The Microbiota-Gut-Liver Axis: Implications for the Pathophysiology of Liver Disease

Interactions between the gut and the liver in relation to immunological responses and metabolic functions have been recognized as central to homeostasis for decades. The roles of gut bacteria in the pathogenesis of certain complications of cirrhosis such as hepatic encephalopathy, spontaneous bacterial peritonitis, and systemic sepsis were also delineated decades ago -what is new is the idea that interactions between luminal bacteria in the gut (microbiota), the gut itself, and the liver may play a more fundamental role in the pathogenesis of a number of metabolic and immunological diseases. From basic animal research, as well as observations in human disease, a general hypothesis has emerged to explain how interplay between these factors might initiate or perpetuate alcoholic liver disease, nonalcoholic fatty liver disease, and even immunologically mediated liver diseases. In this framework, disrupted microbiota and their products gain access to the gut-associated immune system via a permeable gut barrier and generate inflammatory responses. Disruption of the gut vascular barrier then permits access for bacterial components as well as pro-inflammatory cytokines to the portal circulation and onto the liver where inflammatory and metabolic responses drive the genesis of various liver diseases. Cross-reactivity between bacterial antigens and biliary epitopes has also been invoked in relation to primary sclerosing cholangitis and primary biliary cholangitis. As we learn more of the details of these interactions and of the primacy, or otherwise, of the microbiota in this microbiota-gut-liver axis, new preventive strategies and therapeutic avenues may open up.