Vitamin D deficiency results in fewer innate lymphoid cells and severe infection with Citrobacter rodentium.

Abstract

Abstract Vitamin D deficiency results in severe experimental inflammatory bowel disease. We investigated the role of vitamin D following an infectious model of inflammation in the gut following Citrobacter rodentium infection. Vitamin D sufficient (D+) and vitamin D deficient (D−) wild-type (WT) and Cyp27B1 knock-out (CypKO) mice, which lack the enzyme to produce the high affinity ligand, 1,25(OH)2D (1,25D), were infected. In the absence of 1,25D, the low affinity vitamin D ligand (25(OH)D) accumulates in CypKO mice and can replace 1,25D. Therefore it was not surprising that D+ WT and D+ CypKO cleared C. rodentium with identical kinetics. D− WT mice cleared C. rodentium slower than D+ mice and D− CypKO mice developed a lethal infection. Infected D− CypKO and D− WT mice had increased colonic inflammation, systemic bacterial dissemination, but only D− CypKO mice died following infection. Increased colonic IL-17 mRNA in D− versus D+ mice at d14 post-infection was perhaps too late to protect the D− mice from C. rodentium. Innate lymphoid cells (ILCs) are critical sources of early IL-17 and IL-22 that are essential for clearance of C. rodentium. Uninfected D− mice had reduced ILCs in the gut and decreased ILC-derived IL-17 and IL-22 in the small intestine, which is the site of early colonization of C. rodentium. Vitamin D deficiency resulted in delayed clearance of C. rodenitum that was associated with reduced ILC produced early IL-17 and IL-22, more inflammation and IL-17 at the peak of infection. The data suggests that vitamin D may be an important regulator of early cytokine production by ILC in the gut and therefore protection from enteric infection.