Epigenetic Reprogramming Alters Human Intestinal Stem Cell Fate in Pouchitis

To investigate the molecular impact of inflammation on human ISCs and the role of 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 AP-1 transcription factors like c-Jun and excessive STAT1 activity. Loss of c-Jun disrupted ISC viability and enhanced secretory cell differentiation in non-inflamed organoids, while therapies targeting JAK/STAT reversed these ISC defects and chromatin changes in pouchitis organoids.