Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance

The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche. [Display omitted] •pTreg cells affect the intestinal microbiota composition in healthy mice•pTreg cells suppress type 2 responses and preserve a niche for border-dwelling bacteria•pTreg cell-dependent border-dwelling bacteria affect the host metabolome•pTreg cells promote organismal homeostasis in the presence of commensal bacteria Extrathymically generated regulatory (pTreg) cells are induced by bacterial products at mucosal sites. In this issue, Campbell et al. show that pTreg cell deficiency impedes the establishment of a subset of intestinal bacteria due to heightened immune responses, with significant effects on host metabolites and fitness.