Epigenetic Reprogramming Alters Intestinal Stem Cell Fate in Pouchitis

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 and the role of janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, 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, mirroring findings in primary pouch tissue. Chromatin accessibility and histone modification profiling of ISCs revealed inflammation-driven epigenetic remodeling, particularly involving activator protein 1 (AP-1) transcription factors such as c-Jun and excessive STAT1 activity. Loss of c-Jun disrupted ISC viability and enhanced secretory cell differentiation in non-inflamed organoids, whereas therapies targeting JAK/STAT reversed these ISC defects and chromatin changes in pouchitis organoids. Together, these results associated inflammation with epigenetic changes in human ISCs, suggesting that immune-mediated injury has lasting effects on the pouch epithelium that can potentially be reversed through JAK/STAT therapies.