study on DLG5 and OCTN polymorphisms shows association of the OCTN TC risk haplotype with perianal and fistulizing Crohn's disease but not with susceptibility to IBD. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 731]
Achkar JP, Dassopoulous T, Silverberg M, et al. Disease location refines genomic localization in inflammatory bowel disease: IBD is an extensive ulcerative colitis locus. Gastroenterology. 2005;128(suppl 2):A-112-A113. [Abstract 728]
Riis L, Wolters F, Solberg C, et al. ASCA is associated with CARD15 mutations and longitudinal changes in behavior of Crohn's disease: A population based ED-IBD study. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 729]
Picornell Y, Abreu MT, Ippoliti A, et al. CARD8 variant and the expression of anti-OmpC are synergistically associated with internal penetrating Crohn's disease. Gastroenterology. 2005;128(suppl 2):A-113.[Abstract 730]
Bernstein CN, Blanchard JF, Wajda A. A population-based study of comorbidity and other autoimmune diseases in IBD. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 732]
Tang LY, Rawsthorne P, Bernstein CN. In Crohn's disease is there an association between perianal fistulzing disease and luminal fistulizing disease? A population-based study. Gastroenterology. 2005;128(suppl 2):A-113-A114. [Abstract 733]
Bernstein CN, Wajda A, Blanchard JF, et al. The burden of IBD in Canada: A population-based study. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 735]
Johnson P, MacNeill N, Baladjay L, et al. Early post-operative pouch histology predicts future chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 734]
Hoie C, Wolters F, Riis L, et al. Colectomy rates in ulcerative colitis in a European inception cohort followed for ten years by the EC-IBD study group. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 736]
Hoffman SD, Sontag SJ, Levis W, et al. Late onset inflammatory bowel disease in older patients does not require frequent surveillance. Gastroenterology. 2005;128(suppl 2):A-121-A122. [Abstract 777]
Biancone L, Kohn A, Colombo E, et al. Development of neoplasia in Crohn's disease patients treated with infliximab: A case-control study in an Italian population. Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 778]
Rubin DT, Rothe JA, Cohen RD, Hanauer SB. Is dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 779]
Jess T, Loftus EV, Velayos FS, et al. Risk factors for cancer and dysplasia in inflammatory bowel disease: A nested case-control study of population-based cohorts from Copenhagen County and Olmsted County. Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 780]
Wolters F, Schouten L, Sijbrandij J, et al. Increased mortality ten years after diagnosis in a Europe-wide population based cohort of Crohn's disease patients (EC-IBD Study Group). Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 781]
Jess T, Loftus EV, Velayos FS, et al. Are adenomas more harmful than flat low-grade dysplasia in patients with inflammatory bowel disease? A population-based cohort study from Olmsted County, Minnesota, 1940-2002. Gastroenterology. 2005;128(suppl 2):A-123. [Abstract 782]

http://www.medscape.com/viewarticle/506628

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Current Opinion in Gastroenterology

Inflammatory Bowel Disease and Irritable Bowel Syndrome: Separate or Unified?
Sylvie Bradesi, PhD, James A. McRoberts, Ph.D, Peter A. Anton, MD, Emeran A. Mayer, MD

Posted: 07/15/2003; Curr Opin Gastroenterol. 2003;19(4) � 2003 Lippincott Williams & Wilkins

Abstract and Introduction
Abstract
Both irritable bowel syndrome and inflammatory bowel diseases share symptoms of altered bowel habits associated with abdominal pain or discomfort. Irritable bowel syndrome has been referred to as a functional bowel disorder, which is diagnosed by a characteristic cluster of symptoms in the absence of detectable structural abnormalities. Inflammatory bowel disease is a heterogeneous group of disorders characterized by various forms of chronic mucosal and/or transmural inflammation of the intestine. In this review, the authors discuss recent evidence suggesting several potential mechanisms that might play a pathophysiologic role in both syndromes. Possible shared pathophysiologic mechanisms include altered mucosal permeability, an altered interaction of luminal flora with the mucosal immune system, persistent mucosal immune activation, alterations in gut motility, and a role of severe, sustained life stressors in symptom modulation. It is proposed that similarities and differences between the two syndromes can best be addressed within the framework of interactions between the central nervous system and the gut immune system. Based on recent reports of low-grade mucosal inflammation in subpopulations of patients meeting current diagnostic criteria for irritable bowel syndrome, therapeutic approaches shown to be effective in inflammatory bowel disease, such as probiotics, antibiotics, and antiinflammatory agents, have been suggested as possible therapies for certain patients with irritable bowel syndrome.

