The Role of the Intestine in the Pathogenesis of Primary Sclerosing Cholangitis: Evidence and Therapeutic Implications

Abstract

The pathogenesis of primary sclerosing cholangitis (PSC), a progressive biliary tract disease without approved medical therapy, is not well understood. The relationship between PSC and inflammatory bowel disease has inspired theories that intestinal factors may contribute to the development and progression of hepatobiliary fibrosis in PSC. There is evidence from both fecal and mucosa‐associated microbial studies that patients with PSC harbor an abnormal enteric microbiome. These organisms are thought to produce toxic byproducts that stimulate immune‐mediated damage of hepatocytes and the biliary tree. The link between these mechanisms may be related to altered intestinal permeability leading to migration of bacteria or associated toxins to the liver through the portal circulation. In support of these concepts, early trials have demonstrated improved biochemical parameters and symptoms of PSC with oral antibiotics, ostensibly through manipulation of the enteric microbiota. This article reviews the published literature for evidence as well as gaps in knowledge regarding these mechanisms by which intestinal aberrations might drive the development of PSC. We also identify areas of future research that are needed to link and verify these pathways to enhance diagnostic and therapeutic approaches.

Autoimmune biliary diseases: primary biliary cholangitis and primary sclerosing cholangitis

“…The strong association between PSC and IBDs led to the “microbiota hypothesis”, supported by observations both in vitro and in animal models. According to this hypothesis, microbial molecules from intestinal dysbiosis reach the liver through the portal circulation and initiate an aberrant cholangiocytic response, including the induction of senescence 23 , 48 , 56 , 57 . An additional theory regarding PSC pathogenesis is the “gut lymphocyte homing” hypothesis.…”

The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases

“…GP2 is not known to be expressed on the biliary epithelium but is present on intestinal microfold (M) cells and plays a role in antigen sensing of the gut microbiome (116,117). This supports that the gut-liver axis might be key in PSC pathogenesis and loss of tolerance may initially occur in the gut (reviewed in (118)). The presence of anti-GP2 antibodies in individuals with PSC is associated with cholangiocarcinoma, increased mortality and reduced transplant free survival (119,120), indicating anti-GP2 antibodies might play a pathogenic role.…”

Leaky Gut Driven by Dysbiosis Augments Activation and Accumulation of Liver Macrophages via RIP3 Signaling Pathway in Autoimmune Hepatitis

“…It's known that alterations in the gut microbiota have been related with most autoimmune diseases, but in most cases, it remains unclear whether these changes are a cause or effect of the disease or merely a reflection of epidemiological differences between groups. The gut-liver axis has clinical importance as a potential therapeutic target in a wide range of chronic liver diseases (33)(34)(35). Recent evidence suggests that the intestinal environment specifically, modifications of the microbiome profile, regulate the pathogenesis of AIH by inducing intestinal inflammation and increasing gut permeability (36).…”