Hepato-Flame: Studying the interaction of diet, obesity, microbial translocation and inflammatory pathways in hepatobiliary cancer development: A European prospective cohort study

In many world regions including Ireland, the incidence of liver cancer and nearby cancers of the biliary tract (together termed hepatobiliary cancers) is rising steadily, and these deadly cancers have limited available treatments. Increasing rates may be linked to obesity and other components of unhealthy lifestyles which cause disturbances in metabolism and high inflammation that lead to their development. Here, we further postulate that gut microbiota changes to more disease-promoting (pathogenic) strains and weakening of the bowel mucosal barrier allows leakage of bacteria towards the liver, exposing it and the biliary tract to pro-inflammatory and carcinogenic bacterially-derived products such as toxic bile acids. This interactively promotes a highly inflammatory environment and hepatobiliary cancer development.

To provide strong evidence supporting our hypothesis, we will compare how pathogenic microbial and gut barrier disturbances promote inflammation and interactively promote the development of hepatobiliary cancers, and how unhealthy dietary/lifestyle habits impact these processes. We will use existing resources within the large EPIC prospective cohort study (i.e., detailed validated dietary/lifestyle data and biological samples collected before cancer diagnoses from >520,000 participants from 10 Western European countries):

Within EPIC, we will match the 515 participants who have developed hepatobiliary cancers to 515 healthy cohort participants. We will then measure blood biomarkers of gut barrier permeability, pathogenic bacteria, and metabolic perturbations (such as toxic bile acids) leading to cancer development. Our hypothesis will be confirmed if comparisons show that biomarker levels of these processes are statistically higher in cases than in controls. We will also explore the extent to which poor lifestyle and obesity influence our observed associations.

This comprehensive project will provide clear evidence that obesity and unhealthy dietary habits promote hepatobiliary cancer development through increased presence of pathogenic bacteria inflammation and metabolic perturbations. The findings will provide robust information to enhance public cancer prevention policy.

Award Date
01 July 2022
Award Value
€367,057.00
Principal Investigator
Dr David Hughes
Host Institution
University College Dublin
Scheme
ILP