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

描述（由申请人提供）：人类是微生物的杰出宿主，事实上，我们已经共同进化为高度丰富的群落。从新生儿期开始，人类相关微生物（“微生物组”）的数量超过人类细胞数量至少 10 倍。集体基因组（“宏基因组”）的基因含量超过人类基因组 150 倍以上。关于微生物群和早产，通常认为大多数宫内感染起源于下生殖道，微生物群上升到无菌的宫内环境，感染胎盘（早产）、胎膜（绒毛膜羊膜炎）、脐带（绳索炎）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）胎盘实际上不是无菌的，而是含有低丰度的微生物群，这可能是通过口腔微生物群的血行传播获得的。根据我们之前的研究和初步数据，我们的中心假设是，怀孕期间独特且很大程度上共生的常驻微生物组会带来早产的风险。为了证明这一假设，我们将执行三个基本目标：目标 1 将使用基于 16S 的方法和推断的宏基因组学，使用妊娠 <20 周的高危孕妇的样本来揭示与早产相关的不同微生物群落；目标 2 和 3 将使用全基因组鸟枪法测序与集成的宿主基因组学、宏转录组学和代谢组学来构建我们的功能计算管道，并实现物种鉴定、微生物基因目录、代谢重建以及早产易感性机制和网络。此外，我们还描述了我们为建立社区资源而做出的相应努力，以便将来对这组早产、近期和足月出生中获得的宿主和微生物生物标志物进行大规模研究。通过在早产受试者的纵向病例队列中利用我们最先进的技术和分析工具，我们将能够将“基于发现的”宏基因组学和多组学科学转化为易于转化的机制研究，达到前所未有的水平。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”变得可行。由于早产在发达国家和发展中国家都很普遍，这些研究对于我们人口的疾病负担具有广泛的意义，并将带来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.