Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice

Phillipp Hartmann, Katrin Hochrath, Angela Horvath, Peng Chen, Caroline T. Seebauer, Cristina Llorente, Lirui Wang, Yazen Alnouti, Derrick E. Fouts, Peter Stärkel, Rohit Loomba, Sally Coulter, Christopher Liddle, Ruth T. Yu, Lei Ling, Stephen J. Rossi, Alex M. DePaoli, Michael Downes, Ronald M. Evans, David A. BrennerBernd Schnabl

Research output: Contribution to journalArticle

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Abstract

Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant—a human FGF15 ortholog—was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Conclusion: Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).

Original languageEnglish (US)
Pages (from-to)2150-2166
Number of pages17
JournalHepatology
Volume67
Issue number6
DOIs
StatePublished - Jun 2018

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Fibroblast Growth Factor Receptors
Alcoholic Liver Diseases
Bile Acids and Salts
Ethanol
Liver
Metagenomics
choloylglycine hydrolase
Lipid Metabolism
Cytochrome P-450 Enzyme System
Intestines
Alcoholic Fatty Liver
Alcohols
Dysbiosis
Bacterial DNA
Dependovirus
Gastrointestinal Contents
Fibroblast Growth Factors
Enterocytes
Microbiota
Gastroenterology

ASJC Scopus subject areas

  • Hepatology

Cite this

Hartmann, P., Hochrath, K., Horvath, A., Chen, P., Seebauer, C. T., Llorente, C., ... Schnabl, B. (2018). Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology, 67(6), 2150-2166. https://doi.org/10.1002/hep.29676

Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. / Hartmann, Phillipp; Hochrath, Katrin; Horvath, Angela; Chen, Peng; Seebauer, Caroline T.; Llorente, Cristina; Wang, Lirui; Alnouti, Yazen; Fouts, Derrick E.; Stärkel, Peter; Loomba, Rohit; Coulter, Sally; Liddle, Christopher; Yu, Ruth T.; Ling, Lei; Rossi, Stephen J.; DePaoli, Alex M.; Downes, Michael; Evans, Ronald M.; Brenner, David A.; Schnabl, Bernd.

In: Hepatology, Vol. 67, No. 6, 06.2018, p. 2150-2166.

Research output: Contribution to journalArticle

Hartmann, P, Hochrath, K, Horvath, A, Chen, P, Seebauer, CT, Llorente, C, Wang, L, Alnouti, Y, Fouts, DE, Stärkel, P, Loomba, R, Coulter, S, Liddle, C, Yu, RT, Ling, L, Rossi, SJ, DePaoli, AM, Downes, M, Evans, RM, Brenner, DA & Schnabl, B 2018, 'Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice', Hepatology, vol. 67, no. 6, pp. 2150-2166. https://doi.org/10.1002/hep.29676
Hartmann, Phillipp ; Hochrath, Katrin ; Horvath, Angela ; Chen, Peng ; Seebauer, Caroline T. ; Llorente, Cristina ; Wang, Lirui ; Alnouti, Yazen ; Fouts, Derrick E. ; Stärkel, Peter ; Loomba, Rohit ; Coulter, Sally ; Liddle, Christopher ; Yu, Ruth T. ; Ling, Lei ; Rossi, Stephen J. ; DePaoli, Alex M. ; Downes, Michael ; Evans, Ronald M. ; Brenner, David A. ; Schnabl, Bernd. / Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. In: Hepatology. 2018 ; Vol. 67, No. 6. pp. 2150-2166.
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abstract = "Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant—a human FGF15 ortholog—was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Conclusion: Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).",
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AU - Hartmann, Phillipp

AU - Hochrath, Katrin

AU - Horvath, Angela

AU - Chen, Peng

AU - Seebauer, Caroline T.

AU - Llorente, Cristina

AU - Wang, Lirui

AU - Alnouti, Yazen

AU - Fouts, Derrick E.

AU - Stärkel, Peter

AU - Loomba, Rohit

AU - Coulter, Sally

AU - Liddle, Christopher

AU - Yu, Ruth T.

AU - Ling, Lei

AU - Rossi, Stephen J.

AU - DePaoli, Alex M.

AU - Downes, Michael

AU - Evans, Ronald M.

AU - Brenner, David A.

AU - Schnabl, Bernd

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N2 - Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant—a human FGF15 ortholog—was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Conclusion: Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).

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