Gut microbiota derived metabolites 3-idoleacetic acid promotes IL-35+B cell production

Disruptions of microbiota composition by factors such as genetics have been suggested to be critical contributing factors to the growth of the worldwide epidemics of chronic illness such as metabolic diseases. IL-35-producing regulatory B and T regulatory cells are critical regulators to these illnesses. Whether microbiota-derived metabolites can regulate these IL-35+ cells maintain elusive. Here, we found gut genetic factor Reg4 associated lactobacillus could promote the generation of IL-35+ B cells through producing 3-idoleacetic acid (IAA). HuREG4IEC tg mice had markedly accumulation of IL-35+ not only in adipose tissues but also in colon tissues; whereas significantly decreased IL-35+ cells in adipose tissues and colon tissues could be detected in Reg4 KO mice. On the mechanism, IAA-mediated IL35+ B cells was through PXR), RXR and CAR in the presence of LPS. PXR KO, CAR KO and NF-?B KO mice impaired the generation of IAA- IL-35+B cells. Interestingly, lower levels of IAA and IL-35 were also detected in the peripheral blood of individuals with obesity. Thus, IAA is a factor to promote the generation of IL-35+B cells to impede the development of obesity. Overall design: Examination of the enrichment of PXR in the promoter region of P35 gene in WEHI231 cells.