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

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

Schneider, K. M. (author)

Candels, L. S. (author)

Hov, J. R. (author)

Myllys, M. (author)

Hassan, R. (author)

Schneider, C. V. (author)

Wahlström, Annika, 1975 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine

Mohs, A. (author)

Zuhlke, S. (author)

Liao, L. J. (author)

Elfers, C. (author)

Kilic, K. (author)

Henricsson, Marcus, 1975 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine

Molinaro, Antonio (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine

Hatting, M. (author)

Zaza, A. (author)

Drasdo, D. (author)

Frissen, M. (author)

Devlin, A. S. (author)

Galvez, E. J. C. (author)

Strowig, T. (author)

Karlsen, T. H. (author)

Hengstler, J. G. (author)

Marschall, Hanns-Ulrich, 1954 (author): Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory

Ghallab, A. (author)

Trautwein, C. (author)

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2021-09-22
2021
English.
In: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 3:9, s. 1228-1241

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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. Patients with primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease, display changes in the gut microbiota and in bile acid composition. Schneider, Candels and colleagues identify a role for microbiota-dependent regulation of bile acid synthesis through farnesoid X receptor signalling, which is relevant for PSC disease progression.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Keyword

primary sclerosing cholangitis
mucosa-associated microbiota
bile-acids
intestinal microbiota
ursodeoxycholic acid
sequences
metronidazole
metabolism
diversity
dysbiosis
Endocrinology & Metabolism

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ref (subject category)
art (subject category)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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By the university: University of Gothenburg

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