Epigenetic Reprogramming Alters Intestinal Stem Cell Fate in Pouchitis

SUMMARY Intestinal stem cells (ISCs) mediate the continuous renewal of the epithelium during homeostasis and recovery from injury. To investigate the molecular impact of inflammation on human ISCs, we established an organoid model derived from individuals with pouchitis, a form of inflammatory bowel disease that develops in an organ generated from ileal pouch-anal anastomosis (IPAA) surgery. Compared with non-inflamed specimens, pouchitis organoids exhibited increased apoptosis and secretory lineage differentiation that were stable after multiple passages. Chromatin accessibility and histone modification profiling of ISCs revealed inflammation-driven epigenetic remodeling, particularly involving AP-1 transcription factors like c-Jun. Loss of c-Jun disrupted ISC viability and enhanced secretory cell differentiation in organoids, mirroring findings in primary pouchitis tissue. These results highlight how inflammation induces epigenetic changes in human ISCs, suggesting that immune-mediated injury has lasting effects on the epithelium that may contribute to the pathogenesis of pouchitis and other inflammatory intestinal diseases.