The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5,6,7,8,9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10,11,12,13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.
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This work was supported by INSERM, Fondation pour la Recherche Médicale (A.T.) and Fondation de France (S.T.). H.S. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-2016-StG-71577).We are grateful to S. Billon-Crossouard from the Platform of Mass Spectrometry of Nantes University for SCFA analysis. We acknowledge the technical platform metabolism of the Unit “Biologie Fonctionnelle et Adaptative” (University Paris Diderot, Sorbonne Paris Cité, BFA, UMR 8251 CNRS, 75205 Paris, France) for metabolic analysis and the animal core facility “Buffon” of the University Paris Diderot Paris 7/Institut Jacques Monod, Paris for animal husbandry. We are thankful to the Genomics Platform of Translational Research Department, Institut Curie, PSL Research University for sharing their expertise and helping us with NanoString analysis. We thank members of our animal and histology facilities. We thank B. Gaye for his help with statistical analysis. We thank N. Vodovar for discussions and C. Heymes for his help with human sample preparation.
The authors declare no competing interests.
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Laurans, L., Venteclef, N., Haddad, Y. et al. Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med 24, 1113–1120 (2018). https://doi.org/10.1038/s41591-018-0060-4
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