Introduction
Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent two conditions characterized by chronically recurring symptoms of abdominal pain, discomfort (urgency and bloating) and alterations in bowel habits. However, whereas IBD is characterized by inflammation or ulcerations in the small and/or large intestine, such "organic" changes have traditionally not been associated with IBS. IBD is usually classified as ulcerative colitis or Crohn disease, but it also includes forms of microscopic colitis, eg, histologic evidence of mucosal inflammation without macroscopic abnormalities. IBD is characterized by a constellation of patient-reported history and endoscopic, histopathologic, and radiologic findings, often with serologic correlates. Classic signs that reflect the inflammatory process within the gastrointestinal tract are rectal bleeding, diarrhea, fever, and weight loss, occasionally associated with extraintestinal manifestations. Interestingly, in the absence of complications, abdominal pain is not necessarily the most prominent symptom in IBD, despite extensive mucosal inflammation and presumably sensitization of peripheral visceral pain pathways. Genetic predisposition, environmental factors, infectious agents, altered gut epithelial permeability, and impaired immune responses have been incriminated in the still unclear cause of IBD.

By contrast, IBS, classified as functional (as opposed to organic) bowel disorder, is currently diagnosed on the basis of a characteristic cluster of symptoms in the absence of detectable structural abnormalities. As a matter of fact, according to the currently used symptom criteria (Rome criteria), once organic changes are detected, a diagnosis of a functional syndrome can no longer be made.[1] Because of the nonspecificity of the cardinal symptoms of abdominal pain or abdominal discomfort (the latter including bloating-type symptoms, a sensation of rectal urgency, or incomplete evacuation), the current diagnosis of IBS applies to a heterogeneous group of patients, even after attempts to define subgroups based on predominant bowel habit. Current theories to explain the pathophysiology of IBS include alteration in visceral perception, gastrointestinal motility and gut epithelial and immune function. Considerable evidence supports a role of psychosocial and physical (ie, gastroenteric infections) stressors as central and peripheral triggers, respectively, of first symptom onset or exacerbation.[2*] As reflected by an increasing number of publications on the subject, considerable interest in the putative role of low-grade chronic inflammation in the pathogenesis of IBS has recently emerged.[3] Enhanced responsiveness to psychosocial and physical stressors has been suggested as a plausible mechanism that could explain most clinical and experimental findings in IBS, and that is consistent with the majority of the reported physiologic alterations.[4]

Evidence of Mucosal Immune Activation in Patients Meeting Symptom Criteria for Inflammatory Bowel Diseases
Several recent independent studies have demonstrated alterations in the gut-associated immune system. Quantitative assessment in unselected patients with IBS have shown increased mast cell numbers in the ileum[5] and colonic mucosa.[6] Preliminary evidence suggests an increase of overall cellularity in the colonic mucosa[7] and a higher number of mast cells containing tryptase (known to have proinflammatory effects) in the colonic lamina propria of patients with IBS.[8] Additional preliminary results indicate a significant increase of inducible nitric oxide synthase (iNOS) expression in the colonic mucosa from unselected patients with IBS compared with control patients.[9] In the human colon, upregulation of iNOS has been implicated in inflammatory processes, and increased expression has been documented in IBD.[10] More recently, a study by Chadwick et al. [11*] demonstrated intestinal mucosal immune activation in 77 symptomatic patients meeting the Rome criteria (the authors did not specify Rome I vs II criteria). The study included patients with diarrhea, constipation, or both. In 38 of the patients (50%), a normal conventional histologic appearance was seen, but the immunohistologic results were abnormal (intraepithelial lymphocytes-IEL, lamina propria CD25+ and CD3+ lymphocytes). In 40% of patients, nonspecific microscopic inflammation was seen, whereas immunohistologic results showed similar increases in lymphocyte populations as in the first group. However, in contrast to the first group, they also showed increased numbers of neutrophils and mast cells. Ten percent of patients fulfilled the histologic and immunohistologic criteria for lymphocytic colitis. Even though the magnitude of changes in cell numbers was far less than observed in patients with IBD, the increased numbers of IEL, T cells, IL-2 receptor expressing cells, suppressor/cytotoxic T cells, and NK cells were consistent with an increased inflammatory cell presence in a subset of patients with altered bowel habits who met the symptom-based Rome criteria. Because a significant number of patients meeting the Rome criteria also met the histologic criteria for a diagnosis of lymphocytic colitis, the findings highlight a major problem with the way we currently diagnose IBS. By definition, the diagnosis of an organic disease such as lymphocytic colitis is inconsistent with a diagnosis of IBS. Furthermore, it is unclear whether the patients met the Rome criteria because of the presence of discomfort (urgency, bloating) relieved by bowel movements, or whether they reported abdominal pain. Using the current Rome criteria, a diagnosis of IBS can be made in any patient experiencing abdominal discomfort (for example, in the form of urgency or bloating-type symptoms), that is relieved by a bowel movement. In the absence of mucosal histology to rule out macroscopic or microscopic forms of colitis, such a symptom cluster is likely to include a wide range of syndromes with different causes and pathologic mechanisms.

Another study reported neuromuscular and inflammatory abnormalities in the small bowel of 10 patients (8 women; age range 24-55 years) with severe IBS symptoms.[12] Surprising for an IBS population, the symptoms apparently were severe and refractory enough to justify a laparoscopic full-thickness biopsy. The durations of IBS symptoms ranged from 2 to 30 years, and the predominant bowel habits included constipation, diarrhea, and alternating bowel habits. In this study, analysis of full-thickness biopsy specimens of the jejunum from IBS patients (diagnosis having been made on the basis of absence of detectable structural lesions and fulfillment of the Rome I criteria for IBS) showed several histopathologic abnormalities. The authors reported in most patients some neural degeneration in the ganglia of the myenteric plexus associated with infiltration of CD3+ T lymphocytes and longitudinal muscle hypertrophy. In some cases, IEL numbers were increased, and the numbers of interstitial cells of Cajal were also increased. There are two major problems with the reported findings. First is the absence of an appropriate control group. For example, the observed mucosal alterations in the proximal jejunum were compared with biopsy specimens obtained from the distal ileum during colonoscopy, and alterations in the jejunal wall were compared with findings obtained in tissues from deceased patients (of unspecified sex and age). Second, as admitted by the authors, the patients in this study represented a highly selected group with severe symptoms that were apparently refractory to current management. Even though it was stated that patients had normal or nonspecific changes on small intestinal manometry, it is conceivable that the patients had a mild or early form of chronic intestinal pseudoobstruction. Analogous to the comments made above about the nonspecificity of the Rome criteria to differentiate microscopic colitis from IBS, the same argument could be made for chronic intestinal pseudoobstruction.

