Abstract：
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.
摘要：
结直肠癌（CRC）进展（正常-腺瘤-CRC）中血浆和粪便代谢组的变化尚不清楚。这里,从四个独立的队列中收集血浆和粪便样本，包括1,251名个体（422CRC，399结直肠腺瘤[CRA]，和430正常控制[NC])。通过代谢组学分析，特征血浆和粪便代谢物在NC中具有一致的移位，CRA,和CRC被识别，包括富含CRC的油酸和去CRC的异胆酸。油酸在CRC细胞中表现出促致瘤作用，患者来源的类器官，和两个小鼠CRC模型，而异胆酸具有相反的作用。通过综合分析，我们发现油酸或异胆酸直接与CRC细胞中的α-烯醇化酶或法尼醇X受体1结合,分别,调节癌症相关途径。临床上,我们建立了一组17种血浆代谢物,在一个发现和三个验证队列中准确诊断CRC(AUC=0.848-0.987).总的来说,我们表征了代谢物的特征，机械意义，以及血浆和粪便代谢组在CRC中的诊断潜力。
