Intestinal permeability in the pathogenesis of liver damage: From non-alcoholic fatty liver disease to liver transplantation

Abstract

The intimate connection and the strict mutual cooperation between the gut and the liver realizes a functional entity called gut-liver axis. The integrity of intestinal barrier is crucial for the maintenance of liver homeostasis. In this mutual relationship, the liver acts as a second firewall towards potentially harmful substances translocated from the gut, and is, in turn, is implicated in the regulation of the barrier. Increasing evidence has highlighted the relevance of increased intestinal permeability and consequent bacterial translocation in the development of liver damage. In particular, in patients with non-alcoholic fatty liver disease recent hypotheses are considering intestinal permeability impairment, diet and gut dysbiosis as the primary pathogenic trigger. In advanced liver disease, intestinal permeability is enhanced by portal hypertension. The clinical consequence is an increased bacterial translocation that further worsens liver damage. Furthermore, this pathogenic mechanism is implicated in most of liver cirrhosis complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma. After liver transplantation, the decrease in portal pressure should determine beneficial effects on the gut-liver axis, although are incompletely understood data on the modifications of the intestinal permeability and gut microbiota composition are still lacking. How the modulation of the intestinal permeability could prevent the initiation and progression of liver disease is still an uncovered area, which deserves further attention.

Keywords: Bacterial translocation; Cirrhosis; Gut microbiota; Gut-liver axis; Liver disease; Mediterranean diet; Personalized medicine.

Figure 1

Physiological gut barrier.

Figure 2

Intestinal permeability in the pathogenesis of liver damage. Several disorders, such as gut dysbiosis and primary and secondary intestinal diseases, can cause increased intestinal permeability. Consequently, viable bacteria and microbial- associated molecular patterns cross the intestinal epithelial barrier, a process known as bacterial translocation. An efficient immunological barrier limits this process, promoting a local immune response in activated mesenteric lymph nodes. When this primary firewall fails, microbes and microbial compounds reach the liver, where they activate Kupffer cells by binding Toll-like receptors. Kupffer cells orchestrate several processes, such as the release of inflammatory cytokines and reactive oxygen species, the recruitment of innate immune cells, the activation of hepatic stellate cells. The uncontrolled perpetuation of this pathogenic mechanism results in liver inflammation and damage, fibrogenesis and systemic inflammation. See text for further details.