Qing Li, Rodrigo de Oliveira Formiga, Virginie Puchois, Laura Creusot, Ahmad Haidar Ahmad, Salomé Amouyal, Márcio A. C. Ribeiro, Yining Zhao, Danielle M M Harris, Frédèric Lasserre, Sandrine Ellero‐Simatos, Hervé Guillou, Zhan Huang, Loïc Brot, Yuhang Hu, Loïc Chollet, Camille Danne, Cyril Scandola, Tatiana Ledent, Guillaume Chevreux, Rafael J. Argüello, Manoel de Carvalho, Jessica Bettinger, Maud D’Aveni, David Moulin, Stefan Schreiber, Konrad Aden, Nathalie Rolhion, Marie‐Laure Michel, Timothy Wai, Harry Sokol
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 fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. 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. The gut microbiota-derived metabolite indole-3-propionic acid (IPA) is found to enhance mitochondrial fatty acid and amino acid oxidation in CD4+ T cells. In mice, IPA-mediated metabolic reprogramming of CD4+ T cells exerts anti-inflammatory effects and protects against colitis.