Patients in another group, frequently discussed as evidence for a possible role of altered gut immune function in IBS, are those in whom IBS-like symptoms develop after a documented gastroenteric infection (so-called postinfectious IBS [PI-IBS] patients). A history of acute gastroenteritis caused by a variety of bacterial infections as well as parasitic infections was found to increase the risk of the development of persistent IBS symptoms. The risk factors associated with PI-IBS include female gender, duration of the acute illness episode, and a major stressful life event at the time of the infection. Patients with PI-IBS have been reported to show changes in gut motility (eg, reduced rectal compliance) and epithelial function and an increase in enterochromaffin cells.[13, 14] In addition, mucosal immune parameters in these patients exhibit changes that include altered macrophage (CD68) and T lymphocyte (CD3, CD4, CD8) populations and increased expression of IL-1 mRNA.[15] Some of these changes, as well as symptoms of diarrhea, were shown to persist for more than a year in some cases, suggesting chronic immune system activation.[15] Although the mechanisms involved in the ongoing inflammation after clearance of the infectious agent remain unclear, it has been suggested that a subset of IBS patients may have a genetic predisposition to inflammatory dysregulation. Preliminary evidence suggests a reduced frequency of the high producer allele for the antiinflammatory cytokines IL-10 and TGF-, suggesting a reduced production of these cytokines in patients with IBS compared with healthy control subjects.[16] Several important questions have to be addressed before the existence of a distinct pathophysiologic entity of PI-IBS can be confirmed. (1) Even though persistence of low-grade inflammation has been described in individuals who continued to be symptomatic, a causal role of these mucosal changes with IBS symptoms has not been demonstrated.[14, 15] Preliminary reports from a therapeutic trial with an antiinflammatory agent in PI-IBS did not demonstrate any effect on symptoms.[17] (2) There is currently no evidence of visceral hypersensitivity in this patient group, and the reported lower volume thresholds for discomfort simply reflect a reduced rectal compliance. (3) It is unclear whether patients who report their first onset of IBS symptoms after an enteric infection have a history of other intestinal or extraintestinal functional syndromes (such as dyspepsia or chronic constipation) or anxiety disorders. In this case, the persistence of bowel symptoms may simply be a reactivation of a preexisting functional syndrome.

Tibble et al. [18**] compared a large population of patients with altered bowel habits meeting the Rome I criteria for IBS and patients with different organic diseases of the intestine, including IBD, cancer, infectious diarrhea, and celiac disease. They observed that markers for intestinal inflammation, such as fecal calprotectin levels, were elevated in the majority of patients with organic gastrointestinal conditions and decreased in the majority of patients with IBS. The sensitivity and specificity of fecal calprotectin levels for organic intestinal disease were 89% and 79%, respectively. However, the authors observed a significant number of IBS patients whose fecal calprotectin levels were above a normal cutoff value, suggesting some degree of inflammation.

Taken together, the above findings are most consistent with the concept that in a subset of patients meeting the current diagnostic criteria for IBS, chronic low-grade immune activation may be associated with chronic changes in gut motor and secretory function resulting in chronic abdominal discomfort associated with altered bowel habits. However, a causal relationship between visceral hypersensitivity and chronic immune activation has not been demonstrated.

Altered Immune System and Inflammation in Inflammatory Bowel Diseases
Classic histopathologic inspection of tissue from patients with IBD reveals vasodilatation, venocongestion, edema, infiltration of large numbers of inflammatory cells (lymphocytes as well as macrophages and monocytes), and architectural disarray, often with mucosal erosions and/or frank ulcerations. Although the causative triggers remain unclear, the role of a persistent and likely dysregulated mucosal immune response is central to the pathogenesis of IBD. However, it remains unclear whether the persistent inflammation, an intrinsic feature of IBD, reflects a primary aberration in mucosal response or results from an inappropriate persistent stimulation. Accumulating evidence indicates that excessive activation of immunoinflammatory responses in IBD may be initiated by luminal flora. In this regard, recent data showed no difference in the overall composition of mucosal flora in patients with IBD and control subjects but demonstrated a higher concentration of mucosa-associated bacteria in patients with IBD.[19] The authors suggest that the changes in the concentrations of mucosal flora in IBD are not secondary to inflammation but result from a host-specific altered immunoinflammatory mucosal response to "self-flora" in susceptible individuals. The role of genetic factors continues to be explored, with disease susceptibility associated with genetic markers for particular subsets of IBD patients. Recent studies using genome-wide screening provided the first link between NOD2 mutations and the clinical characterization of Crohn disease.[20, 21] NOD proteins are thought to be cytosolic receptors for bacterial signals, and NOD2 is expressed in monocytes and activates nuclear factor kB (NF-kB). However, the mechanisms by which NOD2 mutations contribute to Crohn disease need further investigation. It has been hypothesized that different concentrations of bacteria in the ileum relative to the colon may contribute to the association between NOD2 mutations and ileal disease. A genetic background was also identified in ulcerative colitis associated with HLA genes and regions of the chromosomes 3, 7, and 12.[22] In a recent review, Ardizzone et al. [23**] compiled the genetic factors recently involved in the pathogenesis of IBD. Considering the central role of cytokines in modulating intestinal inflammation, several studies have focused on cytokine genes, looking for mutations or polymorphisms and expression dysregulation.[24] In Crohn disease, an increased expression of T-helper-1 (Th1) cytokines was initially described, whereas an atypical Th2 response was associated with ulcerative colitis, but this assessment is now thought to be too simplistic. Cytokine gene-regulated differences between and within the diseases are clearly more complex. Advances in the understanding of the immune response in IBD have stimulated the development of new therapeutic agents directed against key players in the inflammatory process. A range of therapeutic strategies to block the biosynthesis or action of proinflammatory cytokines, acting directly or though targeting immunoregulatory cytokines, has been developed.[25]

