Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (n = 102), matched controls (n = 102), and patients with CRC (n = 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis.IMPORTANCE Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

中文翻译：

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结直肠腺瘤患者的粪便代谢特征与肠道微生物群和结直肠癌发病机制的早期事件相关。


结直肠腺瘤是结直肠癌 (CRC) 的癌前病变，它提供了一种观察结直肠癌早期发展的关键事件的方法。许多研究调查了肠道微生物群在腺瘤和癌症发展中的变化和作用，强调了其对癌发生的影响。然而，人们对肠道代谢组的关注较少，它介导宿主和肠道微生物之间的相互作用。在这里，我们研究了晚期腺瘤患者 (n = 102)、匹配对照 (n = 102) 和 CRC 患者 (n = 36) 粪便样本的代谢组学特征。我们发现，与对照组相比，腺瘤患者的几类生物活性脂质（包括多不饱和脂肪酸、次级胆汁酸和鞘脂）升高。大多数此类代谢物在结直肠癌患者中表现出方向一致的变化，表明这些变化可能代表癌发生的早期事件。我们还利用这些患者的肠道微生物群概况检查了肠道微生物组与代谢组的关联。我们发现微生物组和代谢组数据之间存在非常强的总体关联，并编目了一系列强相关的细菌分类群和代谢组特征对的列表，其中包括腺瘤的特征。我们的研究结果强调了肠道代谢物的重要性，以及它们与肠道微生物之间潜在的相互作用，在结直肠癌发病机制的早期事件中的重要性。重要性结直肠腺瘤是结直肠癌的前兆。最近，肠道微生物群，即居住在我们肠道中的微生物集合，已被认为是结直肠癌发展的关键因素。 已经有许多针对结直肠腺瘤和结直肠癌的肠道微生物群分析研究；然而，很少有研究考虑肠道代谢组，它是宿主和肠道微生物群之间的化学界面。在这里，我们对结直肠腺瘤和结直肠癌进行了肠道代谢组图谱研究，并分析了代谢组图谱和配对微生物群组成图谱。我们发现了结直肠腺瘤的几种化学特征，这些特征与一些肠道微生物有关，可能预示着未来的结直肠癌。这项研究强调了结直肠癌发病机制中潜在的早期驱动代谢物，并指导进一步的有针对性的实验，从而为制定更好的结直肠癌预防策略提供了重要的垫脚石。