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The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats
Open accessAbstract
Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis.
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“Accordingly, FXR activation by agonists GW4064 or obeticholic acid (OCA) attenuates mucosal injury, ileal barrier permeability, bacterial overgrowth and bacterial translocation in mice and rats 20,21,141,142.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [141]
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“FXR deficiency has therefore been linked to increased intestinal permeability and BTL in noneliver-related gastrointestinal disorders, such as inflammatory bowel disease.(25,26) However, whether FXR dysfunction also relates to BTL in chronic liver disease (and also what are the underlying pathophysiological mechanisms…”
BackgroundResultTight Junction Pore and Leak Pathways: A Dynamic Duo
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Albillos, A., de Gottardi, A., & Rescigno, M. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.10.003 · Cited by 2,166
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Tilg, H., Adolph, T. E., & Trauner, M. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.09.017 · Cited by 843
Mouries, J., Brescia, P., Silvestri, A., Spadoni, I., Sorribas, M., Wiest, R., Mileti, E., Galbiati, M., Invernizzi, P., Adorini, L., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.005 · Cited by 688
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Metadata
- Authors
- Verbeke, L., Farre, R., Verbinnen, B., Covens, K., Vanuytsel, T., Verhaegen, J., Komuta, M., Roskams, T., Chatterjee, S., Annaert, P., Elst, I. V., Windmolders, P., Trebicka, J., Nevens, F., & Laleman, W.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Thomas More Kempen (BE)
- KU Leuven (BE)
- University of Bonn (DE)
- Corresponding author
- Verbeke, Len
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 185
- Issue
- 2
- Pages
- 409-419
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2104582722
- Cited by
- 225
- References
- 54
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 24 · 2023: 11 · 2022: 21 · 2021: 28 · 2020: 18 · 2019: 22 · 2018: 13 · 2017: 18 · 2016: 16 · 2015: 8
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Funders
- Scientific Research–Flanders
- Deutsche Forschungsgemeinschaft (SFB TRR57 project 18)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- obeticholic acid, FXR agonists, bacterial translocation, intestinal barrier dysfunction, cholestasis, bile duct ligation, intestinal permeability, claudin-2, claudin-1, occludin, tight junction proteins, natural killer cells, interferon-gamma, intestinal inflammation, gut-liver axis, liver cirrhosis, Escherichia coli
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Chenodeoxycholic Acid, Cholestasis, Escherichia coli, Gene Expression Regulation, Ileum, Male, Cytokines, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Bacterial Translocation, Rats
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