Among specific targets, tumor necrosis factor- (TNF-) was among the first mucosal cytokines identified as critical in the development and amplification of mucosal inflammation in IBD.[26] Recent clinical trials showed that anti-TNF- antibodies provide marked clinical benefits in some patients with Crohn disease: a translational insight that has now become commonplace in IBD clinical therapy.[27, 28] An inhibitor of mitogen-activated protein kinase (MAPK) appears to be another candidate in novel therapeutic strategies. A beneficial effect of CNI-1493 (MAPK inhibitor) in patients with severe Crohn disease was recently described.[29] A better characterization of the molecular signaling pathways involved in the activation of key immune and inflammatory cells will indubitably provide new targets for the development of therapeutic agents for IBD.

What Unifies and Separates Irritable Bowel Syndrome and Inflammatory Bowel Diseases
Possible Role of Failure to Downregulate Immune Response
A comparison of published data on the activation of the gut-associated mucosal immune system in IBS and IBD reflects both the similarities and the differences in the altered immune response observed in these disorders. However, the triggering factor initiating the inflammatory response remains unclear. In IBS, an immune response to infection,[30] a disinhibition of the immune system during chronic sustained stress (Fig. 1), or a combination of both are plausible mechanisms that could result in the initial immune activation. The persistence of low-grade inflammation after pathogen clearance or after resolution of the psychosocial stressor, in a subset of individuals, may be related to an inability to efficiently downregulate the inflammatory response. This inability may be related to genetic factors or to early programming of antiinflammatory systems, such as the hypothalamic-pituitary-adrenal (HPA).[31*] For example, a hyporesponsive HPA axis in the Lewis rat has been shown to be associated with exaggerated immune responses to various stimuli, including chemically induced colitis.[32] The most recent available data on IBD increasingly emphasize the role of immunogenetics in the predisposition, modulation, and perpetuation of the disease.[33] The abnormal amplification and persistence of inflammation leading to tissue injuries likely reflects the continuing presence of the driving stimulus and self-reinforcing activation of mucosal inflammatory cells mediated by increased expression of cytokines.

