Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications

Abstract

The intestinal lumen is a host place for a wide range of microbiota and sets a unique interplay between local immune system, inflammatory cells and intestinal epithelium, forming a physical barrier against microbial invaders and toxins. Bacterial translocation is the migration of viable or nonviable microorganisms or their pathogen-associated molecular patterns, such as lipopolysaccharide, from the gut lumen to the mesenteric lymph nodes, systemic circulation and other normally sterile extraintestinal sites. A series of studies have shown that translocation of bacteria and their products across the intestinal barrier is a commonplace in patients with liver disease. The deterioration of intestinal barrier integrity and the consulting increased intestinal permeability in cirrhotic patients play a pivotal pathophysiological role in the development of severe complications as high rate of infections, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, progression of liver injury and hepatocellular carcinoma. Nevertheless, the exact cellular and molecular mechanisms implicated in the phenomenon of microbial translocation in liver cirrhosis have not been fully elucidated yet.

Keywords: Bacterial translocation; Cirrhosis; Intestinal bacterial overgrowth; Intestinal barrier; Tight junction.

Figure 1

Pathophysiological overview of intestinal barrier dysfunction in liver cirrhosis and its interconnection with cirrhosis’ complications from diverse organs. Liver cirrhosis delays intestinal motility thus changing the indigenous gut microecology and promoting intraluminal bacterial and endotoxin overgrowth. In parallel, the structural and functional integrity of the intestinal mucosa is disrupted leading to increased gut permeability. Important factors implicated in increased intestinal permeability are the disruption of the tight junctions structural complex and altered epithelial homeostasis, with decreased mitotic activity and increased apoptosis of enterocytes. Systemic cytokinemia and oxidative stress are pivotal promoters of these intestinal alterations. Increased gut permeability permits the escape of intraluminal bacteria and endotoxins initially into portal blood and subsequently, through a decreased clearance capacity of the cirrhotic liver, into systemic circulation. Systemic endotoxemia activates a systemic inflammatory response with release of interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, interferon-γ, nitric oxide and endothelin-1, which can induce circulatory and remote organ dysfunction, partially through promotion of reactive oxygen species formation in the endothelium, lung, kidney, brain, heart and bone marrow. At the same time, the endotoxin-induced increased systemic levels of proinflammatory cytokines and oxidative stress aggravate intestinal and hepatic injury, further promoting bacterial translocation and endotoxemia, thus, maintaining the vicious cycle of gut barrier dysfunction, bacterial and endotoxin translocation, systemic release of proinflammatory cytokines and oxidative stress, complications of cirrhosis from diverse organs. TJ: Tight junction; LPS: Lipopolysaccharide.