P078 MUCOSAL STEM CELL HETEROGENEITY IN PEDIATRIC CROHN’S DISEASE

Crohn’s is an aggressive inflammatory bowel disease driven by interactions of unknown relative significance between the immune system, the microbiome, and the intervening intestinal epithelial barrier. Histopathology analyses and genome-wide association studies (GWAS) have provided renewed focus on the role of the mucosal barrier in this disease. We obtained endoscopic biopsies from 30 patients either newly diagnosed with Crohn’s, under treatment for Crohn’s, or functional controls. Using stem cell cloning technology that maintains cells in their most immature ground state with the potential for conditional differentiation to a mature epithelium1, we analyzed stem cells from each of these cases. We find that pediatric patients with Crohn’s harbor two populations of mucosal stem cells including one that is similar to children without Crohn’s and a second distinguished by three epigenetically maintained traits that are potentially pathogenic. These traits include a robust inflammatory gene signature including many implicated by GWAS in the risk for Crohn’s, defective secretory cell differentiation impacting barrier function, and a profound homeotic transformation of terminal ileum to proximal gastrointestinal tract. Our epistasis analyses indicate that the homeotic transformation dictates both the inflammatory and barrier defects and underlies the absolute concurrence of these traits across cases. Our analysis of barrier function of epithelia formed from these aberrant stem cells shows their enhanced sensitivity to bacterial components, and the pattern of chemokines and cytokines produced by these cells promotes leukocyte extravasation. These findings link an epigenetically distinct subpopulation of intestinal stem cells and the defective epithelial they beget to the pathophysiology of Crohn’s and may reframe therapeutic strategies in this disease.