Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation PMID: 41120706

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
16. Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France. [email protected].
17. Université Paris-Saclay, INRAe, AgroParisTech, Micalis institute, Jouy-en-Josas, France. [email protected].
18. Gastroenterology department, Saint Antoine Hospital, APHP, Paris, France. [email protected].

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.