Unraveling mechanisms by which cervicovaginal microbiota can promote or prevent cervical remodeling and preterm birth

摘要：每年有1500万婴儿早产。超过75%的早产儿（PTB）被称为 自发性（sPTB），导致在妊娠早期时间点分娩，无明确原因。我们缺乏 对促进sPTB的机制和总体发病机制的理解导致有限的成功治疗， 干预措施。虽然子宫收缩和宫颈重塑似乎是强制性的过程， 分娩，这些过程的过早触发仍然不清楚。最近的研究显示， 宫颈阴道（CV）微生物群落与sPTB发生之间的关联。我们尤其 最近研究了一组2000名孕妇，并评估了CV微生物群落、代谢和 怀孕早期的免疫反应，提供了强有力的证据表明，特定细菌类群的定植， 特异性代谢谱和局部免疫应答与sPTB密切相关。但要 制定预防或治疗策略，了解sPTB的原因至关重要。我们推测 CV微生物群落、局部免疫反应和宫颈和阴道上皮细胞之间的相互作用 屏障诱导过早的宫颈重塑并启动sPTB。本研究的总体目标是确定 特异性CV细菌如何与阴道和上皮细胞在临床相关的体外和体内相互作用 模型，并了解这些相互作用如何改变组织重塑和生物力学的怀孕 子宫颈，驱动sPTB。我们提出了一个过程，其中与sPTB高度相关的细菌分类群在 人类引起阴道上皮脱落。这一过程促进上皮-间充质转化 (EMT)来自阴道和宫颈上皮细胞。虽然EMT的激活阻止了这些 在子宫颈组织中，EMT促进了细胞外基质的分解，触发了子宫颈组织中的细胞外基质的分解。 宫颈过早重塑和sPTB。因此，我们的中心假设是，特定的细菌，如 阴道加德纳氏菌（G.vagelia）促进阴道和宫颈上皮屏障的EMT，从而改变阴道和宫颈上皮屏障的功能。 妊娠子宫颈的结构和功能，导致sPTB，即使在没有上行感染的情况下 （子宫颈上方）。这一范式转变的假设将通过一系列的体外和体内实验进行检验。 实验这个提议将首先说明细菌提升进入子宫是否真的是必要的 这些研究有可能重新构建我们对PTB的科学和治疗方法。 然后，我们将展示细菌如何诱导CV上皮屏障中的EMT，以及EMT如何促进 过早的宫颈重塑独特的这一建议，我们将提供定量评估的 妊娠子宫颈，在结构和功能方面，在PTB小鼠模型。一个多学科的团队补充说， 通过将新的概念和技术应用于sPTB的研究，使我们的工作更加严谨。这些研究将提供 对限制或预防sPTB的新的和集中的治疗靶点的见解，并将显著推进这一点 领域

Summary: 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), 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.