Abstract
Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer (CRC). However, the mediating role of the circulating metabolome in this relationship remains unclear. Targeted metabolomics data from 6,055 participants in the EPIC 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-CRC association. PA was inversely associated with CRC risk (odds ratio [OR] per category change: 0.90, 95% confidence intervals [CI]: 0.83, 0.97; p-value = 0.009). PA levels were associated with 24 circulating metabolites after false discovery rate correction (FDR), with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted p-value = 1.18 × 10⁻¹⁰) and lysophosphatidylcholine acyl (lysoPC a) C18:2 (FDR-adjusted p-value = 1.35 × 10⁻⁶). PC ae C34:3 partially mediated the PA-CRC association (natural indirect effect: 0.991, 95% CI: 0.982, 0.999; p-value = 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature. PC ae C34:3 mediates part of the PA-CRC inverse association, but further studies with improved PA measures and extended metabolomic panels are needed. These findings provide insights into PA-related biological mechanisms influencing CRC risk and suggest potential targets for cancer prevention interventions.
Accepted Version
Published Version
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