PRJNA797860
Trim27 deficiency triggers irritable bowel syndrome by inhibiting Wnt/beta-catenin signaling in intestinal stem cells
Gastrointestinal disorders severely impair the quality of life of patients and impose a considerable burden on the global economy. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are two of the most common gastrointestinal disorders, which usually share overlapping symptoms. The pathogenesis of IBD has been elucidated, but the pathogenesis of IBS remains poorly understood, which largely limits the diagnosis and treatment of IBS. Here we identify that Trim27 is a critical host factor for inhibiting IBS, which promotes the activation of Wnt signaling pathway in intestinal stem cells (ISCs) by stabilizing beta-catenin, thus promoting the self-renewal and differentiation of ISCs to maintain intestinal homeostasis. We found that Trim27-knockout (Trim27-/-) mice exhibited elevated levels of pro-inflammatory cytokines, chemokines, 5-HT and disorders of gut microbiota, which phenotypes are consistent with the symptoms of IBS patients. Moreover, complementary expression of Trim27 or beta-catenin can rescue the disruption of organoid formation in mice that Trim27 is specifically knockout in Lgr5-positive ISCs (trim27[Lgr5]). Furthermore, beta-catenin degradation inhibitor or probiotic treatment can ameliorate IBS symptoms in trim27[Lgr5] mice. Collectively, our study reveals the key host regulatory factors and potential pathogenesis of IBS, thus providing novel strategies for the diagnosis and treatment of IBS.