Abstract
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
Highlights
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures
It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma
Adams and colleagues proposed that the hepatic complications of inflammatory bowel disease (IBD) are mediated by mucosal T cells that are recruited to the portal areas in response to aberrantly expressed mucosal addressin cell-adhesion molecule 1 (MAdCAM1), which is normally restricted to the gut [44]
Summary
Many aspects of the pathogenesis of PSC remain unclear. it is generally accepted that the interplay between genetic predisposition and environmental factors contributes to the development of the disease and its progression [6,28]. The activation of Kupffer and hepatic stellate cells and consequent overproduction of proinflammatory cytokines and chemokines, such as tumor necrosis factor, plays a key role in this process and may lead to chronic biliary tract infection and inflammation, resulting in portal fibrosis, and PSC [32,36,37,38,39]. Adams and colleagues proposed that the hepatic complications of IBD are mediated by mucosal T cells that are recruited to the portal areas in response to aberrantly expressed mucosal addressin cell-adhesion molecule 1 (MAdCAM1), which is normally restricted to the gut [44] They revealed that lymphocytes infiltrating to the liver in PSC include T cells recruited to the liver by CCL25 expression, which is a chemokine that activates α4β7 binding to MAdCAM1 on the hepatic endothelium [43]. Vedolizumab, a α4β7 integrin antibody that blocks lymphocyte homing towards MAdCAM-1, appears to be ineffective in PSC [46,47]
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