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 VDRΔIEC] or in colonic epithelial cells (VDRf/f;CDX2-Cre or VDRΔCEC) developed more severe clinical
colitis than VDRf/f control mice, characterized by more robust T-helper (TH)1 and TH17 responses, with greater increases in mucosal
interferon (IFN)-γ+,
interleukin (IL)-17+, and IFN-γ+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 TH1 and TH17 responses in VDRΔCEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b+CD103+ dendritic cells (DCs), known to be critical for TH17-cell activation. Moreover, depletion of gut commensal bacteria with
antibiotics eliminated the robust TH1 and TH17 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 TH1 and TH17 responses. Therefore, gut epithelial VDR signaling controls mucosal
inflammation by suppressing epithelial cell apoptosis.