Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin E2 concentrations after dietary supplementation with ω-3 fatty acids

This study evaluated whether mRNA expression of major genes regulating formation of prostaglandin (PG)E-2 in the colon and colonic fatty acid concentrations are associated with the reduction in colonic mucosal PGE(2) after dietary supplementation with omega-3 (omega-3) fatty acids. Supplementation with omega-3 fatty acids was done for 12 weeks using personalized dosing that was expected to reduce colonic PGE(2) by 50%. In stepwise linear regression models, the omega-3 fatty acid dose and baseline BMI explained 16.1% of the inter-individual variability in the fold change of colonic PGE(2) post-supplementation. Increases in mRNA gene expression after supplementation were, however, modest and were not associated with changes in PGE(2). When baseline expression of PTGS1, PTGS2 and HPGD genes was included in the linear regression model containing dose and BMI, only PTGS2, the gene coding for the inducible form cyclooxygenase, was a significant predictor. Higher relative expression of PTGS2 predicted greater decreases in colonic PGE(2), accounting for an additional 13.6% of the inter-individual variance. In the final step of the regression model, greater decreases in total colonic fatty acid concentrations predicted greater decreases in colonic PGE(2), contributing to an additional 18.7% of the variance. Overall, baseline BMI, baseline expression of PTGS2 and changes in colonic total fatty acids together accounted for 48% of the inter-individual variability in the change in colonic PGE(2). This is consistent with biochemical data showing that fatty acids which are not substrates for cyclooxygenases can activate cyclooxygenase-2 allosterically. Further clinical trials are needed to elucidate the factors that regulate the fatty acid milieu of the human colon and how this interacts with key lipid metabolizing enzymes. Given the central role of PGE(2) in colon carcinogenesis, these pathways may also impact on colon cancer prevention by other dietary and pharmacological approaches.