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Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4+ T Cells to Immunodeficient Mice
Published on: December 16, 2021
Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection
Qing Li1,2, Rodrigo de Oliveira Formiga1,2, Virginie Puchois1,2
1Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
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.
Insights
Indole-3-propionic acid (IPA) enhances T cell mitochondrial respiration by boosting fatty acid and amino acid oxidation. This metabolite also reduces inflammation by reprogramming T cell metabolism.
Area of Science:
- Immunology
- Metabolic studies
- Microbiome research
Background:
- Gut microbiota metabolites significantly influence immune cell function and metabolism.
- Identifying specific metabolites that modulate T cell mitochondrial activity is crucial for understanding immune regulation.
Purpose of the Study:
- To screen gut microbiota metabolites for their effects on T cell mitochondrial metabolism.
- To investigate the impact of indole-3-propionic acid (IPA) on CD4+ T cell function and metabolism.
Main Methods:
- Screening of gut microbiota metabolites for modulators of mitochondrial metabolism in T cells.
- Analysis of IPA's effects on CD4+ T cell respiration, substrate oxidation (fatty acid oxidation [FAO] and amino acid oxidation [AAO]), and glycolytic capacity.
- Investigating the role of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) in mediating IPA's effects.
- In vivo studies using mice with gut bacteria depletion or colitis to assess IPA's therapeutic potential.
Main Results:
- Indole-3-propionic acid (IPA) stimulates mitochondrial respiration in CD4+ T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while decreasing glycolysis.
- IPA inhibits the differentiation of CD4+ T cells into type 1 and type 17 helper T cell phenotypes.
- The metabolic and immune effects of IPA are mediated through peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ).
- IPA administration in mice with gut bacteria depletion or colitis restores mitochondrial respiration in colonic CD4+ T cells by enhancing FAO and AAO, thereby reducing inflammation.
Conclusions:
- The anti-inflammatory effects of IPA are achieved through the metabolic reprogramming of CD4+ T cells, enhancing their mitochondrial respiration.
- IPA represents a potential therapeutic agent for inflammatory conditions by modulating T cell metabolism and function.
