Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Journal

Nature microbiology

ISSN: 2058-5276

Titre abrégé: Nat Microbiol

Pays: England

ID NLM: 101674869

Informations de publication

Date de publication:
01 Mar 2024

Historique:

received: 28 01 2023

accepted: 22 01 2024

medline: 2 3 2024

pubmed: 2 3 2024

entrez: 1 3 2024

Statut: aheadofprint

Résumé

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Identifiants

DOI: 10.1038/s41564-024-01617-w PMID: 38429422

pubmed: 38429422

doi: 10.1038/s41564-024-01617-w

pii: 10.1038/s41564-024-01617-w

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

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