Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848–0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC. [Display omitted] •Altered plasma and fecal metabolites in CRC and colorectal adenoma are identified•CRC-enriched oleic acid and CRC-depleted allocholic acid are key metabolites in CRC•Metabolites bind to tumor cell receptor to modulate downstream oncogenic pathways•Plasma metabolites are potential diagnostic biomarkers of CRC and adenoma Sun et al. reveal signature plasma and fecal metabolites across colorectal cancer (CRC) progression including CRC-enriched oleic acid and CRC-depleted allocholic acid, and decipher their mechanistic role in colorectal tumorigenesis. Sun et al. also demonstrate the diagnostic potential of plasma metabolites in CRC or adenoma patients from four independent cohorts.