Abstract Background Intestinal epithelial stem cells (ISCs) and their transit-amplifying (TA) progeny are essential for mucosal repair and regeneration. However, the impact of chronic inflammation on ISC/TA cell behaviour and differentiation remains incompletely understood in the setting of inflammatory bowel disease (IBD). Methods We integrated bulk RNA sequencing data from the largest IBD mucosal biopsy cohort to date (n 3,000) with single-cell transcriptomic profiling of human colonic biopsies and functional assays using patient-derived intestinal organoids. Bioinformatic and experimental analyses focused on identifying transcriptional, cellular, and differentiation dynamics in ISC/TA populations across inflamed, non-inflamed, and healthy tissues. Results Chronic active inflammation in IBD was associated with a significant depletion of canonical LGR5+ ISCs and a compensatory expansion of OLFM4+ epithelial progenitors, consistent with reprogramming toward an inflammation-adapted epithelial repair phenotype. Both inflamed and adjacent non-inflamed IBD tissues exhibited persistent transcriptional changes in ISC/TA cells, distinct from healthy controls. Single-cell analysis revealed marked heterogeneity, including a novel inflammation-associated ISC/TA cluster enriched for immune signalling pathways and stress response genes. Pseudotime trajectory analysis demonstrated a shift in differentiation towards secretory (Paneth-like/deep crypt) cell lineages under inflammatory stress. Patient-derived organoid experiments recapitulated these lineage and gene expression changes, confirming the sustained impact of chronic inflammation on the epithelial regenerative compartment (Balasubramanian et al.; Patel et al.).. Conclusion Chronic inflammation in IBD drives dynamic and persistent reprogramming of intestinal stem and progenitor cells, promoting altered differentiation and the emergence of immune-responsive epithelial states. The IntestiDyn multi-omics dataset highlights the plasticity and adaptive mechanisms of the human intestinal epithelium in IBD, revealing targets for future therapeutic strategies aimed at promoting epithelial integrity and durable healing. References: Balasubramanian et al., BioRxiv 2025 Patel et al., BioRxiv 2025 Conflict of interest: Ordóñez Morán, Paloma: AstraZeneca funds several of our projects Balasubramanian, Brinda: No conflict of interest Patel, Shivam: No conflict of interest Gall, Louis: No conflict of interest Hannan, Nick: No conflict of interest Dalleywater, William: No conflict of interest Moran, Gordon: Gordon Moran has received research grants from Astra Zeneca, Bristol Myers Squibb, Jansen and Pfizer. He has received consulting fee from Alimentiv, Satisfai Health, Takeda, Abbvie, Jansen, Motilent, and Pfizer. He has received speaker honoraria from Abbvie, Jansen and Bristol Myers Squibb. He has received financial support for attending international meetings from Jansen and Abbvie.
Balasubramanian et al. (Thu,) studied this question.