Role of the Gut–Liver Axis in the Pathobiology of Cholangiopathies: Basic and Clinical Evidence

Abstract

The “Gut–Liver Axis” refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut–liver axis in the pathogenesis of cholangiopathies.

Biliary stem cells in health and cholangiopathies and cholangiocarcinoma

“…As largely demonstrated for the intestine, similarly, the bile duct wall constitutes a well-organized barrier capable of counteracting the toxic environment of bile through active energy expenditure [27]. The histo-morphological, molecular and functional features of the biliary barrier have not largely investigated [27]. The biliary barrier and defense systems include mechanisms shared with the gut, for example, immunoglobulins A (IgA), defensins, Toll-like receptor (TLR)-mediated immune activation, etc.…”

“…As largely demonstrated for the intestine, similarly, the bile duct wall constitutes a well-organized barrier capable of counteracting the toxic environment of bile through active energy expenditure [27]. The histo-morphological, molecular and functional features of the biliary barrier have not largely investigated [27].…”

“…The biliary barrier and defense systems include mechanisms shared with the gut, for example, immunoglobulins A (IgA), defensins, Toll-like receptor (TLR)-mediated immune activation, etc. Microorganisms must possess tolerance mechanisms in order to resist bile action [26,27]. Experiments in germ-free mdr 2 knockout mice show exacerbated biochemical and histological features of sclerosing cholangitis [28].…”

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

“…Under healthy conditions, only a limited number of bacteria and their metabolites can reach the liver and be eliminated by the immune system of the liver. Under pathological conditions, however, disruption of the microbiota causes an increase in intestinal permeability, which results in the transfer of bacteria from the intestines to the liver via the circulation, thereby triggering liver inflammation and fibrosis (Bruneau et al, 2021;Bragazzi et al, 2023;Jiang et al, 2023). Consequently, the degradation of the intestinal barrier and the increase in intestinal permeability caused by intestinal microorganisms, their metabolites, and associated proteins are also essential components of the pathogenesis of AIH.…”

“…The gut microbiota and its metabolites can modulate immune responses in numerous ways to either maintain intestinal homeostasis or induce intestinal inflammation. The gastrointestinal tract is essential for preventing gut microbiota exposure and maintaining immune homeostasis in the host (Chopyk and Grakoui, 2020;Bragazzi et al, 2023). Numerous factors influence the constitution and abundance of intestinal microflora, so its composition is not static.…”