Multiomics Analysis Revealed Colorectal Cancer Pathogenesis

Gut microbiota-derived microbial compounds may link to the pathogenesis of colorectal cancer (CRC). However, the role of the host–microbiome in the incidence and progression of CRC remains elusive. We performed 16S rRNA sequencing, metabolomics, and proteomic studies on samples from 85 CRC patients who underwent colonoscopy examination and found two distinct changed patterns of microbiome in CRC patients. The relative abundances of Catabacter and Mogibacterium continuously increased from intramucosal carcinoma to advanced stages, whereas Clostridium, Anaerostipes, Vibrio, Flavonifractor, Holdemanella, and Hungatella were significantly altered only in intermediate lesions. Fecal metabolomics analysis exhibited consistent increases in bile acids, indoles, and urobilin as well as a decrease in heme. Serum metabolomics uncovered the highest levels of bilin, glycerides, and nucleosides together with the lowest levels of bile acids and amino acids in the stage of intermediate lesions. Three fecal and one serum dipeptides were elevated in the intermediate lesions. Proteomics analysis of colorectal tissues showed that oxidation and autophagy through the PI3K/Akt-mTOR signaling pathway contribute to the development of CRC. Diagnostic analysis showed multiomics features have good predictive capability, with AUC greater than 0.85. Our overall findings revealed new candidate biomarkers for CRC, with potentially significant diagnostic and prognostic capabilities.肠道菌群衍生的微生物代谢产物或与结直肠癌（colorectal cancer, CRC）的发病机制存在关联。然而，宿主-微生物组在结直肠癌发生与进展中的具体作用仍未明确。本研究对85名接受结肠镜检查的结直肠癌患者的样本开展了16S rRNA测序、代谢组学及蛋白质组学研究，发现结直肠癌患者的微生物组存在两种特征显著不同的改变模式。Catabacter属与Mogibacterium属的相对丰度从黏膜内癌阶段持续升高至晚期结直肠癌阶段；而Clostridium属、Anaerostipes属、Vibrio属、Flavonifractor属、Holdemanella属及Hungatella属仅在中间病灶阶段发生显著丰度改变。粪便代谢组学分析显示，胆汁酸、吲哚及尿胆素的水平持续升高，而血红素的水平则出现下降。血清代谢组学分析则发现，在中间病灶阶段，胆色素、甘油酯及核苷的水平达到峰值，而胆汁酸与氨基酸的水平则降至最低。中间病灶阶段的粪便样本中3种二肽、血清样本中1种二肽的水平均出现升高。结直肠组织的蛋白质组学分析显示，通过PI3K/Akt-mTOR信号通路介导的氧化应激与自噬参与了结直肠癌的发生发展。诊断分析结果显示，多组学特征具备良好的预测性能，其受试者工作特征曲线下面积（Area Under Curve, AUC）大于0.85。本研究的整体结果揭示了一批结直肠癌的潜在候选生物标志物，具备潜在的重要诊断与预后应用价值。