Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling
Kai Markus Schneider
(1)
,
Lena Susanna Candels
(1)
,
Johannes Hov
(2)
,
Maiju Myllys
(3)
,
Reham Hassan
(3)
,
Carolin Victoria Schneider
(1)
,
Annika Wahlström
(1)
,
Antje Mohs
(1)
,
Sebastian Zühlke
(1)
,
Lijun Liao
(1)
,
Carsten Elfers
(1)
,
Konrad Kilic
(1)
,
Marcus Henricsson
(4)
,
Antonio Molinaro
(4)
,
Maximilian Hatting
(1)
,
Ayham Zaza
(3)
,
Dirk Drasdo
(5, 6)
,
Mick Frissen
(1)
,
A. Sloan Devlin
(7)
,
Eric Gálvez
(8)
,
Till Strowig
(8)
,
Tom Karlsen
(2)
,
Jan Hengstler
(3)
,
Hanns-Ulrich Marschall
(4)
,
Ahmed Ghallab
(3)
,
Christian Trautwein
(1)
1
UKA -
Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany]
2 Oslo University Hospital [Oslo]
3 IFADO - Leibniz Research Centre for Working Environment and Human Factors [Dortmund]
4 Sahlgrenska Academy at University of Gothenburg [Göteborg]
5 SIMBIOTX - SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires
6 MAMBA - Modelling and Analysis for Medical and Biological Applications
7 Department of Biological Chemistry and Molecular Pharmacology [Harvard Medical School]
8 HZI - Helmholtz Centre for Infection Research
2 Oslo University Hospital [Oslo]
3 IFADO - Leibniz Research Centre for Working Environment and Human Factors [Dortmund]
4 Sahlgrenska Academy at University of Gothenburg [Göteborg]
5 SIMBIOTX - SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires
6 MAMBA - Modelling and Analysis for Medical and Biological Applications
7 Department of Biological Chemistry and Molecular Pharmacology [Harvard Medical School]
8 HZI - Helmholtz Centre for Infection Research
Kai Markus Schneider
- Fonction : Auteur
- PersonId : 793655
- ORCID : 0000-0002-0047-3794
Maiju Myllys
- Fonction : Auteur
- PersonId : 799342
- ORCID : 0000-0001-9117-4572
Reham Hassan
- Fonction : Auteur
- PersonId : 785986
- ORCID : 0000-0002-6569-7676
Antje Mohs
- Fonction : Auteur
- PersonId : 819141
- ORCID : 0000-0001-5937-0696
Marcus Henricsson
- Fonction : Auteur
- PersonId : 804423
- ORCID : 0000-0002-4202-0339
Eric Gálvez
- Fonction : Auteur
- PersonId : 815725
- ORCID : 0000-0001-7459-3871
Till Strowig
- Fonction : Auteur
- PersonId : 792413
- ORCID : 0000-0003-0185-1459
Jan Hengstler
- Fonction : Auteur
- PersonId : 773100
- ORCID : 0000-0002-1427-5246
Hanns-Ulrich Marschall
- Fonction : Auteur
- PersonId : 783383
- ORCID : 0000-0001-7347-3085
Ahmed Ghallab
- Fonction : Auteur
- PersonId : 773099
- ORCID : 0000-0003-0695-3403
Christian Trautwein
- Fonction : Auteur
- PersonId : 758791
- ORCID : 0000-0003-2762-8247
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.