In both studies the authors set out to determine whether microbial metabolites induce pTReg cells. Furusawa et al. found that when mice associated with chloroform-resistant bacteria (selecting for Clostridiales bacteria) were fed a high-fibre diet, but not a low-fibre diet, they had an increased number of pTReg cells compared with germ-free mice. Furthermore, analysis of the faecal metabolites showed that these mice had increased levels of short-chain fatty acids, such as butyrate and propionate. Similarly, Arpaia et al. found that, compared with faecal extracts from microbiota-deficient mice, faecal extracts from specific-pathogen-free (SPF) mice enhanced the induction of FOXP3 expression in CD4+ T cells under TReg cell-inducing conditions in vitro. Faecal extracts from microbiota-deficient mice showed reduced levels of butyrate and propionate, suggesting that commensal bacteria are responsible for the production of short-chain fatty acids that induce pTReg cell differentiation. Next, both groups investigated whether single short-chain fatty acids can promote the generation of pTReg cells in vivo. Indeed, mice fed a starch-rich diet supplemented with butyrate had an increased number of colonic pTReg cells. Of note, Arpaia et al. found that the mode of administration of butyrate affected the result; mice drinking butyrate-supplemented water showed a systemic increase in pTReg cell numbers, but had no difference in the number of colonic pTReg cells or thymus-derived TReg (tTReg) cells. However, giving mice butyrate-supplemented food or butyrate enemas resulted in an increased number of colonic pTReg cells. These data support a role of butyrate in the induction of pTReg cells and suggest that colonic pTReg cells are locally generated.
butyrate specifically induces pTReg cell differentiation in the gut
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