Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses

Ryz NR, Patterson S, Zhang Y, Ma C, Huang T, Bhinder G, Wu X, Chan J, Glesby A, Sham HP, Dutz JP, Levings MK, Jacobson K, Vallance BA. Active vitamin D(1,25-dihydroxyvitamin D-3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses. Am J Physiol Gastrointest Liver Physiol 303: G1299-G1311, 2012. First published September 27, 2012; doi: 10.1152/ajpgi.00320.2012.-Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)(2)D-3 to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25( OH) 2D3 treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)(2)D-3-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)(2)D-3-treated mice showed defects in their production of the antimicrobial peptide REG3 gamma. Taken together, these studies show that 1,25(OH)(2)D-3 suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen.