**1. Introduction**

The progressive accumulation of extracellular matrix (ECM) in the liver, termed fibrosis, is the result of chronic liver damage due to a variety of insults: viral hepatitis (hepatitis B virus (HBV) and hepatitis C virus (HCV)), alcohol or fatty liver disease, drug-induced liver damage, or autoimmunity. While the prevalence of HCV- and HBV-mediated fibrosis has been on the decline since the advent of direct acting antivirals (DAAs) for HCV and improved vaccination/education strategies for HBV, other etiologies are on the rise [1]. The prevalence of non-alcoholic fatty liver disease (NAFLD) and its inflammatory form, non-alcoholic steatohepatitis (NASH), have increased in step with the obesity epidemic and are significant contributors to fibrosis, particularly in Western countries [1]. Indeed, while the prevalence of viral hepatitis dropped between 2000 and 2017, alcoholic cirrhosis increased by 16% and NASH cirrhosis by 33% [1].

The term gut–liver axis defines a bidirectional interaction between the gastrointestinal tract and the liver [2]. While the liver contributes bile acids, IgA, and antimicrobial peptides to the gut via the biliary tract, the portal vein transports gastrointestinal metabolites from the gut into the liver [2]. In the absence of disease, the mucosal barriers within the intestinal tract remain intact, preventing the transport of luminal microbes into the liver. In chronic liver disease (CLD) however, the intestinal barrier is impaired as a result of lifestyle choices (e.g., alcohol or obesity) or portal hypertension secondary to advanced fibrosis/cirrhosis, resulting in the translocation of microbes and their products into the blood.

Translocation of gut-derived antigens into the portal circulation enacts a potent inflammatory response in the liver, which has been well described in alcoholic and fatty liver disease, as well as liver cirrhosis [2]. These antigens not only drive hepatic inflammation and progressive fibrosis, but also contribute to mortality in end-stage liver disease due to their role in secondary infections such as spontaneous bacterial peritonitis (SBP) and hepatic encephalopathy [3]. While intestinal permeability is not the primary driver of liver inflammation and fibrosis, it has become evident that the inflammatory response to microbial antigens as a result of increased intestinal permeability strongly influences the progression of disease.

This review will focus on the multi-systemic nature of the gut–liver axis in health and disease. We have described (1) the intestinal barriers and mechanisms by which they become impaired in chronic liver disease, (2) the contribution of microbial antigens to liver inflammation and fibrosis, and (3), current therapies used to prevent either intestinal permeability or the hepatic inflammatory and fibrotic response.

### **2. Gut Microbiota and Bacterial Translocation in Chronic Liver Diseases**
