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首页> 外文期刊>BMC Genomics >A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat
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A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat

机译：全基因组系统分析揭示了结直肠癌与三甲胺N-氧化物（TMAO）之间的紧密联系，三甲胺N-氧化物是膳食肉和脂肪的肠道微生物代谢产物

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Background Dietary intakes of red meat and fat are established risk factors for both colorectal cancer (CRC) and cardiovascular disease (CVDs). Recent studies have shown a mechanistic link between TMAO, an intestinal microbial metabolite of red meat and fat, and risk of CVDs. Data linking TMAO directly to CRC is, however, lacking. Here, we present an unbiased data-driven network-based systems approach to uncover a potential genetic relationship between TMAO and CRC. Materials and methods We constructed two different epigenetic interaction networks (EINs) using chemical-gene, disease-gene and protein-protein interaction data from multiple large-scale data resources. We developed a network-based ranking algorithm to ascertain TMAO-related diseases from EINs. We systematically analyzed disease categories among TMAO-related diseases at different ranking cutoffs. We then determined which genetic pathways were associated with both TMAO and CRC. Results We show that CVDs and their major risk factors were ranked highly among TMAO-related diseases, confirming the newly discovered mechanistic link between CVDs and TMAO, and thus validating our algorithms. CRC was ranked highly among TMAO-related disease retrieved from both EINs (top 0.02%, #1 out of 4,372 diseases retrieved based on Mendelian genetics and top 10.9% among 882 diseases based on genome-wide association genetics), providing strong supporting evidence for our hypothesis that TMAO is genetically related to CRC. We have also identified putative genetic pathways that may link TMAO to CRC, which warrants further investigation. Through systematic disease enrichment analysis, we also demonstrated that TMAO is related to metabolic syndromes and cancers in general. Conclusions Our genome-wide analysis demonstrates that systems approaches to studying the epigenetic interactions among diet, microbiome metabolisms, and disease genetics hold promise for understanding disease pathogenesis. Our results show that TMAO is genetically associated with CRC. This study suggests that TMAO may be an important intermediate marker linking dietary meat and fat and gut microbiota metabolism to risk of CRC, underscoring opportunities for the development of new gut microbiome-dependent diagnostic tests and therapeutics for CRC.
机译：背景技术饮食中红肉和脂肪的摄入是结直肠癌（CRC）和心血管疾病（CVD）的既定危险因素。最近的研究表明，TMAO，红肉和脂肪的肠道微生物代谢产物与CVD的风险之间存在机械联系。但是，缺少将TMAO直接链接到CRC的数据。在这里，我们提出了一种基于无偏见的数据驱动的基于网络的系统方法来揭示TMAO与CRC之间的潜在遗传关系。材料和方法我们使用来自多个大规模数据资源的化学-基因，疾病-基因和蛋白质-蛋白质相互作用数据构建了两个不同的表观遗传相互作用网络（EIN）。我们开发了一种基于网络的排名算法，可以从EIN中确定与TMAO相关的疾病。我们系统地分析了在不同等级临界值下与TMAO相关的疾病中的疾病类别。然后，我们确定了哪些遗传途径与TMAO和CRC相关。结果我们显示CVD及其主要危险因素在TMAO相关疾病中排名很高，证实了CVD和TMAO之间新发现的机制联系，从而验证了我们的算法。在从两个EIN检索到的TMAO相关疾病中，CRC排名最高（在基于孟德尔遗传学检索的4,372种疾病中排名前0.02％，排名第1，在基于全基因组关联遗传学的882种疾病中排名前10.9％），为CRC提供了有力的支持证据我们关于TMAO与CRC遗传相关的假设。我们还确定了可能将TMAO与CRC相关联的推定遗传途径，值得进一步研究。通过系统的疾病富集分析，我们还证明了TMAO通常与代谢综合征和癌症有关。结论我们的全基因组分析表明，研究饮食，微生物组代谢和疾病遗传学之间的表观遗传相互作用的系统方法为了解疾病的发病机理提供了希望。我们的结果表明，TMAO与CRC遗传相关。这项研究表明，TMAO可能是将饮食中的肉类，脂肪和肠道菌群代谢与CRC风险联系起来的重要中间标记，这突显了开发新的依赖肠道菌群的诊断方法和CRC治疗药物的机会。

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