Modulation of the Gut Microbiome to Improve Clinical Outcomes in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recently, the gut microbiota has been shown to be closely linked to modulation of the immune and inflammatory responses, hence its potential as a therapeutic target. Although still under intense investigation, there exists a 'gut-liver axis' that links changes in the gut to the liver. In this regard, composition of gut microbiota and related metabolites, such as bile acids and short-chain fatty acids, have been shown to orchestrate key immune-metabolic events in liver disease and liver cancer. As hepatic immune cells are important determinants of antitumor responses, it is now increasingly recognized that the gut-liver axis plays a key role in influencing the intrahepatic immune response in HCC to favor a pro- or antitumor immune milieu. Hence, modulation of gut microbiota is potentially an attractive option to reinvigorate the antitumor responses. In this regard, promising evidence from melanoma preclinical and clinical studies has demonstrated the efficacy of gut-based intervention in reinvigorating the antitumor responses and improving responses to immunotherapy. However, the role of gut-based interventions as a therapeutic option in HCC remains to be elucidated. This review details how the gut microbiota and bacterial metabolites affect gut barrier function and ultimately immune response in HCC and raises the question of the potential of gut-based interventions as an adjunct therapy for patients with HCC receiving immunotherapy.

Keywords: gut–liver axis; hepatocellular carcinoma; immune response; immunotherapy; microbiota.

Figure 1

Altered gut–liver axis in patients with HCC. In health, the gut microbiota and bacterial metabolites produced maintain homeostasis of the gut. Preserved gut barrier functions prevent bacterial translocation and subsequent inflammation and allows only selected metabolites through into the circulation. Ultimately, homeostasis in the liver is also maintained, with immune surveillance that prevent hepatocarcinogenesis. However, in patients with HCC, dysbiosis results in dysregulated metabolite pool, including increased bile acids (BAs) and dysregulated BA and short-chain fatty acid (SCFA) signalling. There is also impaired gut barrier function, allowing for translocation of bacteria, bacterial components, and metabolites that induces inflammation. In the liver, these factors also play a role in impairing CD8+ T cell antitumour effector functions and increases Treg functions and immunosuppression. Together, these tumorigenic responses may contribute to the initiation and potentiation of HCC.