Source of the Placental Microbiome

与人类有关的微生物(“微生物群”)的数量超过了 人类细胞至少增加了10倍，集体基因组(“元基因组”)超过了人类基因组 在基因含量方面增加了150倍以上。我们和其他人最近证明了细菌是 使用各种可培养和不可培养的方法在胎盘中检测到。几年来，我们 已经开发并应用了元基因组学来表征胎盘微生物组，并观察到 由于分娩时胎龄的不同，其社区成员及其功能的差异。然而，它 尚不清楚胎盘微生物群的不同母源(S)是什么，以及它是否下沉 通过羊膜腔进入胎儿，因此可以在羊水中测量。 作为对人类胎盘计划的响应，我们建议确定 胎盘微生物组利用两个大的、健壮的和特征良好的现有数据集。我们将生成 无与伦比的元基因组学和代谢组学数据，以测试我们的中心假设胎盘是 由主要来自母体口腔和胃肠道群落的共生微生物区系组成，具有 来自阴道的贡献较小。我们进一步假设胎盘微生物存在于胎儿和 宫内环境，并在中期羊水中可检测到。此外，它们的代谢物还可以 作为微生物功能存在的持久标志。 为了证明这一假设，我们将在总共1230多名受试者中执行三个基本目标 样本来自两个现有的数据集。完成这些目标的最终结果将是首先确定 胎盘微生物区系的母体来源，并使用最先进的单分子验证这些发现 荧光原位杂交和培养。此后，我们将在年中和年初总结这些研究结果。 妊娠中期羊水，从而确定胎盘微生物区系下沉的早期证据。在决赛中 目的：利用LC/MS全光谱代谢组学方法对同一受试者的样品进行鉴定。 微生物组的持久代谢足迹。我们介绍了我们在肝内胆汁淤积方面的概念验证工作。 作为我们方法的可行性、重要性和现成的翻译应用的证据。 作为一支成熟的围产期内科科学家团队，他们的重点和历史都走在了 大数据(特别是元基因组学)科学，我们现在正准备进行复杂的 这些独特的数据集在研究中是可行的、合理的、可能具有长期意义和高度的 冲击力。

Human-associated microorganisms (the “microbiome”) are present in numbers exceeding the quantities of human cells by at least 10-fold, and the collective genome (the “metagenome”) exceeds our human genome in terms of gene content by more than 150-fold. We and others have recently demonstrated that bacteria are detected in the placenta using a variety of culturable and non-culturable approaches. For several years we have developed and employed metagenomics to characterize the placental microbiome, and observed variation in its community membership and their function by virtue of gestational age at delivery. However, it remains unknown what the different maternal source(s) are of the placental microbiome, and whether it sinks to the fetus via the intra-amniotic cavity and thus is measureable in amniotic fluid. In response to the Human Placental Project, we propose to identify the sources and sinks for and of the placental microbiome employing two large, robust and well characterized existing datasets. We will generate unparalleled metagenomics and metabolomics data, in order to test our central hypothesis that the placenta is populated by commensal microbiota which largely arise from the maternal oral and GI communities, with a lesser contribution from the vagina. We further hypothesize that placental microbes populate the fetus and the intrauterine environment, and are detectable in mid-trimester amniotic fluid. Moreover, their metabolites serve as lasting signatures of the microbiotas functional presence. In order to prove this hypothesis, we will execute three essential aims in a total of over 1230 subjects samples from two existing data sets. The net result of the completion of these aims will be to first identify the maternal source of the placental microbiota, and validate these findings using state of the art single molecule fluorescent in situ hybridization and culturation. We will thereafter recapitulate these findings in early and mid- second trimester amniotic fluid and thus identify the early evidence of the placental microbiota sink. In a final aim, we will use LC/MS full spectral metabolomics on these same subjects samples to identify the stable and lasting metabolic footprint of the microbiome. We present our proof of concept work on intrahepatic cholestasis of pregnancy as evidence for the feasibility, significance and ready translational application of our approach. As a proven team of perinatal physician scientists with an emphasis and history of being at the forefront of big data (and notably metagenomics) science, we are uniquely poised to now undertake complex integration of these unique data sets in studies which are feasible, justifiable, and of likely long-term significance and high impact.