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-OufellaHarry Sokol, Benoit Chassaing, Soraya Taleb*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number6390
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2024
Externally publishedYes

Fingerprint

Dive into the research topics of 'Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice'. Together they form a unique fingerprint.

Cite this