Biliary barrier disruption and phosphatidylcholine deficiency in primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a rare chronic cholangiopathy that is strongly associated with inflammatory bowel disease, particularly ulcerative colitis. It is characterized by multifocal biliary strictures, typically producing the classic “beads-on-a-string” appearance on magnetic resonance cholangiopancreatography, and by the histological finding of periductal concentric fibrosis (“onion-skin” fibrosis). Its pathogenesis is multifactorial and involves genetic susceptibility, immune dysregulation, environmental influences, and perturbations of the gut-liver axis. In this context, toxic bile acids and other luminal mediators originating from inflamed bowel mucosa may contribute to cholangiocyte injury. Phosphatidylcholine (PC) plays a central role in membrane integrity, cellular signaling, and inflammatory regulation, and its deficiency may predispose to hepatobiliary damage. Kindlin proteins are key modulators of integrin-mediated functions; notably, kindlin-2 contributes to the stabilization of intercellular junctions, and its loss impairs smooth muscle and intestinal development. Mice with biliary-specific deletion of kindlin-2 develop onion-skin fibrosis in the absence of overt cholestatic abnormalities, thereby supporting the concept of a gut-liver pathogenic axis. Nevertheless, further investigation is required to determine the extent to which this model reproduces human PSC, particularly regarding PC availability and cholangiocyte junctional integrity. Disruption of tight junctions may reduce PC delivery to the biliary mucosa, thereby promoting hepatic injury. Although these findings support the rationale for exploring PC supplementation as a potential therapeutic strategy in PSC, additional studies are required before translation to clinical trials can be justified.

Keywords

kindlin-2 / onion-skin fibrosis / phosphatidylcholine / primary sclerosing cholangitis / tight junctions

References

[1] Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019; 68: 1356-78.

[2] Mirante VG. Surveillance for cholangiocarcinoma in PSC: MRI, ERCP, both-or neither? Explor Dig Dis. 2025; 4: 1005102.

[3] Marya NB, Tabibian JH. Role of endoscopy in the management of primary sclerosing cholangitis. World J Gastrointest Endosc. 2019; 11: 84-94.

[4] Toy E, Balasubramanian S, Selmi C, Li CS, Bowlus CL. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol. 2011; 11: 83.

[5] 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. J Clin Med. 2025; 14: 7817.

[6] Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2011; 25: 727-39.

[7] Tavakoli P, Vollmer-Conna U, Hadzi-Pavlovic D, Grimm MC. A Review of Inflammatory Bowel Disease: A Model of Microbial, Immune and Neuropsychological Integration. Public Health Rev. 2021; 42: 1603990.

[8] Osipova D, Kokoreva K, Lazebnik L, Golovanova E, Pavlov C, Dukhanin A, et al. Regression of Liver Steatosis Following Phosphatidylcholine Administration: A Review of Molecular and Metabolic Pathways Involved. Front Pharmacol. 2022; 13: 797923.

[9] Rao G, Peng X, Li X, An K, He H, Fu X, et al. Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic. Front Med. 2023; 10: 1294267.

[10] Plow EF, Qin J, Byzova T. Kindling the flame of integrin activation and function with kindlins. Curr Opin Hematol. 2009; 16: 323-8.

[11] Pluskota E, Bledzka KM, Bialkowska K, Szpak D, Soloviev DA, Jones SV, et al. Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity. J Physiol. 2017; 595: 6443-62.

[12] Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, Golden JA, et al. Kindlin-2 Is an Essential Component of Intercalated Discs and Is Required for Vertebrate Cardiac Structure and Function. Circ Res. 2008; 102: 423-31.

[13] He X, Song J, Cai Z, Chi X, Wang Z, Yang D, et al. Kindlin-2 deficiency induces fatal intestinal obstruction in mice. Theranostics. 2020; 10: 6182-200.

[14] Lukasova M, Weinberger K, Weiskirchen R, Stremmel W. Onion-skin type of periductular sclerosis in mice with genetic deletion of biliary kindlin-2 as tight junction stabilizer: a pilot experiment indicating a primary sclerosing cholangitis (PSC) phenotype. Metab Target Organ Damage. 2024; 4: 36.

[15] Malik S, Dbouk N, Grant LM, Samant H. Primary Sclerosing Cholangitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026.

[16] Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol. 2020; 73: 651-63.

[17] Arechederra M, Fernandez-Barrena MG, Berasain C, Avila MA. Mouse models of primary sclerosing cholangitis: we just can’t get enough. Metab Target Organ Damage. 2024; 4: 44.

[18] Gauss A, Ehehalt R, Lehmann WD, Erben G, Weiss KH, Schaefer Y, et al. Biliary phosphatidylcholine and lysophosphatidylcholine profiles in sclerosing cholangitis. World J Gastroenterol. 2013; 19: 5454-63.