Vitamin D deficiency and C. rodentium induced colitis Dietary Vitamin D3 deficiency alters intestinal mucosal defense and 1 increases susceptibility to Citrobacter rodentium induced colitis

44 Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to 45 increase risk of bacterial infections, the importance of vitamin D on host defense against 46 intestinal bacterial pathogens is currently unclear since injection of the active form of 47 vitamin D, 1,25(OH)2D3 increased susceptibility to the enteric bacterial pathogen 48 Citrobacter rodentium by suppressing key immune/inflammatory factors. To further 49 characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice 50 either vitamin D3 deficient or vitamin D3 sufficient diets for 5 weeks and then challenged 51 with C. rodentium. Vitamin D3 deficient mice lost significantly more body weight, 52 carried higher C. rodentium burdens, and developed worsened histological damage. 53 Vitamin D3 deficient mice also suffered greater bacterial translocation to extra-intestinal 54 tissues, including mesenteric lymph nodes, spleen and liver. Intestinal tissues of infected 55 vitamin D3 deficient mice displayed increased inflammatory cell infiltrates as well as 56 significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, 57 TGF-β, IL-17A and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these 58 exaggerated inflammatory responses accelerated the loss of commensal microbes and 59 were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, 60 these studies show that dietary-induced vitamin D deficiency exacerbates intestinal 61 inflammatory responses to infection, also impairing host defense. 62 63