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<p>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<sup>+</sup> T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4<sup>+</sup> 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<sup>+</sup> T cells. Adoptive transfer experiments show that IPA acts on CD4<sup>+</sup> 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<sup>+</sup> T cells toward the enhancement of mitochondrial respiration.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Qing Li,
  • Rodrigo de Oliveira Formiga,
  • Virginie Puchois,
  • Laura Creusot,
  • Ahmad Haidar Ahmad,
  • Salomé Amouyal,
  • Márcio Augusto Campos-Ribeiro,
  • Yining Zhao,
  • Danielle M. M. Harris,
  • Frederic Lasserre,
  • Sandrine Ellero-Simatos,
  • Hervé Guillou,
  • Zhan Huang,
  • Loic Brot,
  • Yuhang Hu,
  • Loic Chollet,
  • Camille Danne,
  • Cyril Scandola,
  • Tatiana Ledent,
  • Guillaume Chevreux,
  • Rafael J. Argüello,
  • Marcelo De Carvalho Bittencourt,
  • Jessica Bettinger,
  • Maud D’Aveni-Piney,
  • David Moulin,
  • Stefan Schreiber,
  • Konrad Aden,
  • Nathalie Rolhion,
  • Marie-Laure Michel,
  • Timothy Wai,
  • Harry Sokol

摘要

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.