Biliary barrier disruption and phosphatidylcholine deficiency in primary sclerosing cholangitis

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.