Pathogenesis of Microscopic Colitis: A Systematic Review.

BACKGROUND: Whereas the exact aetiology of microscopic colitis [MC] remains unknown, a dysregulated immune response to luminal factors or medications is the most accepted pathogenesis hypothesis. METHODS: We conducted a systematic review of the pathogenesis of MC. We applied the Joanna Briggs Institute methodologies and the PRISMA statement for the reporting of systematic reviews [PROSPERO Trial Identifier: CRD42020145008]. Populations, Exposure of interest, and Outcome [PEO] questions were used to explore the following topics in MC: 1] intestinal luminal factors; 2] autoimmunity; 3] innate immunity; 4] adaptive immunity; 5] extracellular matrix; 6] genetic risk factors; and 7] mechanism of diarrhoea. A search was done in PubMed, Embase, and Web of Science up to February 2020. A narrative description was performed explaining the findings for each aspect of MC aetiopathogenesis. RESULTS: Thirty-eight documents provided evidence for PEO1, 100 for PEO2, 72 for PEO3 and 4, 38 for PEO5, 20 for PEO6, and 23 for PEO7. The majority of documents were cohorts, case reports, and case series, with a few case-control and some experimental studies. Consistency among data provided by different studies was considered to support pathogenetic hypotheses. MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea. CONCLUSIONS: This is the first systematic review on the aetiology of MC supporting the notion that MC is a multifactorial disease. However, high-profile studies are lacking, and most evidence derives from small heterogeneous studies.

Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.

BACKGROUND AND AIMS: The causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: In total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.

Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria.

BACKGROUND: An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. METHODS: We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNγ and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFα+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). RESULTS: IBD transformers had increased IFNγ+, T-bet+, TNF-α+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFNγ+ and GATA-3+ cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-α+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-α+ and RORc+ cells were seen in LC than in CC. CONCLUSION: Th1/Tc1- and TNFα-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.

Diagnosis and Management of Microscopic Colitis.

Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea, especially in older persons. Associated symptoms, including abdominal pain and arthralgias, are common. The diagnosis is based upon characteristic histological findings in the presence of diarrhea. The two types of MC, collagenous and lymphocytic colitis, share similar clinical features, with the main difference being the presence or absence of a thickened subepithelial collagen band. There are several treatment options for patients with MC, although only budesonide has been well studied in multiple controlled clinical trials. This review will describe the clinical features, epidemiology, pathophysiology, diagnostic criteria, and treatment of patients with MC.

Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

Early, non-refractory celiac disease associated with microscopic colitis and splenomegaly.

Celiac Disease (CD), also known as non-Tropical sprue, and Celiac sprue is an immune-mediated disorder, triggered by gluten containing grains in genetically susceptible people. The disease may be diagnosed at any age and can affect many organ systems. Its diagnosis and management can often be challenging. A high index of suspicion is required to diagnose this disease at an early stage in patients presenting with atypical symptomatology and delayed onset. Although serological tests are widely used, duodenal biopsy remains the gold standard for diagnosis of CD. Even though CD affects various body systems, Microscopic Colitis (MC) and refractory sprue are among the main gastrointestinal complications of CD, which are resistant to Gluten-Free Diet (GFD). A thorough and appropriate evaluation is mandatory for an early and accurate diagnosis of these complications. Herein, we report a case of a young female with CD in early phase in concordance with MC and splenomegaly.

Reduced T cell receptor excision circle levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosa.

Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic biopsies from CC (n = 8), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 3) (LC-HR, n = 6), non-inflamed diarrhoea patients (n = 17), and controls (n = 10) by real-time PCR. We observed lower median TREC levels in both CC and LC patients as well as in LC-HR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did, however, reach statistical significance. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined and reached statistical significance in LC patients compared to controls. In conclusion, reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67(+) T cells, suggests local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.

Auto-antibodies and their association with clinical findings in women diagnosed with microscopic colitis.

