2. Academic Validation
  3. Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation

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

  • Nat Metab. 2025 Oct 21. doi: 10.1038/s42255-025-01396-6.
Qing Li 1 2,  Rodrigo de Oliveira Formiga 1 2,  Virginie Puchois 1 2,  Laura Creusot 1 2,  Ahmad Haidar Ahmad 1 2,  Salomé Amouyal 1 2,  Márcio Augusto Campos-Ribeiro 3,  Yining Zhao 3,  Danielle M M Harris 4 5,  Frederic Lasserre 6,  Sandrine Ellero-Simatos 6,  Hervé Guillou 6,  Zhan Huang 1 2,  Loic Brot 1 2,  Yuhang Hu 1 2,  Loic Chollet 2 7,  Camille Danne 1 2,  Cyril Scandola 8,  Tatiana Ledent 1,  Guillaume Chevreux 9,  Rafael J Argüello 10,  Marcelo De Carvalho Bittencourt 11 12,  Jessica Bettinger 11,  Maud D'Aveni-Piney 11 13,  David Moulin 11,  Stefan Schreiber 4 14,  Konrad Aden 4 14,  Nathalie Rolhion 1 2,  Marie-Laure Michel 2 7,  Timothy Wai 3,  Harry Sokol 15 16 17 18
Affiliations

Affiliations

  • 1 Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
  • 2 Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France.
  • 3 Institut Pasteur, Mitochondrial Biology Unit, CNRS UMR 3691, Université Paris Cité, Paris, France.
  • 4 Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 5 Institute for Human Nutrition and Food Science, Division Nutriinformatics, Kiel University, Kiel, Germany.
  • 6 Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France.
  • 7 Université Paris-Saclay, INRAe, AgroParisTech, Micalis institute, Jouy-en-Josas, France.
  • 8 Institut Pasteur, Université Paris Cité, Ultrastructural Bioimaging Unit, Paris, France.
  • 9 Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.
  • 10 Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
  • 11 Université de Lorraine, CNRS, IMoPA, Nancy, France.
  • 12 Université de Lorraine, CHRU Nancy, Immunology Department, Nancy, France.
  • 13 Université de Lorraine, CHRU Nancy, Hematology Department, Nancy, France.
  • 14 Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 15 Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France. harry.sokol@gmail.com.
  • 16 Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France. harry.sokol@gmail.com.
  • 17 Université Paris-Saclay, INRAe, AgroParisTech, Micalis institute, Jouy-en-Josas, France. harry.sokol@gmail.com.
  • 18 Gastroenterology department, Saint Antoine Hospital, APHP, Paris, France. harry.sokol@gmail.com.
PMID: 41120706 DOI: 10.1038/s42255-025-01396-6
Abstract

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.

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