Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice
Open accessAbstract
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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Bacteria-mediated transformation of host bile has a notable impact on host physiology, regulating bile acid and cholesterol metabolism, host energy balance and weight gain.
“Numerous studies have explicitly demonstrated that bacteria-mediated transformation of host bile has a notable impact on host physiology, regulating bile acid and cholesterol metabolism, host energy balance and weight gain (Hartmann et al., 2018;Pathak et al., 2018;Sayin et al., 2013;Wahlstrom et al., 2016).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Hartmann et al., 2018
The Results section reports that bacterial bile-acid deconjugation changed bile-acid profiles and synthesis in ethanol-fed mice, supporting the bile-acid metabolism portion. The Introduction notes that FGF19 can lower body weight, but the paper does not show that bacterial transformation regulates cholesterol metabolism, energy balance, or weight gain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTargeted interventions can improve bile acid-FXR-fibroblast growth factor 15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, thereby reducing ethanol-induced liver disease in mice.
“These studies suggested that targeted interventions can improve bile acid-FXR-fibroblast growth factor 15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, thereby reducing ethanol-induced liver disease in mice.116”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [116]
ALD-associated microbiota changes lead to alterations in bile acid profiles, including increased amounts of unconjugated bile acids in the small intestine.
“and ALD-associated microbiota changes lead to alterations in bile acid profiles (ie, increased amounts of unconjugated bile acids in the small intestine).116”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [116]
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- Authors
- Hartmann, P., Hochrath, K., Horvath, A., Chen, P., Seebauer, C. T., Llorente, C., Wang, L., Alnouti, Y., Fouts, D. E., Stärkel, P., Loomba, R., Coulter, S., Liddle, C., Yu, R. T., Ling, L., Rossi, S. J., DePaoli, A. M., Downes, M., Evans, R. M., Brenner, D. A., & Schnabl, B.
- Affiliations
- University of California San Diego (US)
- Medical University of Graz (AT)
- University of Nebraska Medical Center (US)
- J. Craig Venter Institute (US)
- UCLouvain (BE)
- The University of Sydney (AU)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Schnabl, Bernd
- ORCID
- Venue
- Hepatology
- Published
- 2018-04-16
- Volume
- 67
- Issue
- 6
- Pages
- 2150-2166
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5962369
- OpenAlex
- W2770310782
- Cited by
- 290
- References
- 50
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 38 · 2023: 31 · 2022: 39 · 2021: 37 · 2020: 36 · 2019: 24 · 2018: 19 · 2017: 1
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX002213)
- Bristol-Myers Squibb
- American Association for the Study of Liver Diseases
- Gilead Sciences
- Office of Research and Development
- Biomedical Laboratory Research and Development, VA Office of Research and Development (I01BX002213)
- NGM Biopharmaceuticals
- Deutsche Forschungsgemeinschaft (HO 5690/1-1, 7336/1-1)
- National Institutes of Health (I01BX002213, R01‐AA020703, U01 AA24726, AA020703, AA24726)
- National Institute on Alcohol Abuse and Alcoholism (R01AA020703, U01AA024726, U01AA021856)
- National Heart, Lung, and Blood Institute (P01HL088093)
- National Cancer Institute (P30CA014195)
- National Institute of Environmental Health Sciences (P42ES010337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- alcoholic liver disease, alcoholic steatohepatitis, bile acid metabolism, farnesoid X receptor, FGF15, FGF19, gut microbiota, bile acid deconjugation, CYP7A1, intestinal barrier, lipid metabolism, commensal bacteria, antibiotic depletion, adeno-associated virus overexpression
- MeSH terms
- Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Ethanol, Animals, Bile Acids and Salts, Fibroblast Growth Factors, Intestinal Mucosa, Intestines, Liver Diseases, Alcoholic, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Mice
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