Identifying Metabolomic Mediators of the Physical Activity and Colorectal Cancer Relationship

Background: Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer. However, the mediating role of the circulating metabolome in this relationship remains unclear. Methods: Targeted metabolomics data from 6,055 participants in the European Prospective Investigation into Cancer and Nutrition cohort were used to identify metabolites associated with PA and derive a metabolomic signature of PA levels. PA levels were estimated using the validated Cambridge PA index based on baseline questionnaires. Mediation analyses were conducted in a nested case–control study (1,585 cases, 1,585 controls) to examine whether individual metabolites and the metabolomic signature mediated the PA–colorectal cancer association. Results: PA was inversely associated with colorectal cancer risk (OR per category change: 0.90, 95% confidence interval, 0.83–0.97; P value ¼ 0.009). PA levels were associated with 24 circulating metabolites after FDR correction, with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted P value ¼ 1.18 Ｘ 10^-10) and lysophosphatidylcholine acyl C18:2 (FDR-adjusted P value ¼ 1.35 Ｘ 10^-6). PC ae C34:3 partially mediated the PA–colorectal cancer association (natural indirect effect: 0.991, 95% confidence interval, 0.982–0.999; P value ¼ 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature. Conclusions: PC ae C34:3 mediates part of the PA–colorectal cancer inverse association, but further studies with improved PA measures and extended metabolomic panels are needed. Impact: These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions.