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

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the third leading cause of cancer-related mortality worldwide. Recent research indicates that altering the gut environment affects liver immune response and cancer progression, through what is known as the ‘gut–liver axis’. HCC patients have dampened anticancer responses, but through modulating the gut environment, there is potential to reinvigorate these ‘exhausted’ immune cells to target tumors. In promising research on melanoma, transplanting stool from healthy donors through faecal microbiota transplantation (FMT) resulted in increased response to immunotherapy treatment in patients who were previously nonresponding. However, manipulating the gut environment as a therapeutic option in HCC remains to be explored. In this review, we explore the mechanisms through which this occurs, including how the gut environment affects gut barrier function, bacterial sensing, and liver immune responses, and how FMT may be a potential therapy for HCC patients nonresponsive to immunotherapy. 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.