Background
Liver hepatocellular carcinoma (HCC) and anatomically-related cancers of the biliary tract share commonalities of high mortality and rising incidence rates, likely due to Western diets and increased obesity. Unhealthy lifestyles promote obesity and metabolic dysfunction by changing gut microbiome profiles and altering colonic barrier integrity. In healthy states, bacterial translocation and leakage of toxins across the gut barrier towards the liver are limited; but are consequences of barrier dysfunctionality leading to a pro-inflammatory environment. We have previously shown that components of these mechanisms are associated with increased HCC risk, however, there is a marked knowledge gap on how these mechanisms interact with obesity and metabolic dysfunction, while very little is known about biliary tract cancers. Objectives & Setting
We hypothesize that higher hepatobiliary exposure to pathobiont/pathogenic bacteria and inflammatory compounds are associated with higher risk of these cancers. Our main objective is to assess the role of gut mucosal barrier integrity, microbial translocation (features of gut barrier damage / dysbiosis) and chronic inflammation as underlying mechanisms in hepatobiliary cancer (HBC) development in a case-control study (515 matched pairs) nested within the EPIC cohort using pre-diagnostic biospecimens. We will measure protein biomarkers of colonic barrier dysfunction (ELISA), antibodies to microbial antigens (Luminex-based panel) and metabolic perturbations (LC-MS chromatography), indicating bacterial encroachment/translocation. From these data, HBC risk will be assessed by logistic regression. We will apply mediation analyses to determine how much these mechanisms may be mediated by diet, lifestyle, obesity, and metabolic factors (e.g., toxic Bile Acids).
The project will contribute new knowledge on the role of microbial factors and gut barrier function in HBC development, including novel underlying mechanisms that we envisage obesity and metabolic dysfunction can promote carcinogenesis. This new information will guide advice on dietary/lifestyle patterns and potential microbiota manipulation strategies for prevention of these lethal cancers.
