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Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice

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Chajadine, Mouna | Laurans, Ludivine | Radecke, Tobias | Mouttoulingam, Nirmala | Al-Rifai, Rida | Bacquer, Emilie | Delaroque, Clara | Rytter, Héloïse | Bredon, Marius | Knosp, Camille | Vilar, José | Fontaine, Coralie | Suffee, Nadine | Vandestienne, Marie | Esposito, Bruno | Dairou, Julien | Launay, Jean Marie | Callebert, Jacques | Tedgui, Alain | Ait-Oufella, Hafid | Sokol, Harry | Chassaing, Benoit | Taleb, Soraya

Edité par CCSD ; Nature Publishing Group -

International audience. Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.

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