Figure 1. Brain-gut immune interactions in irritable bowel syndrome and inflammatory bowel disease: effect of chronic stress on the mucosal immune system. Acute stress causes increases in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of the two branches of the autonomic nervous system (ANS), the sympathetic nervous system (SNS), and the parasympathetic (vagal) system. In patients with irritable bowel syndrome, the peripherally acting products of each of these pathways (cortisol, CORT; norepinephrine, NE; acetylcholine, Ach) can inhibit the mucosal immune system, especially Th1-type responses. This results in a temporary shift toward Th2 cytokine responses (IL-4 and others) that are not as strongly inhibited and that can further inhibit Th1 responses. In patients with inflammatory bowel diseases, the corticotropin-releasing factor (CRF) response may be blunted, leading to diminished CORT and NE release. These changes favor the production of Th1 cytokines and the proliferation of macrophages, natural killer (NK) cells, and cytotoxic T cells (Tc). TNF, which is produced by activated macrophages but can also be released by activated mast cells, stimulates the production of IL-1 (in the Th1 pathway) and IL-6 (by lymphoid and nonlymphoid tissues). With chronic stress in both types of patients, the shift to a Th1 response becomes predominant, with positive feedback loops developing between the gut and the brain. The restraints on immune cell proliferation and activation are compromised by blunting of the HPA axis response due to downregulation of pituitary CRF1 receptors, decreased vagal tone, and downregulation of 2-adrenergic receptors (2-AR) on Th1 immune cells by chronically elevated catecholamines. Circulating levels of TNF-, IL-1, and IL-6 increase to concentrations that synergistically stimulate CRF production in the PVN of the hypothalamus. In irritable bowel syndrome, TNF and IL-1 sensitize primary afferent terminals through long-lasting effects on gene expression, including the expression of neurokinin receptors. Locally acting mast cell products (tryptase and histamine) and proinflammatory compounds (PGE2) can also sensitize primary afferents. Both IFN (Th1 cytokine), which is produced by NK cells in response to TNF, and IL-4 (a Th2 cytokine) have been shown to decrease mucosal barrier function by increasing epithelial permeability,[54,55] thus perpetuating a local inflammatory response by allowing entry of bacteria and bacterial products. Subjective pain responses to peripheral sensitization of visceral afferents in irritable bowel syndrome and inflammatory bowel diseases are likely to be modulated differentially by endogenous pain modulation pathways. DMN, dorsal motor nucleus of the vagus; ACTH, adrenocorticotropin hormone.
Increased Permeability
For both syndromes, histologic and functional alterations of the mucosal barrier have been recently reported.[11*, 12, 24, 25] Small intestinal permeability is abnormal in a wide variety of conditions affecting the small intestine, including celiac disease, Crohn disease, and intestinal infections.[18**] Interestingly, gut permeability assessed by the lactulose/mannitol ratio is significantly elevated in PI-IBS patients.[15] This functional alteration of the intestinal barrier function may be a cause or consequence of inflammation, and a direct link between increased intestinal permeability and the exaggerated immune activation in IBD still needs to be confirmed. In addition to a causative role of peripheral factors, gut permeability changes in animal models have also been reported in response to various stressors. For example, in a rat model of chronic stress, an increase in intestinal epithelial permeability, associated with an increase in mucosal neutrophils and mast cells, has been demonstrated.[34**] In this model, the combination of stress-induced increases in intestinal permeability, allowing easier access of antigens to gut-associated macrophages and dendritic cells, together with stress-induced changes in HPA axis responsiveness and cytokine profiles, resulted in the development of colitis, without any additional chemical or immunologic manipulations. Rats with a history of aversive early life events were more susceptible to these stress-induced changes in gut permeability,[35*] possibly related to early programming of the HPA axis.[31*]

Changes in Luminal Flora
A change in intestinal microflora has been implicated, in association with genetic factors, as a putative mechanism responsible for the initiation and persistence of inflammation in IBD. Indeed, it has been suggested that the failure to maintain immunologic tolerance toward the indigenous microflora leads to a disease-associated dysregulation of the gut-associated immune system. Direct and indirect evidence of altered flora of the large and small intestine has been reported in IBS patients. For example, Balsari et al. [36] observed a decrease in coliforms, lactobacilli, and, to some extent, bifidobacteria in a small group of IBS patients. More recently, preliminary evidence of an alteration of bacterial concentration in colonic biopsy specimens from IBS patients has been reported.[37] Indirect evidence for bacterial overgrowth of the small intestine (in the form of altered hydrogen breath test results) has been reported in patients with IBS, and a recent randomized controlled trial found evidence that antibiotic treatment was beneficial for IBS symptoms of bloating and discomfort.[38] Based on the concept of altered interactions between the colonic flora and the gut-associated immune system, probiotics have been proposed as an alternative strategy for the treatment of several gastrointestinal diseases, including IBD[39] and more recently IBS.[40, 41] However, the reported results are conflicting, and only a small number of double-blind controlled clinical trials support a beneficial health effect in IBD or IBS.[42] The epithelium has recently been recognized as playing an important role in innate immune responses in response to intestinal microorganisms.[43, 44] It expresses a variety of receptors (Toll-like receptor) involved in the recognition of a spectrum of microbial products. This recognition capability may enable an appropriate cytokine and chemokine secretion in response to changes in luminal flora.

