Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC).

Jochen Mattner

doi:10.3390/ijms17111864

Abstract

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.

Highlights

The liver commands several central metabolic and synthetic pathways in the body
An obstruction of the bile flow as it occurs in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) alters the microbiota, the susceptibility to infection, and the integrity of the epithelial layers [6,7,8]
There exists compelling evidence that microbial agents and/or changes in the intestinal/biliary microbiota are involved in the pathogenesis of PBC and PSC

Summary

Introduction

The liver commands several central metabolic and synthetic pathways in the body. Among these is the regulation of bile (acid) metabolism [1]. Bile acids themselves exhibit several fundamentally important functions [2,5]. These include the elimination of many waste products and catabolites such as cholesterol and bilirubin from the body via the feces, the adsorption and digestion of lipids and fat-soluble vitamins in the gut, and—together with immunoglobulin A (IgA) (which is secreted from the epithelium into the bile fluid)—potent anti-microbial properties that inhibit bacterial growth and adhesion, protecting against ascending infections within the biliary tract. As the liver—due to its anatomic location within the blood circulation—is exposed to various nutritional and microbial compounds from the gastrointestinal tract, a metabolic and/or microbial distortion might promote inappropriate inflammatory immune reactions within hepatic tissues

Mutual Interactions between the Bile and the Intestinal Microbiota

Changes in the Composition of the Microbiota in PBC and PSC Patients

Findings

Conclusions