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

摘要：每年有1500万名婴儿早产。超过75%的早产儿(PTB)被称为 自发性(SPTB)在妊娠早期导致分娩，没有明确的原因。我们缺少的是 对促进sPTB的机制和整体发病机制的了解仅能取得有限的成功 干预措施。而子宫收缩和宫颈重塑似乎是 在分娩过程中，这些过程的过早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发生的关系。特别是，我们 最近研究了2000名孕妇的队列，并评估了心血管微生物群落、代谢和 怀孕早期的免疫反应，提供了强有力的证据表明， 特定的代谢特征和局部免疫反应与sPTB密切相关。然而，为了 制定预防或治疗策略，了解肺结核的病因是至关重要的。我们推测 CV微生物群落、局部免疫反应与宫颈和阴道上皮之间的相互作用 屏障可导致早产的宫颈重塑，并引发sPTB。这项研究的总体目标是确定 体内外临床相关的特异性CV细菌与阴道和上皮细胞的相互作用 并了解这些相互作用如何改变孕妇的组织重塑和生物力学 宫颈，驾驶结肠性肺结核。我们提出了一个过程，在这个过程中，与sPTB高度相关的细菌分类群 人类会引起阴道上皮脱落。这一过程促进了上皮向间充质转化。 (EMT)来自阴道和宫颈上皮细胞。虽然EMT的激活阻止了这些 细菌，一种权衡是EMT促进宫颈组织细胞外基质的分解，引发 早产宫颈重塑和单纯性肺结核。因此，我们的中心假设是特定的细菌，如 阴道加德纳菌，促进阴道和宫颈上皮屏障的EMT，从而改变 妊娠宫颈的结构和功能，即使在没有上行感染的情况下也会导致sPTB (宫颈以上)。这一范式转换假说将通过一系列体外和体内实验进行验证。 实验。这项提案将首先解决细菌是否真的有必要进入子宫的问题 这些研究有可能重塑我们对肺结核的科学和治疗方法。 然后，我们将演示细菌如何在血管上皮屏障中诱导EMT，以及EMT如何促进 过早的宫颈重塑。对于这项建议，我们将提供量化评估 在肺结核小鼠模型中，从结构和功能的角度来看，怀孕的宫颈。一个多学科团队补充道 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 洞察新的和集中的治疗目标，以限制或预防肺结核，并将显著推动这一点 菲尔德。

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.