Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.

Animals Tryptophan / metabolism Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism Atherosclerosis / metabolism Diet, High-Fat / adverse effects Mice Serotonin / metabolism Intestinal Mucosa / metabolism Mice, Inbred C57BL Kynurenine / metabolism Male Gastrointestinal Microbiome Indoles / pharmacology Inflammation / metabolism Mice, Knockout Intestines / pathology T-Lymphocytes / metabolism Disease Models, Animal

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
29 Jul 2024

Historique:

received: 04 08 2023

accepted: 22 07 2024

medline: 31 7 2024

pubmed: 31 7 2024

entrez: 30 7 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-50807-x PMID: 39080345

pubmed: 39080345

doi: 10.1038/s41467-024-50807-x

pii: 10.1038/s41467-024-50807-x

doi:

Substances chimiques

Tryptophan 8DUH1N11BX

Indoleamine-Pyrrole 2,3,-Dioxygenase 0

Serotonin 333DO1RDJY

Kynurenine 343-65-7

Indoles 0

IDO1 protein, mouse 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

6390

Subventions

Organisme : Agence Nationale de la Recherche (French National Research Agency)

ID : ANR-22CE14-0014-01

Informations de copyright

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