Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer
Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer
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DOI：
10.1128/msystems.00065-17
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发表时间：
2017-09-01
期刊：
影响因子：
6.4
通讯作者：
Hurwitz, Bonnie L.
中科院分区：
文献类型：
--
作者：
Daniel, Scott G.;Ball, Corbie L.;Hurwitz, Bonnie L.
结直肠癌是最易治疗的癌症之一，5年生存率接近，但美国每年仍有超过50,000人死亡。在15%的病例中，错配修复缺陷会导致转化生长因子-β(TGF-β)II型受体零突变，但单靠基因并不能导致肿瘤的发生。以前在小鼠身上的工作表明，转化生长因子-β信号的中断与肝螺杆菌结合会导致肿瘤发生，这表明基因和微生物环境之间存在协同效应。在这里，我们使用整合组学的方法来研究结直肠癌患者肠道微生物组的功能变化，以理清宿主基因、炎症和微生物生态的作用。我们描述了40只有/没有转化生长因子-β信号缺陷的小鼠的肠道微生物组，这些小鼠来自SMAD3(母亲抗十足瘫痪同系物-3)基因敲除和有/没有接种肝炎杆菌。与特定细菌物种相关的微生物群中明显的功能差异出现在与人类结肠癌相关的四个途径中：脂多糖(LPS)的产生、多胺的合成、丁酸代谢和氧化磷酸化(OXPHOS)。具体地说，沙氏粘虫数量的增加会促进内毒素的产生，而内毒素的产生与炎症反应有关。我们观察到沙棘科细菌A4的丁酸产量相应减少，这可能会促进肿瘤的形成。肝炎会导致OXPHOS的增加，这可能会增加破坏DNA的自由基。最后，多种细菌会增加与结肠癌相关的多胺，这不仅与饮食有关，还与多胺水平的微生物群有关。这些对微生物组、宿主基因型和炎症之间的相互作用的洞察可能会促进癌症诊断和治疗的发展。重要的是，大多数关于结肠癌肠道微生物组的研究集中在利用16S rRNA基因测序在属水平上的分类变化。在这里，我们开发了一种新的方法来整合DNA和RNA数据集，以检查物种水平的功能变化，这些变化对肿瘤的发展非常重要。我们发现了微生物组中的几种代谢途径，当被宿主遗传学和肝炎杆菌接种所干扰时，这些代谢途径有助于结肠癌。本文介绍的工作为改进的生物信息学方法奠定了基础，以密切检查特定生物和宿主之间的串扰，这对诊断和前/益生菌治疗的发展非常重要。
Colorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of similar to 64%, yet over 50,000 deaths occur yearly in the United States. In 15% of cases, deficiency in mismatch repair leads to null mutations in transforming growth factor beta (TGF-beta) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-beta signaling combined with Helicobacter hepaticus cause tumorigenesis, indicating a synergistic effect between genotype and microbial environment. Here, we examine functional shifts in the gut microbiome in CRC using integrated - omics approaches to untangle the role of host genotype, inflammation, and microbial ecology. We profile the gut microbiome of 40 mice with/without deficiency in TGF-beta signaling from a Smad3 (mothers against decapentaplegic homolog-3) knockout and with/without inoculation with H. hepaticus. Clear functional differences in the microbiome tied to specific bacterial species emerge from four pathways related to human colon cancer: lipopolysaccharide (LPS) production, polyamine synthesis, butyrate metabolism, and oxidative phosphorylation (OXPHOS). Specifically, an increase in Mucispirillum schaedleri drives LPS production, which is associated with an inflammatory response. We observe a commensurate decrease in butyrate production from Lachnospiraceae bacterium A4, which could promote tumor formation. H. hepaticus causes an increase in OXPHOS that may increase DNA-damaging free radicals. Finally, multiple bacterial species increase polyamines that are associated with colon cancer, implicating not just diet but also the microbiome in polyamine levels. These insights into cross talk between the microbiome, host genotype, and inflammation could promote the development of diagnostics and therapies for CRC.IMPORTANCE Most research on the gut microbiome in colon cancer focuses on taxonomic changes at the genus level using 16S rRNA gene sequencing. Here, we develop a new methodology to integrate DNA and RNA data sets to examine functional shifts at the species level that are important to tumor development. We uncover several metabolic pathways in the microbiome that, when perturbed by host genetics and H. hepaticus inoculation, contribute to colon cancer. The work presented here lays a foundation for improved bioinformatics methodologies to closely examine the cross talk between specific organisms and the host, important for the development of diagnostics and pre/probiotic treatment.