BACKGROUND: Microscopic colitis (MC) is a disease manifested by diarrhoea and is divided into collagenous and lymphocytic colitis. The aetiology is unknown, but auto-immunity is suggested. Auto-antibodies have been only rarely examined in this entity. The aim of the study was to examine the prevalence of auto-antibodies, and to examine associations between the presence of antibodies and clinical findings. METHODS AND FINDINGS: Women with MC verified by biopsy and younger than 73 years, at any Department of Gastroenterology, in the district of Skåne, between 2002 and 2010 were invited to participate in this study. The patients were asked to complete both a questionnaire describing their medical history and the Gastrointestinal Symptom Rating Scale (GSRS). Blood samples were collected. Anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), and antibodies against glutamic acid decarboxylase (anti-GAD), islet antigens-like insulin 2 (anti-IA2), thyroid peroxidase (anti-TPO), and thyrotropin receptor (TRAK) were analysed. Of 240 women identified, 133 were finally included in the study, median age 63 (59-67) years. Apart from the MC diagnosis, 52% also suffered from irritable bowel syndrome, 31% from hypertension and 31% from allergy. The prevalence of ANA (14%), ASCA IgG (13%), and anti-TPO antibodies (14%) for these patients was slightly higher than for the general population, and were found together with other concomitant diseases. Patients had more of all gastrointestinal symptoms compared with norm values, irrespective of antibody expression. CONCLUSIONS: Women with MC have a slightly increased prevalence of some auto-antibodies. These antibodies are not associated with symptoms, but are expressed in patients with concomitant diseases, obscuring the pathophysiology and clinical picture of MC.

Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

BACKGROUND: Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients. METHODS: Mucosal biopsies from CC (n=10), LC (n=5), and CC or LC patients in histopathological remission (CC-HR, n=4), (LC-HR, n=6), ulcerative colitis (UC, n=3) and controls (n=10) were analysed by real-time PCR and Luminex for expression/production of IL-1ß, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-γ, TNF-α, T-bet and RORC2. RESULTS: Mucosal mRNA but not protein levels of IFN-γ and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1ß mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-γ, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients. Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-α protein was increased in CC, LC as well as in UC patients. Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production. CONCLUSION: LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

Gastrointestinal symptoms and psychological well-being in patients with microscopic colitis.

OBJECTIVE: Microscopic colitis (MC) and irritable bowel syndrome (IBS) are both gastrointestinal disorders with female predominance that affect well-being. Autoantibodies against gonadotropin-releasing hormone (GnRH) have recently been detected in IBS patients. The purpose of this study was to compare gastrointestinal symptoms and well-being in MC female outpatients, with or without coexisting IBS-like symptoms, and to examine the prevalence of GnRH antibodies in these patients. MATERIAL AND METHODS: Women with biopsy-verified MC, at any outpatient clinic of the Departments of Gastroenterology, Skåne, between 2002 and 2010 were invited to participate in the study. The questionnaires Gastrointestinal Symptom Rating Scale (GSRS), Psychological General Well-being Index (PGWB), Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS), and Rome III were answered and blood samples collected. Autoantibodies (IgG, IgA, and IgM) against GnRH and GnRH-R (extracellular peptide of receptor) were determined by an enzyme-linked immunosorbent assay. RESULTS: Altogether, 158 (66%) of 240 invited patients with MC were recruited to the study. Of these, 133 (55%) patients also accepted to provide blood samples. Patients with IBS-like symptoms (55%) experienced more symptoms and worse psychological well-being in all dimensions in GSRS and PGWB, and in all symptoms but constipation in VAS-IBS compared to patients without IBS symptoms. Only a minority of patients expressed antibodies against GnRH or GnRH-R, which did not differ between groups. CONCLUSIONS: MC patients fulfilling criteria for IBS experience more gastrointestinal symptoms and worse psychological well-being than those who do not. Autoantibodies against GnRH or GnRH-R are not frequently observed in MC patients.

Foxp3 expression patterns in microscopic colitides: a clinicopathologic study of 69 patients.

