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Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2−/− mice by modulating composition, signalling and excretion of faecal bile acids
Open accessAbstract
Background and aims Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis. Methods Mdr2−/− mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2−/− mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis. Results Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus. Conclusion Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2−/− mice.
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The BA sequestrant colesevelam and ASBT inhibitors (lopixibat and A4250) completely reversed liver and bile duct injury in Mdr2/Abcb4-/- mice.
“The BA sequestrant colesevelam and ASBT inhibitors (lopixibat and A4250) completely reversed liver and bile duct injury in Mdr2/Abcb4–/– mice,198–200”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [200]
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Novel therapeutic targets for cholestatic and fatty liver disease
Trauner, M., & Fuchs, C. D. (2022) · Gut · doi:10.1136/gutjnl-2021-324305 · Cited by 204
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Metadata
- Authors
- Fuchs, C. D., Paumgartner, G., Mlitz, V., Kunczer, V., Halilbasic, E., Leditznig, N., Wahlström, A., Ståhlman, M., Thüringer, A., Kashofer, K., Stojakovic, T., Marschall, H.-U., & Trauner, M.
- Affiliations
- Medical University of Vienna (AT)
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- University of Gothenburg (SE)
- Medical University of Graz (AT)
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
- Corresponding author
- Trauner, Michael
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2018-04-10
- Volume
- 67
- Issue
- 9
- Pages
- 1683-1691
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC6109278
- OpenAlex
- W2797871134
- Cited by
- 76
- References
- 32
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 12 · 2023: 3 · 2022: 11 · 2021: 12 · 2020: 16 · 2019: 6 · 2018: 6
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Austrian Science Fund
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- colesevelam, bile acid sequestrants, sclerosing cholangitis, Mdr2 knockout mice, cholestatic liver injury, bile duct injury, enterohepatic circulation, fecal bile acids, secondary bile acids, glucagon-like peptide-1, exendin-4, FGF15, proglucagon, gut microbiota, Deltaproteobacteria, Lactobacillus, cholangiocyte proliferation, liver fibrosis
- MeSH terms
- Colesevelam Hydrochloride, Animals, Anticholesteremic Agents, Bile Ducts, Cholestasis, Disease Models, Animal, Homeostasis, Liver, Cholangitis, Sclerosing, Treatment Outcome, Mice, Knockout, Mice, Glucagon-Like Peptide 1
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