Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies

Abstract

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived therefrom, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies.

Keywords: cholestatic; etiopathogenesis; metabolites.

Figure 1

Conceptual model of the etiopathogenesis and natural history of primary sclerosing cholangitis. Biliary epithelial cells, i.e. cholangiocytes, exist in an environment with multiple potential etiologic mediators of hepatobiliary injury. A growing body of basic, translational, and clinical evidence suggests that among these, microbially derived molecules may be central to hepatobiliary injury in and thus the etiopathogenesis of PSC. However, whether there is (1) increased exposure to microbial molecules (e.g. through the enterohepatic circulation, facilitated by compromised intestinal barrier function), (2) alterations in microbial diversity and/or the repertoire of microbial molecules (e.g. due to intestinal microbial dysbiosis), and/or (3) an aberrant or exaggerated cholangiocyte or other hepatic cell response to microbial molecules (e.g. induction of cholangiocyte senescence and the senescence-associated secretory phenotype) remains uncertain. In addition, host immunogenetics may modulate the impact of any of these variables (4) and thus likely play a role in determining whether hepatobiliary injury resolves or if it persists and results in chronic disease (i.e. PSC). These variables may also determine whether PSC progresses to its associated major adverse endpoints, including development of cholangiocarcinoma (CCA), liver failure, and death. Further investigation of the cellular, molecular, and microbial interactions and phenomena represented in this figure, including through previously unavailable (meta)genomic and bioinformatics techniques, will undoubtedly be pursued in future research and is expected to advance current understanding of the etiopathogenesis of PSC.