The gut microbiome and liver cancer: mechanisms and clinical translation

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising.

Figure 1. Contribution of the gut microbiota to hepatocarcinogenesis: mechanisms and therapeutic targets.

Dysbiosis and the leaky gut promote the progression of liver disease and the development of hepatocellular carcinoma (HCC) via multiple mechanisms, including the release of cancer-promoting and senescence-promoting metabolites such as deoxycholic acid (DCA) from the dysbiotic microbiota, and increased hepatic exposure to gut-derived microbe-associated molecular patterns (MAMPs) such as lipopolysaccharide (LPS), which in turn promote hepatic inflammation, fibrosis, proliferation and the activation of anti-apoptotic signals. These cancer-promoting signalling pathways can be interrupted at several levels: using probiotics to restore eubiosis; using antibiotics to eliminate disease-promoting bacteria and decrease the release of MAMPs and metabolites from the leaky gut; using agents to improve the gut barrier; and potentially using inhibitors of bacterial metabolism to reduce the production of cancer-promoting metabolites by the gut microbiota. HSC, hepatic stellate cell; TLR, Toll-like receptor; SASP, senescence-associated secretory phenotype; FXR, farnesoid X receptor.