Intestinal permeabililty in portal hypertension

Translocation of bacteria and bacterial products from the intestinal lumen into the systemic circulation is a key contributing factor in the pathogenesis of complications of cirrhosis such as spontaneous bacterial peritonitis and hepatorenal syndrome. Three critical factors that facilitate translocation of bacteria in patients with cirrhosis are: alterations in the intestinal microbiota, defective immune system and dysfunction of the intestinal epithelial barrier. . Translocation of bacterial products, such as endotoxins, across the intestinal epithelium occurs via the transcellular and paracellular routes. Transport of solutes across the transcellular route is carrier-mediated and occurs with the help of transporters and channels. Transport of molecules through the paracellular route across the intestinal epithelium occurs by the process of diffusion and is not carrier-mediated. An intact intestinal epithelial barrier prevents penetration of the intestinal mucosa by noxious substances such as intestinal microbes and microbial products. Disruption of this barrier system results in a “leaky” intestine, which increases its permeability. The overall function of transport through the intestinal epithelial paracellular route can be assessed functionally by estimating intestinal permeability. Specialized cell–cell junctional complexes allow selective paracellular transport while maintaining intercellular adhesion (intermediate junctions and desmosomes) and permitting intercellular communication (gap junctions). A tight junction (TJ) at the apico-lateral epithelial surface is potent in restricting the paracellular movement of even very small (2 kD) molecules, thereby preventing the transepithelial transport not only of bacteria, but also of macromolecules such as lipopolysaccharides (LPSs). TJs are made up of several transmembrane and intracytoplasmic proteins. Some of the important transmembranous proteins are: claudins (claudin 2, 3 and 4), occludin and junction adhesion molecule. Some of the intra-cytoplasmic proteins are: ZO-1, ZO-2 and ZO-3, which acts as scaffold between the transmembrane proteins and intracellular actin and myosin filaments. Coordinated interactions of these proteins are important for the regulation and maintenance of TJ and paracellular permeability.