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A preclinical model of irritable bowel syndrome driven by CHRM3 activation

ABSTRACT: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder that significantly reduces patients' quality of life. However, current animal models have limitations in replicating the complex pathophysiology of IBS. In this study, we successfully developed a mouse model by mating intestinal epithelium-specific Cre tool mice with chemically modified human muscarinic acetylcholine receptor 3 (hCHRM3) mice, resulting in specific expression of the hCHRM3 in the intestinal epithelial cells. Activation of the hCHRM3 with clozapine-N-oxide (CNO) mimicked IBS attacks. The model mice exhibited typical IBS symptoms such as diarrhea, pain, and visceral hypersensitivity, along with pathological changes like intestinal edema and inflammatory cell infiltration, and disruption of the intestinal mucosal barrier. RNA sequencing revealed significant differentially expressed genes between the model and control groups, with KEGG and GO enrichment analyses indicating significant enrichment of immune and inflammation-related pathways. Additionally, the model mice showed increased levels of short-chain fatty acids and imbalances in the diversity and composition of the gut microbiota. This new IBS mouse model effectively simulates the symptoms and pathological processes of human IBS, providing a powerful tool for in-depth research into the pathogenesis of IBS and the development of therapeutic strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE289595 | GEO | 2025/02/19

REPOSITORIES: GEO

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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.\

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A preclinical model of irritable bowel syndrome driven by CHRM3 activation

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