Exploring the role of microbiota and metabolic interactions in the development of liver and pancreatic cancers.

Disturbances to the normal gut microbiota flora (dysbiosis) and resultant alterations in microbial products are increasingly implicated in cancer development [1]. While most of these studies have focused on colorectal cancer, there is emerging evidence of a link between microbiome dysbiosis and altered metabolism in the development of cancers at various sites in the gastrointestinal tract, including liver (beyond hepatitis) and pancreatic cancers, which form the focus of this PhD project [2-4]. However, epidemiological evidence, especially from prospective cohorts, is sparse. Recent data on gut barrier function in liver cancer from our project collaborators indicates that leakage of bacterial toxins and bacterial translocation from the gut via the portal vein exposes the liver to a high inflammatory environment, leading to cancer development [5,6]. Furthermore, although most studies on the microbial dysbiosis in cancer have focused on bacterial species, recent reports suggest an appreciable influence of the fungal mycobiome in development of gastrointestinal cancers such as colorectal cancer [7] and pancreatic cancer [8].
The main aims of this project will be to analyse interactions between microbiome sequence data (tissue analyses) and antibodies to bacterial species (blood screening), metabolites such as bile acids and short chain fatty acids (human and microbiota-derived), and markers of gut barrier function, to assess their contribution to the risk of microbial-mediated gastrointestinal cancer development. A secondary aim will be to study the interactions with host genetics and nutritional factors as potential mediators of microbiota disease pathogenesis. The project will highlight the importance of the interaction between microbial infection, dysbiosis (including bacterial, viral, and fungal), gut barrier function, and metabolism in the aetiology of hepatobiliary and pancreatic cancers.
The PhD project will benefit from a collection of European human cohort studies, including case-control and nested case control studies of hepatocellular carcinoma (the main type of liver cancer) and other cancers of the hepatobiliary tract (together termed hepatobiliary cancers) and pancreatic cancers to analyse metagenomic sequences, antigen serology data, metabolite data, and markers of gut barrier function to test the hypothesis of a major contribution from microbial dysbiosis and metabolic dysfunction to gastrointestinal cancer aetiology.
This PhD will involve both laboratory assays such as ELISA assays, qPCR, metagenomic sequencing, mass spectrometry, but there will be a major focus on biostatistical and bioinformatic approaches. These analytical methods will be used to examine modification of microbial associations by gut permeability and microbial and human metabolites, nutrient levels, host genetic variation and other dietary/lifestyle factors.

The project will add to our existing data on hepatitis infection status and a host of other biomarker data on the hepatobiliary cancer cases and controls from a prospective cohort, including targeted and untargeted metabolomics and Metabolic Syndrome Score assessments. These analyses will be combined with metagenomic data and human host genetic data (e.g., immune gene variants, bile acid receptors gene variants, etc) that are available in data repositories. This project will be nested within a larger ongoing examination of the aetiology of gastrointestinal cancers related to the same factors.