Gut microbiome in primary sclerosing cholangitis: A review

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease (IBD) and the “gut-liver” axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including bile acids (BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.

Keywords: Bile acids; Colitis; Inflammatory bowel disease; Microbiome; Microbiota; Primary sclerosing cholangitis

Core tip: The frequent coexistence of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) points to the gut-liver axis as central to pathogenesis. The gut microbiome is hypothesized to be involved. A growing body of literature supports that PSC and PSC-IBD are associated with a distinct gut microbiome and more recent animal studies suggest a potential causal relationship. Microbial metabolites, such as bile acids, may mediate the effects of the gut microbiota in PSC. A sound understanding of the PSC microbiome has the potential to inform the development of microbe-altering therapeutic interventions.