Deciphering the Role of Vaginal Microbes in Preterm birth

每年有1500万名婴儿早产。超过75%的早产(PTB)被称为自然分娩 (SPTB)在妊娠早期没有明确原因的情况下导致分娩。我们缺乏理解 对促进sPTB的机制和整体发病机制的了解导致了有限的成功干预。 虽然子宫收缩和宫颈重塑似乎是分娩时的强制性过程，但早产 这些过程的触发因素仍然很少被阐明。最近的研究表明， 宫颈阴道(CV)微生物群落与sPTB的发生特别是，我们最近研究了一种 2000名孕妇的队列，并评估了心血管微生物群落、代谢和免疫 在怀孕早期的反应，提供了强有力的证据，用特定的细菌分类群，特定的 代谢特征和局部免疫反应与肺结核密切相关。然而，要发展 无论是预防还是治疗策略，了解肺结核的病因是至关重要的。我们推测这种相互作用 心血管微生物群落、局部免疫反应与宫颈和阴道上皮屏障之间的关系 诱发早产宫颈重塑，引发sPTB。这项研究的总体目标是定义具体到什么程度 在临床相关的体外和体内模型中，CV细菌与阴道和上皮细胞相互作用，并 了解这些相互作用如何改变怀孕宫颈的组织重塑和生物力学，从而推动 SPTB。我们提出了一种过程，在这种过程中，与人类中的sPTB高度相关的细菌分类群引发了 阴道上皮脱落。这一过程促进了两者的上皮-间充质转化(EMT) 阴道和宫颈上皮细胞。虽然EMT的激活阻止了这些细菌的上升，但 权衡是EMT促进了宫颈组织中细胞外基质的分解，引发了早产 宫颈重塑与单纯性肺结核。因此，我们的中心假设是特定的细菌，如 阴道加德纳氏菌和米氏移动杆菌，促进阴道EMT和 宫颈上皮屏障，改变妊娠宫颈的结构和功能，导致sPTB，甚至 在没有上行性感染的情况下(在宫颈以上)。这一范式转换假说将得到检验 通过一系列的体外和体内实验。这项提议将首先解决是否提升 细菌进入子宫实际上是肺结核发生所必需的；这些研究有可能重新构建我们的 结核病的科学和治疗方法。然后，我们将演示细菌如何在CV上皮细胞中诱导EMT 以及EMT如何促进早产的宫颈重塑。对于此提案，我们将提供 在肺结核小鼠模型中，从结构和功能方面对怀孕的宫颈进行定量评估。一个 多学科团队将新的概念和技术应用到sPTB的研究中，使我们的工作更加严谨。 这些研究将为限制或预防肺结核的新的和重点治疗目标提供洞察力，并将 大大推进这一领域的发展。

Every year, 15 million babies are born premature. Over 75% of preterm births (PTBs) are termed spontaneous (sPTB) resulting in parturition at early gestational time points without clear causes. Our lack of understanding of the mechanisms and overall pathogenesis that promotes sPTB results in limited successful interventions. While uterine contractility and cervical remodeling appear to be obligatory processes in parturition, premature triggers of these processes remain poorly elucidated. Recent studies reveal close associations between cervicovaginal (CV) microbial communities and the occurrence of sPTB. In particular, we recently studied a cohort of 2000 pregnant women and assessed the CV microbial communities, metabolic and immune responses early in pregnancy, providing strong evidence that colonization with specific bacterial taxa, specific metabolic profiles, and local immune responses were strongly associated with sPTB. However, to develop preventive or therapeutic strategies, understanding the cause of sPTB is essential. We speculate that interplay between the CV microbial communities, local immune response and the cervical and vaginal epithelial barriers induce premature cervical remodeling and initiate sPTB. The overall goal of this study is to define how specific CV bacteria interact with vaginal and epithelial cells in clinically relevant in vitro and in vivo models and to understand how those interactions modify tissue remodeling and biomechanics of the pregnant cervix, driving sPTB. We propose a process whereby bacterial taxa that are highly associated with sPTB in humans provoke exfoliation of the vaginal epithelium. This process promotes epithelial-mesenchymal transition (EMT) from both vaginal and cervical epithelial cells. While activation of EMT prevents the ascension of these bacteria, a tradeoff is that EMT fosters breakdown of the extracellular matrix in the cervical tissue, triggering premature cervical remodeling and sPTB. Therefore, our central hypothesis is that specific bacteria, such as Gardnerella vaginalis (G.vaginalis) and Mobiluncus mulieris (M. Mulieris), promote EMT of the vaginal and cervical epithelial barrier which alters the structure and function of the pregnant cervix, leading to sPTB, even in the absence of ascending infection (above the cervix). This paradigm-shifting hypothesis will be tested through a series of in vitro and in vivo experiments. This proposal will first address whether ascension of bacteria into the uterus is actually necessary for PTB to occur; these studies have the potential to reframe our scientific and therapeutic approach to PTB. We will then demonstrate how bacteria induce EMT in CV epithelial barriers and how EMT might promote premature cervical remodeling. Unique to this proposal, we will provide quantitative assessment of the pregnant cervix, in terms of structure and function, in a mouse model of PTB. A multidisciplinary team adds rigor to our work by applying novel concepts and techniques to the study of sPTB. These studies will provide insight as to new and focused therapeutic targets to limit or prevent sPTB and will significantly advance this field.