Microbial metabolite Indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation

The gut microbiota and its metabolites critically regulate immune cell phenotype, function, and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here, we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells by increasing the oxidation of fatty acids and amino acids (FAO and AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behavior by inhibiting their differentiation to TH1 and TH17 phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by Peroxisome Proliferator-Activated Receptor-beta/delta. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+ T cells. Adoptive transfer experiments show that IPA acts on CD4+T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration.