P171 Rescuing Intestinal Stem Cells via TMEM219 inhibition promotes mucosal healing in Crohn’s disease

Abstract

Abstract Background Intestinal mucosa regeneration is disrupted in inflammatory bowel disease as Chron’s disease, but whether this relies on a defect in intestinal stem cells remains to be established. Methods Transcriptome and receptome profile in Crohn’s disease bioptic samples demonstrated a defect in intestinal stem cells (ISCs). The TMEM219 knockout mouse, in which TMEM219 expression is abrogated on ISCs was tested in dextran sulfate sodium (DSS) acute colitis model. DSS-induced chronic colitis was also used to confirm in vivo relevance for TMEM219 blockade in mucosal recovery. Results An increased intestinal stem cells death and dysfunction in colonic samples obtained from patients with Crohn’s disease was observed, which is controlled through the death factor TMEM219. Based on a receptome analysis, we documented large alterations in the expression of the death receptor TMEM219 in patients with Crohn’s disease, particularly in those with refractory disease and/or non responders to conventional therapy, which were paralleled by altered peripheral levels of the TMEM219 ligand, insulin-like growth factor binding protein 3 (IGFBP3). Pharmacological blockade of the IGFBP3/TMEM219 axis restored the self-renewal abilities of mini-guts generated from patients with Crohn’s disease in vitro, ameliorated DSS-induced colitis in vivo and favored mucosal healing. Genetic deletion of TMEM219 in intestinal stem cells in newly generated TMEM219flflLGR5cre mice restored mucosal regenerative abilities both in vitro and in vivo. Conclusion Our findings demonstrate that genetic and pharmacological TMEM219 blockade re-establishes intestinal self-renewal properties and offers a therapeutic opportunity for mucosal healing in inflammatory bowel disease.