Changes in plasma and faecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and faecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma (CRA), 430 normal controls (NC)). By metabolomic profiling, we identified signature plasma and faecal metabolites with consistent shift across NC, CRA, and CRC, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibited pro-tumourigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid had opposing effects. By integrative analysis, we identified that oleic acid or allocholic acid directly bound with ENO1 or FXR1 in CRC cells to respectively modulate PI3K/Akt or MAPK pathways. Clinically, we established a panel of 17 plasma metabolites that accurately diagnosed CRC in discovery cohort and three validation cohorts (AUC=0.848-0.987). Overall, we characterised metabolite signatures, mechanistic significance, and diagnostic potential of plasma and faecal metabolomes in CRC.
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