Characterisation of Host-Microbiome Interactions and Colorectal Cancer (CRC)

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Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, making up approximately 10% of cancers globally. However, there is a large geographical disparity in incidence, with the highest rates observed in North America, Australia, New Zealand and Europe and the lowest in rural Africa and Asia. Additionally, extremely high incidence is observed within the Native Alaskan population, with rates exceeding 100 cases per 100,000. Both migration and experimental studies suggest that environmental factors play a more significant role in CRC development than genetic dysfunction, particularly the consumption of a 'westernised' (high fat, low fibre) diet. Furthermore, it is theorised that diet associated risk is, in part, mediated via colonic microbial metabolism, and the subsequent production of pro-inflammatory and carcinogenic metabolites combined with reduced production of metabolites that promote colonic health and exhibit antineoplastic effects. However, the precise mechanism by which CRC risk is modulated via the nutrition-microbiome axis is yet to be definitively elucidated. Using a systems medicine approach, we will attempt to further define key host-microbiome interactions and metabolic pathways in high and low risk ethnic populations, namely, Urban Africans, Semi-urban Africans and Native Alaskans. Samples have been previously obtained by collaborators at Pittsburgh University (Prof. Steve O'Keefe) and consist of urine, faeces and plasma along with nutritional data, clinical outcome data and microbiome data. Samples will also be obtained from a randomised, controlled, clinical trial currently being carried out in Anchorage, Alaska. The study cohort, consisting of Alaskan Natives (highest risk population), are receiving dietary supplementation of resistant starch (a soluble prebiotic fibre), to establish the effect of prebiotic supplementation on CRC risk, through microbiome and subsequent metabolome manipulation. We hypothesise that the increased production of colonic health promoting and anti-neoplastic metabolites, derived from microbiota-mediated metabolism of resistant starch, will counteract the effect of luminal carcinogens, thereby supressing biomarkers of CRC risk. As such, this work aims to elucidate the key microbiome-host interactions, modulated by diet, that mediate CRC risk and furthermore, potentially demonstrate the effectiveness of a high fibre, low risk diet in the prevention of CRC development.