Investigating how the microbiota may contribute to the development of colorectal adenomas

Identifying risk factors for precancerous colorectal adenoma (CRA) development is important in colorectal cancer (CRC) screening and prevention. Infections by bacterial pathogens, dysregulation of commensal microbes, and resultant alterations in microbial products are increasingly implicated in colorectal cancer (CRC) development. However, there is little information on how their interactions and geographical differences contribute to disease aetiology. Little is currently known on whether there are CRA and CRC development pathways particularly affected by the microbiome. Detailed investigation is required to define microbiota patterns during the CRA to CRC transition, e.g., we reported for the first time that Fusobacterium nucleatum (Fn) was associated with progressive stages of adenoma development. Moreover, work is needed on whether such microbiome changes have any aetiological role in the rare occasions that adenomas transit to carcinomas.

Our goal will be to evaluate the microbiome as risk factors for CRC development via two adenomatous pathways (common CRAs and rarer sessile serrated adenomas, SSA) and ascertain two possible mechanisms of microbial-mediated disease risk, i.e. markers of gut permeability and exposure to microbial products. This will be addressed by the PhD student investigating in Czech and Irish adenoma samples 1) SSA development as our hypothesized main pathway of bacterial induced adenomatous growth and colorectal carcinogenesis, 2) Markers of gut barrier dysfunction in CRAs in general, and 3) Modification of microbial associations by gut permeability and microbial metabolites, dietary/lifestyle factors, and host genetic variation. We have already undertaken microbial metagenomic sequencing and metabolomic interactions in CRC/CRA samples from the same research groups in a novel exploration of human CRC microbiome evolution in the context of its metabonome. Our data suggests that the developing tumour is highly metabolically active and that pathobionts such as Fn may be attracted to the advancing tumour by its distinctive metabolic environment. Previously in contrast to CRC, we have found in metagenomic sequencing that classical CRA and healthy colon control samples were taxonomically indistinct. This project will assess the microbiota in SSAs and markers of gut barrier integrity in both CRA and SSA. This project will be nested within a larger ongoing examination of the aetiology of CRC related to the same factors.

The successful candidate should have interests in microbial, nutrition, genomics and biostatistical research in cancer. Preferred fields of study and training include Epidemiology, Microbiology, Nutrition, and Genetics. A knowledge and / or enthusiasm for molecular analyses (such as blood serotyping, DNA/RNA extraction, real-time quantitative PCR, genetic variation analyses, next generation sequencing, and metabolomics) is essential. The candidate must either have experience of or be willing to learn biostatistical and bioinformatic methodologies for the analyses required in this project.

Full details of the projects and how to apply, can be found at http://www.ucd.ie/sbbs/research/researchvacancies/