Omega-3 Polyunsaturated Fatty Acids for the Prevention and Treatment of Colorectal Cancer

Although the preventability estimate for colorectal cancer (CRC) is more than 50%, CRC remains the second most common cause of cancer mortality in the UK. A potential prevention strategy for CRC prevention is use of omega-3 polyunsaturated fatty acids (O3FAs) through dietary guidance (fish intake) and/or supplementation with purified O3FAs. This thesis advances the precision use of O3FAs in the prevention of CRC, using a biomarker-driven, epidemiological approach and a parallel translational, mechanistic study to delineate the potential benefits of O3FAs based on host, tumour, and gut microbiota factors. A comprehensive literature review outlined the pre-existing evidence for the use of O3FAs in the treatment and prevention of CRC. It identified potential strategies based on host (low plasma O3FA levels, ethnicity, male sex), tumour (proximal colon, MSI high tumours), and microbiota factors. An observational study within the UK Biobank (UKBB) (n=121,650 participants) found that dietary O3FA intake (oily fish and fish oil supplements [FOS]) predicted plasma O3FA levels, with FOS use roughly equivalent to a weekly portion of oily fish. Mean plasma O3FA levels of 0.51 mmol/L were associated with a 12% reduction (hazard ratio 0.88 [95% CI 0.80-0.97]) in CRC risk within UKBB participants (n=248,487, of which there were 2,756 CRC cases). Increasing plasma docosahexaenoic acid levels were associated with a reduced risk of CRC in male participants and with reduced proximal colon cancer risk. A parallel in vitro colonic fermentation model explored the interaction between O3FAs and the fibre inulin on short chain fatty acid (SCFA) production, revealing a mean increase of 12.9 mmol/L in total SCFA production at 24 hours, which was associated with SCFA-producing microbiota within the model. This thesis works towards a targeted approach for the use of O3FAs in CRC prevention based on host (males), tumour (proximal colon) and microbiome (O3FA-inulin interaction) factors.