The role of the gut microbiome in the development of hepatobiliary cancers

Abstract

Hepatobiliary cancers, including hepatocellular carcinoma and cancers of the biliary tract, share high mortality and rising incidence rates. They may also share several risk factors related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and rates of obesity. Recent data also suggest a role for the gut microbiome in the development of hepatobiliary cancer and other liver pathologies. The gut microbiome and the liver interact bidirectionally through the "gut-liver axis," which describes the interactive relationship between the gut, its microbiota, and the liver. Here, we review the gut-liver interactions within the context of hepatobiliary carcinogenesis by outlining the experimental and observational evidence for the roles of gut microbiome dysbiosis, reduced gut barrier function, and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to hepatobiliary cancer development. We also outline the latest findings regarding the impact of dietary and lifestyle factors on liver pathologies as mediated by the gut microbiome. Finally, we highlight some emerging gut microbiome editing techniques currently being investigated in the context of hepatobiliary diseases. Although much work remains to be done in determining the relationships between the gut microbiome and hepatobiliary cancers, emerging mechanistic insights are informing treatments, such as potential microbiota manipulation strategies and guiding public health advice on dietary/lifestyle patterns for the prevention of these lethal tumors.

Graphical abstract

FIGURE 1

The gut-liver axis. Unhealthy dietary/lifestyle exposures may lead to gut microbiome disturbances (and potentially pathogenic dysbiosis) with resultant alterations in SCFA concentrations and reduced gut barrier integrity, allowing leakage of bacterial products, such as LPS, and translocation of bacteria toward the liver through the portal vein and systemic circulation, where they are bound by TLRs causing an increase in NF-kB–mediated inflammatory cytokine and ROS production. Dysbiosis also causes an increase in secondary BAs, the majority of which return to the liver through the portal vein and may disrupt BA homeostasis by binding FXR. These mechanisms are thought to increase steatosis and steatohepatitis, and ultimately impact carcinogenesis. Abbreviations: BA, bile acid; BMI, body mass index; FXR, Farnesoid X receptor; LPS, lipopolysaccharide; MAMP, microbe-associated molecular pattern; ROS, reactive oxygen species; SASP, secretory associated senescent phenotype; SCFA, short-chain fatty acid; TLR, toll-like receptor.