TY - JOUR
T1 - Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice
AU - Chajadine, Mouna
AU - Laurans, Ludivine
AU - Radecke, Tobias
AU - Mouttoulingam, Nirmala
AU - Al-Rifai, Rida
AU - Bacquer, Emilie
AU - Delaroque, Clara
AU - Rytter, Héloïse
AU - Bredon, Marius
AU - Knosp, Camille
AU - Vilar, José
AU - Fontaine, Coralie
AU - Suffee, Nadine
AU - Vandestienne, Marie
AU - Esposito, Bruno
AU - Dairou, Julien
AU - Launay, Jean Marie
AU - Callebert, Jacques
AU - Tedgui, Alain
AU - Ait-Oufella, Hafid
AU - Sokol, Harry
AU - Chassaing, Benoit
AU - Taleb, Soraya
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85199985082&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-50807-x
DO - 10.1038/s41467-024-50807-x
M3 - Article
C2 - 39080345
AN - SCOPUS:85199985082
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6390
ER -