Influence of Sustained Psychosocial Stressors on Mucosal Immune System Activation
Even though stress has been less recognized as a factor in the natural history of IBD, considerable evidence supports a prominent role for it in the pathophysiology and clinical presentation of both IBD and IBS symptoms.[45] Patients with IBS seem to have a greater reactivity to stress than do control subjects or IBD patients. Yet, sustained psychologic stressors have been associated with the onset and exacerbation of symptoms in both IBS and IBD.[46-48] The development of persistent IBS symptoms after acute gastroenteritis has been associated with major life events around the time of infection.[14] Similarly, for IBD, a wide range of clinical studies indicates a strong link between sustained psychosocial stressors and IBD activity.[49] Levels of long-term perceived stress have been shown to correlate with changes in mucosal appearance and relapse in ulcerative colitis.[50*] Further evidence of an influence of stress on inflammatory processes comes from animal studies showing a modulation of the immune function at different levels, including immune cell distribution, cytokine profiles, or susceptibility to infection in na�ve or colitic animals.[51] In view of the established concept of an altered immune response in IBD patients, and the suspected low-grade inflammation in some patients meeting the symptom criteria for IBS, it is reasonable to consider a bidirectional model of brain-gut interactions as an important determinant of gut-associated immune activation in both disorders.

Chronic Inflammation and Alteration of Sensory-Motor Functions of the Gastrointestinal Tract
Despite the common assumption that chronic gut mucosal inflammation is associated with sensory-motor dysfunction of the gastrointestinal tract in inflammatory as well as functional intestinal disorders, the relationship between chronic inflammation and the generation of gastrointestinal symptoms remains unclear. The development of IBS-like symptoms in some patients with quiescent ulcerative colitis was suggested as an indication of the role of inflammation on altered sensory and motor function.[8] The concept of long-lasting postinflammatory changes in gut motility is supported by the observation of altered anorectal and colonic motility in patients in remission from ulcerative colitis and Crohn disease.[52] However, chronic abdominal pain and visceral hypersensitivity-classic features in patients with IBS-do not appear to be a hallmark of ulcerative colitis or Crohn disease.[53] One may speculate that various patient populations with different degrees of intestinal inflammation (patients with IBD and PI-IBS, and possibly small subsets of those with IBS) do not necessarily experience pain and discomfort from these mucosal changes. Whereas the effects of the immune activation are likely to affect enteric nervous system circuits and smooth muscle function, altering intestinal compliance and reflex activity and producing such symptoms as diarrhea and urgency, the effects on visceral perception are less predictable. An important variable in symptom generation is the differences in the ability of the brain and its endogenous pain inhibitory pathways to counteract the changes in peripheral viscerosensory pathways.

Conclusion
The recent observation of an activated immune system in some IBS patients associated with persistent low-grade mucosal inflammation provides evidence for the reconsideration of the symptom-criteria-based diagnosis of functional bowel disorders. The development and use of biologic markers identifying low-grade inflammation would improve the characterization of subsets of IBS patients in whom peripheral mechanisms may participate in specific symptom genesis and could be considered in the choice of the therapy.

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Authors and Disclosures
Sylvie Bradesi, PhD*; James A. McRoberts, Ph.D*; Peter A. Anton, MD*; Emeran A. Mayer, MD*

CNS: Center of Neurovisceral Sciences & Women's Health, Division of Digestive Diseases and Brain Research Institute, Departments of Medicine*, Physiology, and Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA

Reprint Address
Emeran A. Mayer, MD, CNS: Center of Neurovisceral Sciences and Women's Health, VAGLAHS, Bldg.115/CURE, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA;

Abbreviation Notes
HPA: hypothalamic-pituitary-adrenal; IBD: inflammatory bowel diseases; IBS: irritable bowel syndrome; IELs: intraepithelial lymphocytes; iNOS: inducible nitric oxide synthase; MAPK: mitogen-activated protein kinase; PI-IBS: postinfectious irritable bowel syndrome; Th1: T helper 1; TNF-

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