Activation of adenosine receptor A2a by gut symbionts promotes immune tolerance

The gut microbiota is critical to immune homeostasis, but our understanding of the underlying molecular mechanisms is very limited. Here, we demonstrate a division of labor among members of the eight-membered “model microbiome” altered Schaedler flora in promoting distinct immunophenotypes. We report that Parabacteroides goldsteinii ASF519 induces immune tolerance by promoting interleukin (IL)-10 production in a variety of myeloid-derived immune cells. The IL-10 induction is dependent on the activation of adenosine receptor A2a by microbial enzymes of the methionine cycle. ASF519 colonization in mice increased the level of adenosine in ceca and induced IL-10 secreting dendritic cells in colonic lamina propria. These immunophenotypes were pharmacologically reversed by A2a blockage. In mouse models of human autoimmune diseases, ASF519 supplementation significantly ameliorated insulitis in type 1 diabetes and collagen-induced arthritis. This study unveils a novel paradigm of gut microbiota-adenosine receptor interactions in immune tolerance and potentially provides a new therapeutic strategy for immune disorders.