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

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 acid-induced colitis model, mice carrying VDR deletion in gut epithelial cells [VDRflox/flox (VDRf/f); Villin-Cre or VDR Delta IEC] or in colonic epithelial cells (VDRf/f; CDX2-Cre or VDR Delta CEC) developed more severe clinical colitis than VDRf/f control mice, characterized by more robust T-helper (T-H)1 and T(H)17 responses, with greater increases in mucosal interferon (IFN)-gamma(+), interleukin (IL)-17(+), and IFN-gamma+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 Delta CEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b(+) CD103(+) dendritic cells (DCs), known to be critical for T(H)17-cell 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.