The gut liver axis in liver disease: pathophysiological basis for therapy.
The gut liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established through the vascular route of the portal vein that carries gut derived products directly to the liver, and the liver feed back route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintain homeostasis of the gut liver axis, and as part of the two way communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut liver axis at multiple interconnected levels, including the gut microbiome, mucus, epithelial barrier and antimicrobial peptides production, which increases the microbial exposure and the pro inflammatory environment of the liver. Growing evidences indicate the pathogenetic role of microbe derived metabolites, such as trimethylamine, secondary bile acids, SCFA and ethanol, in the pathogenesis of non alcoholic fatty liver disease. Cirrhosis by itself is associated to profound alterations in gut microbiota and damage at the different levels of defense of the intestinal barrier, including the epithelial, the vascular and the immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut liver axis primarily damaged in each chronic liver disease offers possibilities to intervention. Beyond antibiotics, upcoming therapies centered in the gut include new generations of probiotics, bacterial metabolites (postbiotics) fecal microbial transplantation, and carbon nanoparticles. FXR agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new approaches of treatment.
Journal of hepatology