Revealing the role of the cervico-vaginal microbiome in spontaneous preterm birth

揭示宫颈阴道微生物群在自发性早产中的作用

• 批准号: 8659638
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 54.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-28 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659638
• 关键词: Address; Area; Behavioral; Biological Markers; Biological Response Modifiers; Birth Rate; Caring; Cells; Cervical; Cervix Uteri; Child; Clinical; Clinical Trials; Data; Disease; Economic Burden; Ensure; Environmental Risk Factor; Epidemiology; Epithelial; Epithelial Cells; Event; Gastrointestinal tract structure; Genes; Health; Homeostasis; Human; Immune; Immune response; Immunology; Infant; Infection; Intervention; Knowledge; Lactobacillus; Lead; Leukocytes; Link; Live Birth; Long-Term Care; Mediating; Medical; Methods; Microbiology; Modeling; Molecular; Molecular Profiling; Monitor; Mucosal Immune Responses; Neonatal; Pathogenesis; Pathway interactions; Perinatal Nursing; Play; Pregnancy; Pregnant Women; Premature Birth; Process; RNA; Race; Reproductive Medicine; Research; Risk; Risk Factors; Role; Smoking; Social Behavior; Specimen; Time; Time Study; Tissues; United States; Uterine Contraction; Vagina; Woman; base; case control; cervicovaginal; clinical care; cohort; cost; high risk; microbial community; microbiome; microorganism; neurobehavioral disorder; novel therapeutics; premature; prevent; prospective; protein expression; public health relevance; social; uterine contractility

DESCRIPTION (provided by applicant): Worldwide, 13 million infants are born preterm each year. In the United States, approximately 1 in 8 live births are preterm. The economic burden from prematurity is enormous costing over 28 billion dollars a year. These costs are not just for immediate neonatal care but also for long term care of these preterm children who are at increased risk for a spectrum of medical and neurobehavioral disorders. Currently, we have no effective strategies to predict or to prevent the majority of preterm births (PTBs). Based on the current model, key events in the pathogenesis of PTB are uterine infection and contractility. Assuming this model to be valid, the only strategies to decrease the risk for PTB are to monitor for increased uterine contractility and/or to treat the presumed underlying infectious process. Unfortunately, clinical trials attempting to treat or prevent uterine contractions and/or to treat infections have failed. Based in part on new findings linking, for example, dysbiosis of microbial communities (microbiota) inhabiting the human gastrointestinal tract to disease states through immune responses at the mucosal barriers, we propose a revised paradigm for the pathogenesis of PTB. Whereas PTB result from microbiota dysbiosis in the cervicovaginal (CV) compartment leading to a local immune response and altered tissue (cervix) homeostasis. The dysregulated immune response, mediated by the CV epithelial barrier, promotes changes in the cervix which leads to PTB. Furthermore, we propose that certain factors (e.g. behavior, social, environmental) known to mildly increase the risk for PTB, actually serve to alter the CV microbiota; thus, contributing to the pathogenesis of PTB. We hypothesize that microbial communities in the CV space will be stably composed of Lactobacillus spp. throughout pregnancy in women who are destined to have a term delivery. However, we propose that microbial communities will be less stable and enter states depleted of Lactobacillus spp. in women destined to have a PTB. Furthermore, specific microbial communities will induce an unfavorable immune response from the CV mucosal barrier; thus, microbial communities will be found to play a mechanistic role in PTB. This new paradigm will dramatically alter clinical care by allowing the identification, through the characterization of the CV microbiota, of the majority of women at risk-months prior to a clinical event- thus, providing opportunities for low-risk, feasible interventions. We have assembled an interdisciplinary team of experts in the field of reproductive medicine, microbiology, and perinatal nursing. We propose to assemble a prospective cohort, enriched with women with a prior PTB, that will allow for 3 longitudinal assessments during the 2nd and early 3rd trimester. At each study time point, we will determine the CV microbiota, the CV host immune response and determine if there are any molecular changes in the cervix consistent with premature cervical remodeling. In addition, we will comprehensively assess if behavioral, social and/or environmental factors modify the CV microbiota and/or its association with PTB.

描述（由申请人提供）：全世界每年有 1300 万婴儿早产。在美国，大约八分之一的活产婴儿是早产儿。早产带来的经济负担是巨大的，每年造成的损失超过 280 亿美元。这些费用不仅用于新生儿的即时护理，还用于这些早产儿的长期护理，这些早产儿患一系列医学和神经行为疾病的风险增加。目前，我们没有有效的策略来预测或预防大多数早产（PTB）。根据目前的模型，PTB发病机制的关键事件是子宫感染和收缩。假设该模型有效，降低 PTB 风险的唯一策略是监测子宫收缩力的增加和/或治疗假定的潜在感染过程。不幸的是，试图治疗或预防子宫收缩和/或治疗感染的临床试验失败了。部分基于新的发现，例如，通过粘膜屏障的免疫反应将人类胃肠道中微生物群落（微生物群）的失调与疾病状态联系起来，我们提出了一种修改后的 PTB 发病机制范式。而 PTB 是由子宫颈阴道 (CV) 区室微生物群失调引起的，导致局部免疫反应和组织（子宫颈）稳态改变。由CV上皮屏障介导的失调的免疫反应促进子宫颈的变化，从而导致PTB。此外，我们提出，已知会轻微增加 PTB 风险的某些因素（例如行为、社会、环境）实际上会改变 CV 微生物群； thus, contributing to the pathogenesis of PTB.我们假设 CV 空间中的微生物群落将稳定地由乳杆菌属组成。注定要足月分娩的妇女在整个怀孕期间。然而，我们认为微生物群落将不太稳定，并进入乳酸杆菌耗尽的状态。 in women destined to have a PTB.此外，特定的微生物群落会诱导CV粘膜屏障产生不利的免疫反应。因此，微生物群落将被发现在PTB中发挥机械作用。这种新模式将极大地改变临床护理，允许在临床事件发生前几个月通过CV微生物群的特征来识别大多数处于危险中的女性，从而为低风险、可行的干预措施提供机会。我们组建了一支由生殖医学、微生物学和围产期护理领域的跨学科专家组成的团队。我们建议组建一个前瞻性队列，其中包含既往患有 PTB 的女性，以便在妊娠第二个月和第三个月早期进行 3 次纵向评估。在每个研究时间点，我们将确定 CV 微生物群、CV 宿主免疫反应，并确定子宫颈中是否存在与过早宫颈重塑一致的分子变化。此外，我们将全面评估行为、社会和/或环境因素是否改变了CV微生物群和/或其与PTB的关联。