Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China.
Int J Colorectal Dis. 2024 Jul 24;39(1):116. doi: 10.1007/s00384-024-04686-9.
Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.
We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.
We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.
Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.
最近的研究将肠道微生物组的改变和代谢紊乱与结直肠癌（CRC）的侵袭行为和转移联系起来，从而影响患者的预后。然而，肠道微生物组、代谢物谱和突变的 RAS/BRAF 转移性结直肠癌（M-mCRC）之间的具体关系仍不清楚。此外，需要更好地了解 M-mCRC 患者肠道微生物组改变引起的代谢变化的潜在机制和预后意义。
我们进行了孟德尔随机化（MR）来评估 196 种肠道微生物组特征和 1400 种血浆代谢物/代谢物比值的遗传预测与 M-mCRC 特异性生存的因果关系。此外，我们根据 M-mCRC 确定了显著的肠道微生物组-代谢物/代谢物比值的关联。对显著代谢物比值对应的共享蛋白进行代谢物信息注释和功能注释及通路富集分析，旨在揭示肠道微生物组通过调节人体代谢影响 M-mCRC 预后的潜在机制。
我们确定了 11 种与 M-mCRC 特异性生存相关的肠道微生物组特征和 49 种已知的代谢物/代谢物比值。此外，我们还确定了 17 种与 M-mCRC 特异性相关的肠道微生物组-代谢物/代谢物比值的关联，涉及 8 种脂质代谢物和 3 种胆红素降解产物。显著代谢物比值对应的共享蛋白主要位于膜的整合成分中，具有酶活性，如葡萄糖醛酸转移酶和 UDP-葡萄糖醛酸转移酶，在葡萄糖醛酸化、胆汁分泌和脂质代谢等过程中起着重要作用。此外，这些蛋白在与抗坏血酸和醛酸代谢、戊糖和葡萄糖醛酸相互转化、类固醇激素生物合成和胆汁分泌相关的途径中显著富集。
我们的研究为肠道微生物组对 M-mCRC 预后影响的潜在机制提供了新的见解。这些发现为未来探索潜在的治疗靶点和策略提供了有意义的参考。