Microscopic colitides, including lymphocytic (LC) and collagenous colitis (CC), are well-described pathologic conditions. An altered immune response is implicated in the pathogenesis of both entities. CD8+ T lymphocytes (CTLs) secrete interleukin 2 which stimulates proliferation of regulatory T cells (Tregs), and Tregs, in turn, inhibit CTLs, inducing cytotoxic tissue damage. In Tregs, Foxp3 regulates T-cell-related immune responses. The distribution of Tregs and CTLs in microscopic colitides has remained underexplored. To characterize differences in the distribution pattern of Foxp3 in biopsy specimens from patients with LC and CC, 71 colonic biopsy specimens from 69 consecutive patients were categorized into 1 of 3 diagnoses: no significant histopathologic abnormality (NSHPA), LC, or CC. Further immunohistochemical evaluation of all biopsy specimens was conducted using a panel of markers including CD8 and Foxp3. Our study demonstrated that CTL distribution pattern differences exist among these 2 colitides and that differences in the immunologic recruitment of Foxp3+ Tregs in the colonic mucosa correlate with differences in the spectrum of morphologic changes seen in patients with either LC or CC.

Lymphocytic and collagenous colitis: an overview of so-called microscopic colitis.

The entity of 'microscopic colitis' is being diagnosed with increasing frequency and is a well-established clinicopathological diagnosis that is underpinned by a triad of watery diarrhea, normal results on endoscopy and characteristic microscopic findings. Careful histopathological evaluation and awareness of its numerous associations (especially with drugs and celiac disease) and mimics will lead to the correct diagnosis of microscopic colitis. The etiology of microscopic colitis remains enigmatic and is multifactorial with different elements being more influential in different individuals. Treatment includes antidiarrheal agents and anti-inflammatory drugs (including steroids). The purpose of this article is to provide some clarity on nomenclature, discuss the multitude of conditions that can occur synchronously or metachronously with microscopic colitis and their role in the etiopathogenesis of this condition, provide a detailed review of the pathological aspects of the disease and to briefly discuss treatment trends.

Anti-Yersinia antibodies are not associated with microscopic colitis in an American case-control study.

BACKGROUND: Microscopic colitis (MC), which consists of lymphocytic colitis and collagenous colitis, may be triggered by gastrointestinal infections. Studies have suggested a relationship between MC and Yersinia enterocolitica infection. We tested this hypothesis in a case-control study of American patients with MC. METHODS: Serum was collected from 47 patients with MC and 44 age- and gender-matched healthy controls at a large referral center in the mid-western United States. Anti-IgA and IgG antibodies to Y. enterocolitica were measured using an enzyme-linked immunosorbent assay (ELISA). Fisher's exact test was used to assess statistical significance. RESULTS: There were no differences between the two groups for seroprevalence of anti-Yersinia IgA (cases 2.1%, controls 2.3%, p = 1.00) or IgG antibodies (cases 4.3%, controls 6.8%, p = 0.67). There was no correlation between antibody titers and duration of MC diagnosis. CONCLUSION: Our data do not support the role of exposure to Y. enterocolitica in an American group of patients with MC.

Celiac disease and microscopic colitis: a report of 4 cases.

Celiac disease (CD) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people at all ages. However, it can be associated also to other immunopathological disorders, and may be associated with abnormal histology in segments of the gut other than the small bowel including colonic inflammation. While guidelines for endoscopic investigation of the jejunum are well defined, no indication is defined for colonic investigation. We describe four cases of concurrent CD and microscopic colitis (MC) diagnosed at our department over a 10-year period and analyzed the main features and outcomes of CD in this setting. The symptoms of these patients were improved initially by a gluten-free diet before the onset of MC symptoms. Two of the patients were siblings and had an atypical form of CD. The other two patients with CD and MC also presented with fibrosing alveolitis and were anti-Saccharomyces cerevisiae antibody positive. The co-existence of immune-mediated small bowel and colonic inflammatory and pulmonary diseases are not well-known, and no systematic approach has been used to identify the lifelong patterns of these immune-based diseases. Patients can develop, or present with CD at any stage in life, which can co-exist with other gastrointestinal diseases of (auto-) immune origin. In addition, the familial co-existence and prevalence of MC in patients with a prior diagnosis of CD are unclear. Clinicians managing celiac disease should be aware of these associations and understand when to consider colon investigation.

Cytokine gene polymorphism in microscopic colitis association with the IL-6-174 GG genotype.

