The microbiota and the gut–liver axis in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut–liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut–liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut–liver axis. Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease (IBD) and potentially provides unique insights into the gut–liver axis. This Review explores these links and provides an overview of the gut microbiome in PSC, including PSC–IBD, exploring related hypotheses of disease mechanisms. Key points The close association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) makes PSC a prototype model disease for exploring the gut–liver axis. Clinical data suggest that intestinal inflammation, an intact colon and antibiotics might influence the disease course of sclerosing cholangitis both before and after liver transplantation. The gut microbiota composition in PSC differs from that of healthy individuals as controls and from those with IBD without PSC, but confounding factors and the potential influence of disease stage and IBD activity are so far understudied. Experimental models suggest that the gut microbiota influences sclerosing cholangitis, with both harmful and beneficial effects having been identified. The relative importance of individual microorganisms (‘pathobionts’) versus specific by-products of microbial activity (microbial metabolites) in PSC development is currently unknown. The current sum of evidence provides a strong rationale for clinical trials of therapies that target the gut in PSC.