Gut–liver axis: barriers and functional circuits

• Published in: Nature reviews. Gastroenterology & hepatology 2023-07, Vol.20 (7), p.447-461
• Main Authors: Pabst, Oliver, Hornef, Mathias W., Schaap, Frank G., Cerovic, Vuk, Clavel, Thomas, Bruns, Tony
• Format: Article
• Language: English
• Subjects: 692/4020; 692/4020/1503; 692/4020/2741/2135; 692/4020/2741/288; 692/4020/2741/520; Biomedicine; Digestive system; Endothelium; Environmental factors; Epithelium; Functional morphology; Gastroenterology; Gastrointestinal tract; Hepatology; Immune response; Liver; Medicine; Medicine & Public Health; Microbiomes; Review Article; Structure-function relationships
• ISSN: 1759-5045; 1759-5053
• DOI: 10.1038/s41575-023-00771-6

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut–liver axis. In this Review we discuss the gut–liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches. In this Review, Pabst and colleagues discuss the gut–liver axis, with an emphasis on the establishment and regulation of structural and functional barriers, dynamics within the axis (immune responses and microbiome) and clinical implications. Key points The concept of a ‘gut–liver axis’ emphasizes the clinically relevant link between gut and liver diseases, and the reciprocal interactions between both organs and the microbiome. The enterohepatic tissues form a series of semi-permissive physical, chemical and immunological barriers that limit dissemination of gut content including live microorganisms. Gut epithelial barriers do not simply exclude luminal antigen; they enable a regulated uptake tailored to support different requirements of the tissue at different ages, and different anatomical sites. The liver limits dissemination of gut material via blood whereas gut-draining lymph nodes restrict lymphogenic spread and induce homeostatic immune responses. Microbial and dietary metabolites and the immune system tune barriers of the gut–liver axis to establish a homeostatic balance in the healthy gut and liver. Microbiome-based strategies such as use of antimicrobials, prebiotics, probiotics, synbiotics, bacteriophage therapy and faecal microbiota transplantation aim to restore intestinal homeostasis in liver diseases.