Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of sigmoid colon mucosal biopsies from irritable bowel syndrome patients and healthy control subjects

ABSTRACT: Irritable bowel syndrome (IBS) is a highly prevalent disorder of the gastrointestinal tract characterized by abdominal pain, bloating, and disturbed bowel function. Here we report on the analysis of microarray expression profiles of sigmoid colon mucosal biopsies from IBS patients and healthy control subjects. Two samples were collected from each individual. From 10 individuals, a third sample was collected 2-3 months after the initial collection. The repeat samples were used to assess the robustness of the expression profiles over different locations within the colon and over time. This analysis revealed a number of differentially expressed genes in IBS patients, which point to functional alterations of specific components of the host defence system and the immune response. This is in support of an important role for peripheral gastrointestinal changes underlying the aetiology of IBS. Two gene probe sets with the most strikingly increased expression in mucosal colon biopsies of IBS patients represent a gene that is, as yet, uncharacterised (DKFZP564O0823). We propose to rename this gene IBS1. We also report on the identification of specific sets of gene probes on the microarray, so-called molecular signatures, which enable the distinction of IBS patients from healthy controls. The expression profiles in IBS are consistent across different sites within the sigmoid colon and are stable over time.

ORGANISM(S): Homo sapiens

SUBMITTER: Jeroen Aerssens

PROVIDER: E-TABM-176 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome.

Aerssens Jeroen J Camilleri Michael M Talloen Willem W Thielemans Leen L Göhlmann Hinrich W H HW Van Den Wyngaert Ilse I Thielemans Theo T De Hoogt Ronald R Andrews Christopher N CN Bharucha Adil E AE Carlson Paula J PJ Busciglio Irene I Burton Duane D DD Smyrk Thomas T Urrutia Raul R Coulie Bernard B

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 20080201 2

<h4>Background & aims</h4>Irritable bowel syndrome (IBS) has been associated with mucosal dysfunction, mild inflammation, and altered colonic bacteria. We used microarray expression profiling of sigmoid colon mucosa to assess whether there are stably expressed sets of genes that suggest there are objective molecular biomarkers associated with IBS.<h4>Methods</h4>Gene expression profiling was performed using Human Genome U133 Plus 2.0 (Affymetrix) GeneChips with RNA from sigmoid colon mucosal bio ...[more]

PMID: 18237869

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Project description:We conducted a microarray study of sigmoid mucosal gene expression in pilot sample of Rome III+ IBS patients and age and sex-matched HCs. This sample was balanced by sex, free of active psychiatric disease and had limited use of medications. Rome III+ IBS patients and HCs ages 18-55 were recruited primarily by community advertisement. Bowel habit subtypes (IBS with diarrhea (IBS-D), constipation (IBS-C) and mixed pattern (IBS-M)) were based on the Rome III criteria. The diagnosis was confirmed by a clinician with expertise in IBS. Rome III+a IBS patients and HCs ages 18-55 were recruited primarily by community advertisement. Bowel habit subtypes (IBS with diarrhea (IBS-D), constipation (IBS-C) and mixed pattern (IBS-M)) were based on the Rome III criteria. The diagnosis was confirmed by a clinician with expertise in IBS. HCs had no personal or family history of IBS or other chronic pain conditions. Additional exclusion criteria for all subjects included: infectious or inflammatory disorders, active psychiatric illness over the past 6 months as assessed by structured clinical interview for the DSM-IV (MINI),b use of corticosteroids in the past six months, use of narcotics, antidepressants or other medications that could affect neuroendocrine function in the past two months, or current tobacco or alcohol abuse. Participants were compensated. Our goal was to evaluate women during the follicular phase or days 4-14 of their menstrual cycle if on oral contraceptive pills. Phase was determined by date of last menstrual period and progesterone levels. The study was approved by the UCLA Institutional Review Board, and all subjects signed a written informed consent prior to start of study. IBS symptom severity over the prior week was assessed with a numeric rating scale (0-20).c Current anxiety and depression symptoms were measured with the Hospital Anxiety and Depression (HAD) scale.d Sigmoid biopsies (30cm from the anal verge) were obtained by flexible sigmoidoscopy following tap water enemas. Specimens were immediately flash frozen in liquid nitrogen. RNA was extracted with TRIzol. Sigmoid biopsies (30cm from the anal verge) were obtained by flexible sigmoidoscopy following tap water enemas. Specimens were immediately flash frozen in liquid nitrogen. Differential expression analysis was done on mRNA only (\\ormalized_Unfiltered_mRNAonly.txt\\) using limma[1]. Weighted gene coexpression network analysis (WGCNA[2]) was done using all targets after removing those on X and Y chromosomes and filtered by mean raw signal >200. 1. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3. 2. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.\

Project description:Study 1: Transcriptomic profiles in colon tissue from inflammatory bowel diseases patients in relation to N-nitroso compound exposure and colorectal cancer risk Study 1: N-nitroso compounds (NOC) have been suggested to play a role in human cancer development but definitive evidence is still lacking. In this study we investigated gene expression modifications induced in human colon tissue in relation to NOC exposure to gain insight in the relevance of these compounds in human colorectal cancer (CRC) development. Since there are indications that inflammation stimulates endogenous NOC formation, the study population consisted of patients with inflammatory bowel disease (IBD) and irritable bowel syndrome patients as controls without inflammation. Strong transcriptomic differences were identified in colonic biopsies from IBD patients and compared to controls that enhance the understanding of IBD pathophysiology. However, fecal NOC levels were not increased in IBD patients, suggesting that inflammation did not stimulate NOC formation. By relating gene expression changes of all subjects to fecal NOC levels, we did, however, identify a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending the molecular basis of NOC-induced carcinogenesis. We conclude that NOC exposure is associated with gene expression modifications in the colon that may increase CRC risk in humans. Study 2: Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon Study 2: Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat intake on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to transcriptomic changes induced in colonic tissue. In order to evaluate the potential effect of an inflamed colon on endogenous nitrosation, the study population consisted of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) control subjects without inflammation. The intervention had no effect on fecal NOC formation but fecal water genotoxicity significantly increased in response to red meat intake. Since IBD patients showed no difference in fecal NOC formation or fecal water genotoxicity levels as compared to IBS controls, for transcriptomic analyses, all subjects were grouped together. Genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated that are known to play a part in the carcinogenic process in the human colon. These results are in line with a possible oxidative effect of dietary heme. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a possible risk of CRC development in humans. The study investigated transcription levels in human colon biopsies obtained during a colonoscopic exam in 32 subjects suffering from either inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). IBS patients served as control patients for comparison with IBD patients (see Study 1). 12 of these patients (6 IBD and 6 IBS) also followed a 7-day diet high in red meat (300 grams/day) after which a second colonscopic exam was performed to obtain colon biopsies to investigate the effect of the red meat intervention (Study 2). For each subject, cRNA copies of mRNA isolated from the colon biopsies were labeled with one dye (Cy3) and each sample was hybridized on a separate array. One replicate per subject or before/after red meat intervention (so 44 arrays in total, i.e. 20 before patients and 12 before and after patients).

Dataset Information

Transcription profiling of sigmoid colon mucosal biopsies from irritable bowel syndrome patients and healthy control subjects

Publications

Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome.

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