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 there from, 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.

Autophagy and senescence in fibrosing cholangiopathies

“…The epithelial lining cells (cholangiocytes) exhibit heterogeneities in their morphologies, phenotypes and gene expression along the biliary tree and function as a secretory/absorptive epithelium and other physiological roles [5][6][7][8]. Cholangiopathies are a diverse group of biliary disorders of distinct etiologies, and they include, for example, immune-mediated, drug-induced and infectious cholangiopathies [1,2,[9][10][11][12]. Among them, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) are characterized by cholangiocytic injuries and progressive fibrous obliteration of the biliary tree associated with nonspecific inflammatory cell infiltration [1,2,[9][10][11][12].…”

“…Cholangiopathies are a diverse group of biliary disorders of distinct etiologies, and they include, for example, immune-mediated, drug-induced and infectious cholangiopathies [1,2,[9][10][11][12]. Among them, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) are characterized by cholangiocytic injuries and progressive fibrous obliteration of the biliary tree associated with nonspecific inflammatory cell infiltration [1,2,[9][10][11][12]. Whereas PSC and BA are considered complex disorders involving multiple etiopathogenetic factors, immune system-mediated assaults against the cholangiocytes are regarded a central feature [1,2,[9][10][11][12][13][14][15][16].…”

The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease

“…7 Data from basic and clinical studies have long supported the hypothesis that the intestinal microbiota may have a role in PSC pathogenesis. [8][9][10] Recently, studies using next-generation sequencing have reported a distinct fecal or mucosal microbiota composition in PSC-IBD patients. [11][12][13][14][15][16][17][18] There is a close interplay between gut flora and BA metabolism.…”

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

“…Composition of microbiota from intestinal biopsies of healthy controls and PSC patients demonstrated lower diversity and richness in PSC patients compared with non-inflammatory controls [161] . In line with the hypothesis that intestinal microbiome plays a role in pathogenesis of PSC [162] , interfering with the microbiome by antibiotic treatment may change the course of the liver disease. Various absorbable/systemic and non-absorbable antibiotics have been tested in PSC [163] and reported to induce biochemical improvement, with vancomycin being the most promising agent [164] .…”