Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice

Mouna Chajadine, Ludivine Laurans, Tobias Radecke, Nirmala Mouttoulingam, Rida Al-Rifai, Emilie Bacquer, Clara Delaroque, Héloïse Rytter, Marius Bredon, Camille Knosp, José Vilar, Coralie Fontaine, Nadine Suffee, Marie Vandestienne, Bruno Esposito, Julien Dairou, Jean Marie Launay, Jacques Callebert, Alain Tedgui, Hafid Ait-Oufella, Harry Sokol, Benoit Chassaing and Soraya Taleb ()
Additional contact information
Mouna Chajadine: PARCC
Ludivine Laurans: PARCC
Tobias Radecke: PARCC
Nirmala Mouttoulingam: PARCC
Rida Al-Rifai: PARCC
Emilie Bacquer: PARCC
Clara Delaroque: INSERM U1306
Héloïse Rytter: INSERM U1306
Marius Bredon: Gastroenterology Department
Camille Knosp: PARCC
José Vilar: PARCC
Coralie Fontaine: Université de Toulouse
Nadine Suffee: PARCC
Marie Vandestienne: PARCC
Bruno Esposito: PARCC
Julien Dairou: Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
Jean Marie Launay: Hôpital Lariboisière
Jacques Callebert: Hôpital Lariboisière
Alain Tedgui: PARCC
Hafid Ait-Oufella: PARCC
Harry Sokol: Gastroenterology Department
Benoit Chassaing: INSERM U1306
Soraya Taleb: PARCC

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50807-x

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