A Multi'omics Approach towards Deciphering the Influence of the Microbiome on Pre

描述(申请人提供)：人类是微生物的重要宿主，事实上，我们已经共同进化为高度过剩的群落。从新生期开始，与人类相关的微生物(“微生物组”)的数量至少是人类细胞数量的10倍。就基因含量而言，集体基因组(“元基因组”)比人类基因组的基因含量高150多倍。关于微生物区系和早产，一般认为大多数宫内感染起源于下生殖道，微生物区系上升到否则无菌的宫内环境中，感染胎盘(早产)、胎膜(绒毛膜羊膜炎)、脐带(胃底炎)和胎儿(败血症)。然而，我们和其他人最近证明：(1)阴道和肠道微生物群落在怀孕期间具有明显的结构，(2)胎盘实际上并不是无菌的，而是含有一个低丰度的微生物群，这可能是通过血液传播的口腔微生物群获得的。基于我们以前的研究和初步数据，我们的中心假设是，怀孕期间不同的和基本上共生的驻留微生物群会导致早产的风险。为了证明这一假设，我们将执行三个基本目标：Aim 1将使用基于16S的方法并推断元基因组学，使用来自怀孕20周的高危孕妇的样本来揭示与早产相关的独特微生物群落；Aim 2和3将使用全基因组鸟枪测序与集成的宿主基因组学、代谢转录组学和代谢组学相结合，以构建我们的功能计算管道，并使物种鉴定、微生物基因目录、代谢重建以及早产的易感性机制和网络成为可能。此外，我们还描述了我们为未来在这组早产、近产和足月出生中获得的宿主和微生物生物标记物的大规模研究建立社区资源所做的相应努力。通过在早产受试者的纵向病例队列中利用我们最先进的科学技术和分析工具，我们将能够将“基于发现”的元基因组学和多组学科学转化为以前无与伦比的易于翻译的机械论研究。我们经过验证的执行此类临床研究和利用高通量技术的能力使这种大规模的“团队科学”成为可能。由于早产在发达国家和发展中国家都很普遍，这些研究对我们人口的疾病负担具有广泛的意义，并将导致潜在的创新干预措施。

DESCRIPTION (provided by applicant): Humans are remarkable hosts to microbes, and we have in fact co-evolved as highly plethoric communities. Human-associated microorganisms (the "microbiome") are present in numbers exceeding the quantities of human cells by at least 10-fold beginning in the neonatal period The collective genome (the "metagenome") exceeds our human genome in terms of gene content by more than 150-fold. With respect to microbiota and preterm birth, it has generally assumed that the majority of intrauterine infections originate in the lower genital tract, with microbiota ascending into the otherwise sterile intrauterine environment to infect the placenta (preterm birth), fetal membranes (chorioamnionitis), umbilical cord (funisitis), and the fetus (sepsis). However, we and others have recently demonstrated that (1) the vaginal and gut microbiome communities are distinctly structured in pregnancy, and (2) the placenta is in fact not sterile, but rather harbors a low-abundance microbiome which is likely acquired through hematogenous transmission of the oral microbiome. Based on our prior studies and preliminary data, our central hypothesis is that a distinct and largely commensal resident microbiome in pregnancy renders risk for preterm birth. In order to prove this hypothesis, we will execute three essential aims: Aim 1 will use 16S-based approaches with inferred metagenomics employing samples from at-risk gravidae enrolled at <20 weeks gestation to reveal distinct microbial communities which occur in association with preterm birth; Aims 2&3 will use whole-genome shotgun sequencing with integrated host genomics, metatranscriptomics, and metabolomics to build on our functional computational pipelines and enable species identification, microbial gene catalogues, metabolic reconstructions, and mechanisms and networks of susceptibility to preterm birth. In addition, we describe our concomitant efforts to build a community resource for future large-scale studies on host and microbe biomarkers acquired in this set of preterm, near term, and term births. By utilizing our state-of-the-science technology and analysis tools in a longitudinal case-cohort of preterm birth subjects, we will be able to transform "discovery based" metagenomics and multi'omics science into readily translatable mechanistic studies at a previously unparalleled level. Our proven abilit to execute such clinical studies and utilize high-throughput technologies makes such large-scale "team science" feasible. Because preterm birth is prevalent in both the developed and developing world, these studies are of broad significance to our population's disease burden and will lead to potential innovative interventions.