Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis

Lei He, Tianjing Liu, Yongyan Shi, Feng Tian, Huiyuan Hu, Dilip K Deb, Yinyin Chen, Marc Bissonnette, Yan Chun Li
2017 Endocrinology  
Recent studies show that colonic vitamin D receptor (VDR) signaling protects the mucosal epithelial barrier and suppresses colonic inflammation, but the underlying molecular mechanism remains to be fully understood. To investigate the implication of colonic VDR downregulation seen in patients with inflammatory bowel disease, we assessed the effect of gut epithelial VDR deletion on colonic inflammatory responses in an experimental colitis model. In a 2,4,6-trinitrobenzenesulfonic acidinduced
more » ... tis model, mice carrying VDR deletion in gut epithelial cells [VDR flox/flox (VDR f/f );Villin-Cre or VDR DIEC ] or in colonic epithelial cells (VDR f/f ;CDX2-Cre or VDR DCEC ) developed more severe clinical colitis than VDR f/f control mice, characterized by more robust T-helper (T H )1 and T H 17 responses, with greater increases in mucosal interferon (IFN)-g + , interleukin (IL)-17 + , and IFN-g + IL-17 + T cells. Accompanying the severe mucosal inflammation was more profound colonic epithelial cell apoptosis in the mutant mice. Treatment with caspase inhibitor Q-VD-OPh dramatically reduced colitis severity and attenuated T H 1 and T H 17 responses in VDR DCEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b + CD103 + dendritic cells (DCs), known to be critical for T H 17cell activation. Moreover, depletion of gut commensal bacteria with antibiotics eliminated the robust T H 1 and T H 17 responses and CD11b + CD103 + DC induction. Taken together, these observations demonstrate that gut epithelial VDR deletion aggravates epithelial cell apoptosis, resulting in increases in mucosal barrier permeability. Consequently, invading luminal bacteria activate CD11b + CD103 + DCs, which promote mucosal T H 1 and T H 17 responses. Therefore, gut epithelial VDR signaling controls mucosal inflammation by suppressing epithelial cell apoptosis.
doi:10.1210/en.2017-00748 pmid:29228157 fatcat:bzwfqznh5fhyrluccndqopwhwq