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

描述（由申请人提供）：全球每年有1300万婴儿早产。在美国，大约八分之一的活产婴儿是早产儿。早产造成的经济负担是巨大的，每年要花费超过280亿美元。这些费用不仅用于新生儿的即时护理，而且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障碍的风险增加。目前，我们没有有效的策略来预测或预防大多数早产（PTBs）。基于目前的模型，PTB发病的关键事件是子宫感染和收缩。假设该模型是有效的，那么降低PTB风险的唯一策略就是监测子宫收缩性增强和/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都失败了。部分基于新的发现，例如，通过粘膜屏障的免疫反应，将居住在人类胃肠道中的微生物群落（微生物群）的生态失调与疾病状态联系起来，我们提出了PTB发病机制的修订范式。然而，PTB是由宫颈阴道（CV）腔室微生物群失调引起的，导致局部免疫反应和组织（宫颈）稳态改变。由CV上皮屏障介导的失调免疫反应促进子宫颈的变化，从而导致PTB。此外，我们提出某些已知的因素（如行为、社会、环境）会轻度增加患PTB的风险，实际上有助于改变CV微生物群；因此，有助于PTB的发病机制。我们假设，在注定足月分娩的妇女的整个怀孕期间，CV空间中的微生物群落将稳定地由乳酸杆菌组成。然而，我们提出，微生物群落将不太稳定，进入状态的乳酸菌耗尽的妇女注定有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，微生物群落将在PTB中发挥机制作用。这种新模式将极大地改变临床护理，因为它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妇女，从而为低风险、可行的干预措施提供机会。我们在生殖医学、微生物学和围产期护理领域组建了一支跨学科的专家团队。我们建议组建一个前瞻性队列，其中包括有PTB病史的妇女，这将允许在妊娠2月和3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，并确定宫颈中是否存在与宫颈过早重塑相一致的分子变化。此外，我们将全面评估行为、社会和/或环境因素是否会改变CV微生物群和/或其与PTB的关系。

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.