Source of the Placental Microbiome

胎盘微生物组的来源

• 批准号: 9307127
• 负责人: Kjersti Marie Aagaard
• 金额: $ 70.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307127
• 关键词: Amniocentesis; Amniotic Fluid; Bacteria; Bayesian Modeling; Big Data; Birth; Cells; Chorionic villi; Clinical Management; Cohort Studies; Common Good; Communities; Complex; Data; Data Science; Data Set; Data Sources; Disease; Environment; Etiology; Feces; Fetus; Fluorescent in Situ Hybridization; Funding; Generations; Genes; Genome; Genotype; Gestational Age; Goals; Health; Human; Human Genome; Knowledge; Label; Linear Models; Mass Fragmentography; Measures; Metabolic; Metagenomics; Microbe; Modeling; Nuclear; Oral; Perinatal; Phenotype; Physicians; Placenta; Placental Biology; Placental microbiome; Pregnancy; Premature Birth; Process; Recording of previous events; Ribosomal RNA; Risk; Role; Sampling; Science; Scientist; Second Pregnancy Trimester; Shotguns; Source; Structure; Symbiosis; Taxonomy; Testing; Time; United States National Institutes of Health; Vagina; Variant; Whole-Genome Shotgun Sequencing; Work; amniotic cavity; base; clinical Diagnosis; cohort; commensal microbes; data integration; experience; insight; intrahepatic cholestasis of pregnancy; light microscopy; liquid chromatography mass spectrometry; metabolome; metabolomics; metagenome; metagenomic sequencing; microbial community; microbiome; microbiota; microorganism; oral microbiome; petabyte; predictive signature; response; single molecule; tool; vaginal microbiome; whole genome

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.

与人类相关的微生物（“微生物组”）的数量超过了 人类细胞至少是人类基因组的 10 倍，并且集体基因组（“宏基因组”）超过了人类基因组 基因含量提高了150倍以上。我们和其他人最近证明细菌是 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 开发并采用宏基因组学来表征胎盘微生物组，并观察到 其群落成员及其功能因分娩胎龄而异。然而，它 目前仍不清楚胎盘微生物组的不同母体来源是什么，以及它是否下沉 通过羊膜腔到达胎儿，因此可以在羊水中进行测量。 为了响应人类胎盘项目，我们建议确定胎盘的来源和汇 胎盘微生物组采用两个大型、稳健且特征良好的现有数据集。我们将生成 无与伦比的宏基因组学和代谢组学数据，以检验我们的中心假设：胎盘是 由共生微生物群组成，这些微生物群主要来自母体口腔和胃肠道群落，具有 来自阴道的贡献较小。我们进一步假设胎盘微生物居住在胎儿和胎儿中 宫内环境，并可在妊娠中期羊水中检测到。此外，它们的代谢物还具有 作为微生物群功能存在的持久特征。 为了证明这一假设，我们将在总共 1230 多个受试者中执行三个基本目标 来自两个现有数据集的样本。完成这些目标的最终结果将是首先确定 胎盘微生物群的母体来源，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，我们将在早期和中期重述这些发现 中期妊娠羊水，从而确定胎盘微生物群库的早期证据。在决赛中 我们的目标是，我们将对这些相同的受试者样本使用 LC/MS 全谱代谢组学来鉴定稳定的和 微生物组的持久代谢足迹。我们展示了肝内胆汁淤积的概念验证工作 怀孕作为我们方法的可行性、重要性和准备转化应用的证据。 作为一支经过验证的围产期医师科学家团队，他们的重点和历史一直处于最前沿 大数据（尤其是宏基因组学）科学，我们现在已经准备好进行复杂的整合 研究中这些独特的数据集是可行的、合理的，并且可能具有长期意义和高度 影响。