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Review

Gut–Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview

by
Fotios S. Fousekis
1,*,
Konstantinos Mpakogiannis
1,
Georgios D. Lianos
2,
Elisabetta Antonelli
3,
Gabrio Bassotti
3 and
Konstantinos H. Katsanos
1
1
Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45500 Ioannina, Greece
2
Department of Surgery, University Hospital of Ioannina, 45500 Ioannina, Greece
3
Gastroenterology, Hepatology and Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia Medical School, 06123 Perugia, Italy
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(21), 7817; https://doi.org/10.3390/jcm14217817
Submission received: 13 October 2025 / Revised: 27 October 2025 / Accepted: 1 November 2025 / Published: 3 November 2025
(This article belongs to the Special Issue Advances in Primary Sclerosing Cholangitis: Pathogenesis, Diagnosis and Emerging Therapies)
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Abstract

Primary sclerosing cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive bile duct inflammation and fibrosis. Its strong association with inflammatory bowel disease (IBD) highlights the possible role of the gut–liver axis in disease pathogenesis. Here, we review the mechanisms that may contribute to the disruption of the gut–liver axis, leading to liver injury and the development of PSC. In particular, disruption of the intestinal barrier allows microbial products to enter the portal circulation, stimulating hepatic immune cells and triggering biliary inflammation. Concurrently, gut-primed lymphocytes expressing mucosal homing receptors migrate aberrantly to the liver, where they may contribute to biliary epithelial cell injury. Dysbiosis, characterized by reduced microbial diversity and the expansion of bile-tolerant and pro-inflammatory taxa, amplifies this immune activation and disturbs gut–liver homeostasis. Moreover, bile acids act as signaling molecules, regulating metabolism and immune responses through receptors such as FXR and TGR5. Dysregulation of these pathways may promote cholestasis, inflammation, and fibrosis. By understanding these interactions, we may identify novel therapeutic targets for PSC.
Keywords: primary sclerosing cholangitis; gut; microbiome; intestinal barrier; dysbiosis; inflammation; fibrogenesis; immune activation primary sclerosing cholangitis; gut; microbiome; intestinal barrier; dysbiosis; inflammation; fibrogenesis; immune activation

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MDPI and ACS Style

Fousekis, F.S.; Mpakogiannis, K.; Lianos, G.D.; Antonelli, E.; Bassotti, G.; Katsanos, K.H. Gut–Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview. J. Clin. Med. 2025, 14, 7817. https://doi.org/10.3390/jcm14217817

AMA Style

Fousekis FS, Mpakogiannis K, Lianos GD, Antonelli E, Bassotti G, Katsanos KH. Gut–Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview. Journal of Clinical Medicine. 2025; 14(21):7817. https://doi.org/10.3390/jcm14217817

Chicago/Turabian Style

Fousekis, Fotios S., Konstantinos Mpakogiannis, Georgios D. Lianos, Elisabetta Antonelli, Gabrio Bassotti, and Konstantinos H. Katsanos. 2025. "Gut–Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview" Journal of Clinical Medicine 14, no. 21: 7817. https://doi.org/10.3390/jcm14217817

APA Style

Fousekis, F. S., Mpakogiannis, K., Lianos, G. D., Antonelli, E., Bassotti, G., & Katsanos, K. H. (2025). Gut–Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview. Journal of Clinical Medicine, 14(21), 7817. https://doi.org/10.3390/jcm14217817

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