OBJECTIVES: Microscopic colitis (MC) is a chronic inflammatory disease with unknown pathogenesis. Very little is known about polymorphisms in the cytokine genes in MC. We have investigated the occurrence of well-characterized polymorphisms of interleukins (IL-6, IL-1ß, IL-1 receptor antagonist, IL-10) and CD14 in MC. We also determined the serum IL-6 levels. METHODS: We genotyped 81 patients with MC and 178 controls for polymorphisms of IL-6-174, IL-1ß-511, IL-1ß-3953, IL-1 receptor antagonist, IL-10-1082 and CD14-159. Serum concentration of IL-6 was measured in 72 patients. RESULTS: Genotype GG of IL-6-174 was more prevalent in MC compared with the controls (P=0.030; odds ratio: 1.941; confidence interval: 1.078-3.495), and the frequency of allele G of IL-6-174 was higher in MC (0.55 vs. 0.47; P=0.036; odds ratio: 1.514; confidence interval: 1.041-2.203). However, after correction for multiple comparisons, the difference became nonsignificant. IL-6 genotype and the serum IL-6 concentration showed no association. The concentration of IL-6 was higher in patients with collagenous colitis than in those with lymphocytic colitis (median 1.73 vs. 1.34 pg/ml, P=0.011). No association between polymorphisms of other cytokine genes and MC was seen. CONCLUSION: The IL-6-174 gene polymorphism has a possible association with MC, as the IL-6 GG genotype was more frequent in patients with the disease. As this genotype may be linked with an enhanced IL-6 production, we speculate that this polymorphism can influence the pathogenesis of MC by evoking a proinflammatory bias in the mucosal cytokines. The enhanced concentration of IL-6 in collagenous colitis compared with lymphocytic colitis supports a difference in the pathogenetic mechanisms between the two subgroups of MC.

Defining eosinophilic colitis in children: insights from a retrospective case series.

OBJECTIVES: Although it is a well-described syndrome in infants, eosinophilic colitis is a loosely defined and poorly understood diagnosis in older children. The aims of this case series were to characterise colonic eosinophilia in children and to determine whether it represents a distinct clinicopathological condition. METHODS: We retrospectively reviewed symptomatic children older than 12 months with the principal diagnosis of colonic eosinophilia who presented between January 2000 and February 2007 (n = 38) and a further 10 children whose colonic biopsies were reported as histologically normal. The eosinophil density in all available gastrointestinal biopsies (n = 620) of these children was determined using a validated quantitative morphometric method. Patients were subdivided according to mean colonic eosinophil levels into 3 groups (marked, moderate, or minimal colonic eosinophilia). The following patient information was obtained and compared among patient groups: symptoms prompting endoscopy, atopic history, outcome, serum C-reactive protein and total immunoglobulin E (IgE) levels, erythrocyte sedimentation rate, blood eosinophil count, and endoscopic findings. RESULTS: In all 3 patient groups, there was a colonic gradient of decreasing eosinophil density from caecum to rectum. Upper gastrointestinal tract biopsies did not exhibit eosinophilia. Although a significant association (P = 0.03) between abnormal total IgE levels and moderate or severe colonic eosinophilia was found, there was no significant difference (P > 0.05) in other patient characteristics. Furthermore, follow-up data did not show a consistent relation between eosinophil density and progression of symptoms. CONCLUSIONS: We find no association between "eosinophilic colitis," defined as a histologically demonstrated marked colonic eosinophilia, and symptoms, history of atopy, inflammatory markers, or clinical outcome.

Paucicellular lymphocytic colitis: is it a minor form of lymphocytic colitis? A clinical pathological and immunological study.

OBJECTIVES: It has been suggested that paucicellular lymphocytic colitis (PLC) should be considered to be part of the morphological spectrum of microscopic colitis. The aim of the study was to evaluate whether PLC may be considered to be a true microscopic colitis, and in this case, whether it is a minor form of lymphocytic colitis (LC) or a different entity. METHODS: All incident cases of PLC, LC, and collagenous colitis (CC) during the period 2004-2006 were included. The incidence rate and the clinical, histopathological, and immunological features of PLC were assessed and compared with those of both LC and CC. Immunoreactivities to CD25, c-Kit, and FOXP3 in lamina propria were assessed. RESULTS: In all, 19 patients with CC, 19 with LC, and 26 with PLC were identified. CD25+FOXP3+ expression was seen only in classical forms of microscopic colitis: 12 of 19 LC, 14 of 20 CC, and none of 20 PLC cases (P < 0.0001). Diarrhea ceased in 21 of the 26 patients, with a decrease in the daily stool number from 5.08 +/- 0.44 to 1.7 +/- 0.2 (P < 0.005). The five patients with no response to therapy fulfilled the Rome II criteria of irritable bowel syndrome (IBS). CONCLUSIONS: The incidence rate of PLC, identified using objective histological criteria, was higher than those of CC and LC. The lack of expression of CD25+FOXP3+ cells in PLC, in contrast to those seen in both LC and CC, would suggest the existence of different pathophysiological mechanisms and does not support that PLC is a minor form of LC.

Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms.

OBJECTIVES: Immune activation may be involved in the pathogenesis of irritable bowel syndrome (IBS). However, the relative magnitude of this immune component and its correlation with gender and gastrointestinal complaints in IBS patients remains poorly elucidated. METHODS: We enrolled 48 IBS patients, with either diarrhea or constipation, 12 patients with microscopic colitis, 20 patients with ulcerative colitis, and 24 healthy controls. Colonic immunocytes were identified with quantitative immunohistochemistry on mucosal biopsies. Gastrointestinal symptoms were assessed using a validated questionnaire. RESULTS: IBS patients showed a significant 72% increase in mucosal immune cells compared to controls (P<0.001). Further analyses showed that increased immune cells were present in 50% of the IBS patients. The magnitude of the immune infiltrate in IBS was significantly lower than that of microscopic colitis or ulcerative colitis (42% and 124% increases vs. IBS, respectively; P<0.001). Compared with controls, IBS patients had increased numbers of CD3+, CD4+, and CD8+ T cells and mast cells (P<0.001). Compared to male IBS patients, female IBS patients had greater numbers of mast cells (P=0.066), but lower numbers of CD3+ and CD8+ T cells (P=0.002 and <0.001, respectively). Mucosal mast cell infiltration of IBS patients was significantly associated with abdominal bloating frequency (P=0.022) and with symptoms of dysmotility-like dyspepsia (P=0.001), but not ulcer-like dyspepsia. CONCLUSIONS: A large subset of IBS patients shows gender-dependent mucosal infiltration of immunocytes that correlates with abdominal bloating and dysmotility-like dyspepsia. These results provide the rationale for considering immune mechanisms as a pathophysiological component in a subset of IBS patients.

Microscopic colitis demonstrates a T helper cell type 1 mucosal cytokine profile.

BACKGROUND: Microscopic colitis (MC) is an inflammatory disorder of unknown aetiology. AIM: To characterise the mucosal cytokine profile of MC, with a view to understanding its potential pathogenic mechanisms. METHODS: Cytokine profiles of mucosal biopse specimens taken at flexible sigmoidoscopy from 18 patients (8 with lymphocytic colitis and 10 with collagenous colitis) were analysed using real-time reverse transcriptase-PCR, in comparison with those from 13 aged-matched controls with diarrhoea-predominant irritable bowel syndrome. Biopsy specimens from six patients with histologically documented remission were available for comparative analysis. Biopsy specimens were also taken to determine the cellular expression of cytokine and cytokine-related proteins using immunohistochemistry. RESULTS: Mucosal mRNA levels were 100 times greater for interferon (IFN)gamma and interleukin (IL) 15, 60 times greater for tumour necrosis factor alpha, and 35 times greater for inducible nitric oxide synthase in MC compared with controls. Apart from a trend for increased levels of IL10, levels of other T helper cell type 2 (T(H)2) cytokines including IL2 and IL4 were too low to be accurately quantified. Mucosal IFNgamma mRNA levels correlated with the degree of diarrhoea, and returned to normal in remission. The immunohistochemical expression of cell junction proteins E-cadherin and ZO-1 was reduced in active disease. No differences were noted between lymphocytic and collagenous colitis for any of the above parameters. CONCLUSIONS: MC demonstrates a T(H)1 mucosal cytokine profile with IFNgamma as the predominantly upregulated cytokine, with concurrent induction of nitric oxide synthase and down regulation of IFNgamma-related cell junction proteins. This pattern is similar to that in coeliac disease and suggests that it might represent a response to a luminal antigen.