Microbiota-Dependent Induction of Colonic Cyp27b1 Is Associated With Colonic Inflammation: Implications of Locally Produced 1,25-Dihydroxyvitamin D3 in Inflammatory Regulation in the Colon

Our recent studies demonstrated that intestinal epithelial vitamin D receptor (VDR) signaling plays a critical role in regulating colonic inflammation by protecting epithelial barrier integrity. Epithelial VDR is downregulated in colitis, but how mucosal inflammation affects local 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] production is unknown. Here we showed that cytochrome P450 27b1 (Cyp27b1), a cytochrome P450 enzyme necessary for 1,25(OH)(2)D-3 biosynthesis, is highly induced in colonic mucosa in inflammatory response. Although VDR is reduced in colon biopsies from patients with ulcerative colitis, Cyp27b1 is markedly upregulated in these samples. Colon mucosal Cyp27b1 was also markedly induced in an experimental colitis mouse model, and this local Cyp27b1 induction and colonic inflammation required the presence of commensal bacteria. Vitamin D deficiency further exaggerated colonic Cyp27b1 induction and aggravated colonic inflammation in mice. In HCT116 cells, lipopolysaccharide or tumor necrosis factor-alpha treatment induced Cyp27b1 in time- and dose-dependent manners, and the induced Cyp27b1 was enzymatically active. The inflammation-induced upregulation of Cyp27b1 was mediated by nuclear factor kappa B. Collectively these data suggest that induction of colonic epithelial Cyp27b1, which is expected to increase local production of 1,25(OH)(2)D-3, is a protective mechanism that partially compensates for the downregulation of epithelial VDR during colonic inflammation. Increased local 1,25(OH)(2)D-3 maintains 1,25(OH)(2)D-3-VDR signaling to protect the mucosal barrier and reduce colonic inflammation.