Microbiome-liver crosstalk: A multihit therapeutic target for liver disease

Abstract

Liver disease has become a leading cause of death, particularly in the West, where it is attributed to more than two million deaths annually. The correlation between gut microbiota and liver disease is still not fully understood. However, it is well known that gut dysbiosis accompanied by a leaky gut causes an increase in lipopolysaccharides in circulation, which in turn evoke massive hepatic inflammation promoting liver cirrhosis. Microbial dysbiosis also leads to poor bile acid metabolism and low short-chain fatty acids, all of which exacerbate the inflammatory response of liver cells. Gut microbial homeostasis is maintained through intricate processes that ensure that commensal microbes adapt to the low oxygen potential of the gut and that they rapidly occupy all the intestinal niches, thus outcompeting any potential pathogens for available nutrients. The crosstalk between the gut microbiota and its metabolites also guarantee an intact gut barrier. These processes that protect against destabilization of gut microbes by potential entry of pathogenic bacteria are collectively called colonization resistance and are equally essential for liver health. In this review, we shall investigate how the mechanisms of colonization resistance influence the liver in health and disease and the microbial-liver crosstalk potential as therapeutic target areas.

Keywords: Microbiome; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Liver disease; Microbiome-host crosstalk; Gut homeostasis; Microbial metabolites

Core Tip: The influence of the gut microbiome on various body systems has important implications for health and disease, such as liver disease. While the exact mechanisms of how the microbiome contributes to liver disease are unknown, there is strong evidence that the translocation of various metabolites across the mucosal barrier plays a strong role, which is precipitated by dysbiotic gut microbiota. Considering the importance of the microbiome in liver disease, powerful therapeutic options that can manipulate the gut microbiome are being explored. These approaches could have the potential for effective treatments for various stages of liver disease. This review will explore how the mechanisms of colonization resistance influence the liver in health and disease and finally examine potential therapeutic targets in the gut-liver axis.