The gut-liver axis in liver disease: Pathophysiological basis for therapy

Abstract

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 by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback 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 maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and 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 for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal 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 therapeutic approaches.

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

“…The interface between the liver and the gut microbiota is shaped by the mucosal barrier, consisting of the gut epithelial barrier and the gut vascular barrier. The integrity of this intestinal mucus barrier and the physiological composition of the intestinal microbiome are critical for maintaining homeostasis of the liver-gut axis [111]. Metabolic toxins, especially alcohol abuse or high fat/low fiber diet in NAFLD have been described to disrupt intestinal homeostasis by increasing intestinal permeability and altering microbiota [112,113].…”

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

“…The term gut–liver axis highlights the increasingly recognized cross‐talk between both organs that are strictly anatomically and functionally related . The gut and the liver communicate through the biliary tract, the portal vein, and systemic circulation exchanging a myriad of signaling compounds.…”

Probiotics Dietary Supplementation for Modulating Endocrine and Fertility Microbiota Dysbiosis

“…It is also very important to guarantee the transfer to the final site of colonisation, in order to exert the expected clinical effect. Therefore, in the topic of research on fertility, probiotics could reach the vaginal niche by physical transfer or ascendant route, haematogenous route and lymphatic nodes transfer [27]. For the treatment of vulvovaginal infections, probiotics can be administered by the vaginal route in order to control the Lactobacilli recolonisation [25], as a result, these probiotics do not pass through the gastrointestinal tract protecting them from the acidic environment.…”