Vitamin D Deficiency Exacerbates Colonic Inflammation Due to Activation of the Local Renin-Angiotensin System in the Colon.

ABSTRACT

BACKGROUND: The renin-angiotensin system (RAS) is activated in inflammatory bowel disease (IBD), and vitamin D deficiency aggravates the development of colitis, but the relationship between the local colonic RAS and vitamin D is unclear with regard to the pathogenesis of IBD. AIMS: To investigate whether vitamin D suppresses the local colonic RAS to prevent colonic mucosal inflammation in a mouse model of experimental colitis. METHODS: C57BL/6 mice fed vitamin D-deficient (VDD) diet for 8 weeks were induced to colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS), with mice fed vitamin D-sufficient (VDS) diet as controls. Colitis severity was assessed by histology, and pro-inflammatory cytokines, RAS components, and signaling pathways were quantified by real-time RT-PCR and Western blotting. RESULTS: C57BL/6 mice fed the VDD diet for 8 weeks exhibited significantly lower serum 25(OH)D3 concentrations compared to mice fed the VDS diet. When these VDD mice were induced to colitis by TNBS, they exhibited more severe colonic inflammation and developed more severe colitis compared to the VDS counterparts. VDD diet feeding resulted in higher production of mucosal pro-inflammatory cytokines, higher activation of the myosin light chain kinase-tight junction regulatory pathway, and greater increases in mucosal permeability. VDD diet feeding also enhanced colonic RAS activation. Treatment with angiotensin II receptor blocker losartan markedly alleviated colitis in TNBS-induced VDD mice. CONCLUSION: Vitamin D deficiency promotes colonic inflammation at least in part due to over activation of the local RAS in the colon.