A Novel <scp>CHRM3</scp> ‐Driven Preclinical Model of Irritable Bowel Syndrome

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.