The rising burden of hepatocellular carcinoma in non-alcoholic fatty liver disease: epidemiology, gut microbiota & immunopathogenesis

Abstract

In Australia, non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest-growing cancers. NAFLD related HCC (NAFLD-HCC) is associated with poor prognosis and is a leading cause of cancer-related death. The work in this thesis provides insight to host determinants of this disease in New South Wales, with a particular focus on metabolic comorbidities and their impact on survival. Moreover, we provide evidence for interactions between the gut microbiome and its metabolites in orchestrating aberrant peripheral and intrahepatic immune responses associated with poor outcomes. We make several key observations: 1) NAFLD-HCC is a distinct clinical entity, whereby the accumulation of metabolic risk factors and presence of type II diabetes are independent negative predictors of survival 2) Divergence in gut microbiome composition and function occurs in NAFLD-HCC, distinct from NAFLD-cirrhosis, and appear to direct the peripheral immune response toward an immunosuppressive phenotype ex vivo that is associated with poor outcomes and 3) In longitudinal animal studies, gut dysbiosis occurs early in the trajectory of liver injury, and occurs in parallel to immunosuppressed peripheral and intrahepatic immune responses that develop as HCC ensues. This data provides evidence for the identification of patients with NAFLD-HCC who are at risk of poor outcome and serves as a platform for the development of gut-based interventions, which, when timed early, may offset the burden of this deadly disease.