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Abstract

Diet and gut microbial ecology may underlie the increasing incidence of certain inflammatory diseases. Here, we found that key features of autoimmune diabetes in NOD mice, such as gender differences and protection in MyD88-/- NOD mice, correlated closely with blood and fecal concentrations of the short chain fatty acids (SCFAs) acetate and butyrate. We then used specialized diets to deliver high concentrations of acetate and butyrate to the colon and hepatic portal vein of NOD mice, when tolerance to islet antigens has already been broken. High acetate or butyrate yielding diets significantly reduced progression to diabetes, through effects on the colonic microbiota, improved gut epithelial integrity and reduced concentrations of IL-21 and TNF�±. Both acetate and butyrate diets led to dramatically decreased numbers of autoreactive T-cells in lymphoid tissues. A high butyrate yielding diet promoted conversion of naive T-cells into Foxp3+ Treg cells in vivo, through histone modification at the Foxp3 promoter that led to increased numbers of Treg cells in both the gut and the periphery. In contrast, an acetate yielding diet inhibited histone deacetylase-3 transcription in B-cells, which led to markedly reduced expression of CD86 and MHC-I and reduced capacity to expand autoreactive CD8+ T cells in vivo. Control of autoimmune T-cell frequencies and protection from diabetes relied in part on the metabolite-sensor GPR43, a receptor for both acetate and butyrate. Specialized diets that yield high acetate or butyrate may represent an effective non pharmacologic means to limit autoreactive T-cell numbers and prevent autoimmune disease progression.

Biography

Email: eliana.marino@monash.edu