Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling.

ATP Binding Cassette Transporter, Subfamily B / genetics Animals Anti-Bacterial Agents / administration & dosage Bile Acids and Salts / metabolism Cholangitis, Sclerosing / metabolism Cholestasis / metabolism Gastrointestinal Microbiome Humans Liver / metabolism Mice Prognosis Receptors, Cytoplasmic and Nuclear / metabolism Signal Transduction ATP-Binding Cassette Sub-Family B Member 4

Journal

Nature metabolism

ISSN: 2522-5812

Titre abrégé: Nat Metab

Pays: Germany

ID NLM: 101736592

Informations de publication

Date de publication:
09 2021

Historique:

received: 10 05 2021

accepted: 06 08 2021

entrez: 23 9 2021

pubmed: 24 9 2021

medline: 15 12 2021

Statut: ppublish

Résumé

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.

Identifiants

DOI: 10.1038/s42255-021-00452-1 PMID: 34552267

pubmed: 34552267

doi: 10.1038/s42255-021-00452-1

pii: 10.1038/s42255-021-00452-1

doi:

Substances chimiques

ATP Binding Cassette Transporter, Subfamily B 0

Anti-Bacterial Agents 0

Bile Acids and Salts 0

Receptors, Cytoplasmic and Nuclear 0

farnesoid X-activated receptor 0C5V0MRU6P

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1228-1241

Informations de copyright

Références

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