Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer
Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer
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综合宏基因组和代谢组分析揭示了早发性结直肠癌中独特的肠道微生物组衍生表型
DOI：
10.1136/gutjnl-2022-327156
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发表时间：
2022-08-11
期刊：
影响因子：
24.5
通讯作者：
Ma, Yanlei
中科院分区：
文献类型：
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作者：
Kong, Cheng;Liang, Lei;Ma, Yanlei
目的，早期发作的结直肠癌（EO-CRC）的发生率正在稳步增加。在这里，我们旨在表征EO-CRC患者中肠道微生物组，代谢产物和微生物酶之间的相互作用，并评估其作为EO-CRC的非侵入性生物标志物的潜力。设计我们进行了宏基因组和代谢组分析，确定了多组学标记物和发现的CRC分类器，用于发现COVICE群体，其中有130个晚期CRC（LO-CRC），114位EO-CRC受试者和年龄匹配的健康对照组（97 LO-CONTOL和100 EO-CONTOL和100 EO-CONTROL）。分析了38个Lo-CRC，24个EO-CRC，22个LO控制和24个EO控制的独立队列，以验证结果。结果与对照组相比，在LO-CRC和EO-CRC受试者中，α多样性的降低均显而易见。尽管存在共同的变化，但综合分析确定了LO-CRC和EO-CRC中不同的微生物组 - 代谢组关联。核细菌核富集和短链脂肪酸消耗，包括降低的微生物GABA生物合成以及乙酸/乙醛代谢向乙酰-COA产生的转移表征LO-CRC。相比之下，EO-CRC的多素学特征往往与富集的黄牙原染色器plauti相关，并增加了色氨酸，胆汁酸和胆碱代谢。值得注意的是，与红肉摄入相关的物种，胆碱代谢产物和KEGG矫正物（KO）PLDB和CBH基因轴可能是EO-CRC中的潜在肿瘤刺激剂。基于宏基因组，代谢组和KO基因标记的预测模型实现了将EO-CRC与对照区分开的强大分类性能。结论我们的大样本多组学数据表明，改变的微生物组 - 代谢组相互作用有助于解释EO-CRC和LO-CRC的发病机理。微生物组衍生的生物标志物作为有希望的非侵入性工具的潜力可用于对EO-CRC个体的精确检测和区分。
Objective The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC. Design We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. Results Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome-metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls. Conclusion Our large-sample multiomics data suggest that altered microbiome-metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.