Zinc supplementation modulates T helper 17 cells via its effect on gut microbiome

Abstract Zinc is an essential micronutrient involved in many cellular functions in both humans and bacteria. In the gut, the availability of zinc may impact survival and pathogenicity of the gut microbiota. Recent studies show that changes in levels of dietary zinc can alter the composition of the gut microbiota, however how this impacts mucosal immune responses is not known. Here, we show that supplementing mice with zinc sulfate in drinking water for a week resulted in significant changes in gut microbial composition, as well drastic reduction in microbial diversity. More importantly we saw that zinc supplementation attenuated the T helper 17 cell number and activity in murine small intestine. Th17 induction via adherent microbes is mediated by upregulation of Serum Amyloid A (SAA) from epithelial cells. We see a reduction in SAA in zinc-supplemented mice. Furthermore, T regulatory cell numbers and IL-10 cytokine levels, which are known to antagonizes Th17 induction, is unchanged during zinc supplementation. Using 16S rRNA sequencing, we found major shifts in community composition of the mucosal-associated microbiota upon zinc supplementation. To determine if zinc-dependent changes in gut microbiota are sufficient to limit Th17 response, we transplanted microbiome from zinc treated mice into germ-free mice. We saw that germ-free mice that received cecal contents from zinc treated mice have reduced Th17 response thus establishing that dietary zinc changes immune potential of gut microbiome. Th17 cells mediate antimicrobial response in the gut and are involved in the pathogenesis of many autoimmune diseases. Our work thus provides a novel nutritional approach for remodeling microbiota to dampen inflammatory immune response in the gut.