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

描述(申请人提供)：全球每年有1300万早产婴儿。在美国，大约八分之一的活产是早产。早产造成的经济负担是巨大的，每年造成超过280亿美元的损失。这些费用不仅用于新生儿的即时护理，也用于这些早产儿的长期护理，这些早产儿患上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(PTB)。根据目前的模型，在肺结核发病机制中的关键事件是子宫感染和收缩。假设这个模型是有效的，降低肺结核风险的唯一策略是监测子宫收缩能力的增加和/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的微生物群落(微生物区系)的微生物群落(微生物区系)与疾病状态联系起来，我们提出了一个修订的肺结核发病机制范式。而肺结核是由于宫颈阴道室的微生物区系失调导致局部免疫反应和组织(宫颈)动态平衡改变所致。由CV上皮屏障介导的失调免疫反应促进了宫颈的变化，从而导致肺结核的发生。此外，我们认为，某些已知的因素(如行为、社会、环境)会轻微增加患肺结核的风险，但实际上却会改变心血管微生物区系，从而导致肺结核的发病。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。在整个怀孕期间，注定要有足月分娩的妇女。然而，我们认为微生物群落将不太稳定，并进入乳杆菌枯竭状态。在注定要患肺结核的女性身上。此外，特定的微生物群落会诱导来自CV粘膜屏障的不利免疫反应，因此，微生物群落将被发现在肺结核中起着机械作用。这一新的范式将极大地改变临床护理，通过对心血管微生物区系的描述，识别大多数处于风险中的妇女--在临床事件发生前几个月--从而为低风险、可行的干预提供机会。我们已经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。我们建议建立一个前瞻性队列，由有过肺结核病史的妇女组成，这将允许在怀孕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微生物区系、CV宿主免疫反应，并确定宫颈是否有任何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心血管微生物区系和/或其与肺结核的关系。

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.