PSC and colitis: A complex relationship

Primary sclerosing cholangitis is one of the most challenging conditions in hepatology, and due to our limited understanding of its pathogenesis, no causal therapies are currently available. While it was long assumed that a minority of people with inflammatory bowel disease (IBD) also develop primary sclerosing cholangitis (PSC), which is sometimes labeled an extraintestinal manifestation of IBD, the clinical phenotype, genetic, and intestinal microbiota associations strongly argue for PSC-IBD being a distinct form of IBD, existing alongside ulcerative colitis and Crohn's disease. In fact, the liver itself could contribute to intestinal pathology, clinically overt in 60%-80% of patients. Recent studies suggested that on a molecular level, almost all people with PSC have underlying colitis. The extent to which the liver and gut influence each other clinically and in terms of disease progression has not yet been conclusively revealed. However, while it seemed intuitive that the 2 diseases have a negative influence on each other, evidence suggests that sclerosing cholangitis can also be protective for the gut and that colitis can, in certain settings, ameliorate liver pathology. This underscores the complex pathophysiological relationships, where factors such as genetic predisposition, changes in the intestinal microbiota, altered bile acid metabolism, and immune cell migration are among the suspected contributors. PSC is an emerging disease with a significant impact on the health-related quality of life of affected people. With this review, we aim to summarize the current knowledge on the gut-liver axis in PSC-IBD, provide new perspectives on risk stratification and treatment, and identify gaps in our current knowledge. Our understanding of this complex relationship will therefore help to design clinical trials and shape the future therapy of PSC-IBD.