Mechanisms of Successful Vaginal Estrogen Prophylaxis for Postmenopausal Women with Recurrent Urinary Tract Infections: Urogenital Microbiota and Host Immune Responses

摘要/摘要 反复尿路感染(RUTI)是老年女性中的一个重大问题：13%的女性 医疗保险受益人每年至少经历一次尿路感染，其中40%发展为慢性复发性尿路感染。 尽管经阴道雌激素治疗(VET)可显著减少尿路感染，但仍有50%的患者继续使用VET 以体验尿路感染的复发。目前尚不清楚为什么一些女性从职业教育中受益，而另一些女性则没有。这 应用侧重于审问可能对职业教育和培训有效性至关重要的两种机制。第一 是不是泌尿生殖道微生物区系：阴道乳酸菌的增加是兽医所谓的机制 减少了鲁蒂。然而，最近的研究表明，并不是所有的乳酸菌都是同样有益的：阴道微生物区系 可能是通过产生D-乳酸来抑制E. Coli生长)。重要的和悬而未决的问题包括VET如何影响特定的乳杆菌属， 对特定乳杆菌的改变是否是成功预防的关键，以及VET如何影响 尿微生物区系，这可能在尿路感染易感性中起关键作用。第二个机制是由这个 应用是宿主对阴道和尿液的免疫反应。雌激素似乎影响本地化 泌尿生殖免疫反应，包括Th17和Th1对Th2途径的信号传导。动物研究表明 这些区隔的免疫反应在尿路感染易感性中起着关键作用，但人类数据 缺乏。该应用程序将解决这些悬而未决的问题。绝经后妇女会出现乳头肌无力 接受兽医治疗。在VET前后采集的样本将表征阴道和尿液微生物区系(16S RRNA基因测序)，两个隔室中的可溶炎症介质，以及阴道D-乳酸。 本提案的目标1和目标2将调查职业教育对泌尿生殖道微生物区系和泌尿生殖道的影响。 分别是免疫反应。目标3将描述以下参与者的泌尿生殖系统环境 与那些保持无UTI的人相比，在VET期间继续体验RUTI。这些目标的实现 将为更大规模和更明确的临床试验提供试点数据。因此，此应用程序响应于 计划公告PAS-20-160，支持小型临床试验以提供关键的初步数据。 这项拟议的研究将提供必要的数据，以计划一项严格的、足够强大的试验，以确定 与成功的Ruti预防相关的特征。这些拟议的研究是迈向我们的 确定可靠地预测RUTI预防成功应答的生物标志物的目标和确定 成功预防尿路感染所需的生物学条件。归根结底，对 RUTI预防机制将使制定新的和有效的预防战略成为可能 绝经后妇女患乳癌。

Summary/ Abstract Recurrent urinary tract infections (rUTI) are a significant problem among older women: 13% of female Medicare beneficiaries experience at least one UTI annually and >40% of these develop chronic recurrent UTI. Although UTIs are significantly reduced by vaginal estrogen therapy (VET), 50% of those using VET continue to experience UTI recurrences. It is unknown why some women benefit from VET while others do not. This application focuses on interrogating two mechanisms likely to be central to the effectiveness of VET. The first is the urogenital microbiota: an increase in vaginal lactobacilli is the purported mechanism by which VET reduces rUTI. However, recent studies suggest that not all lactobacilli are equally beneficial: vaginal microbiota dominated by L. crispatus may be more protective (possibly via the production of D-lactic acid, which inhibits E. coli growth). Important and unanswered questions include how VET influences specific Lactobacillus spp., whether changes to specific Lactobacillus spp are the key to successful prophylaxis, and how VET affects the urinary microbiota, which may play a critical role in UTI susceptibility. A second mechanism addressed by this application is the host vaginal and urinary immune response. Estrogen appears to influence localized urogenital immune responses, including Th17 and Th1 versus Th2 pathway signaling. Animal studies suggest that these compartmentalized immune responses play a critical role in UTI susceptibility, but human data are lacking. This application will address these unanswered questions. Postmenopausal women with rUTI will be treated with VET. Samples collected before and after VET will characterize vaginal and urinary microbiota (16S rRNA gene sequencing), soluble mediators of inflammation in both compartments, and vaginal D-lactic acid. Aims 1 and 2 of this proposal will investigate the impact of VET on the urogenital microbiota and urogenital immune responses, respectively. Aim 3 will characterize the urogenital environments of participants who continue to experience rUTI during VET versus those who remain UTI-free. The accomplishment of these aims will provide pilot data for a larger and more definitive clinical trial. Thus, this application is responsive to program announcement PAS-20-160, which supports small clinical trials to provide critical preliminary data. This proposed research will provide data needed to plan a rigorous, adequately powered trial to identify the characteristics associated with successful rUTI prevention. These proposed studies are a key step toward our goals of identifying biomarkers that reliably predict a successful response to rUTI prophylaxis and ascertaining the biological conditions required for successful UTI prevention. Ultimately, an understanding of the mechanisms of rUTI prevention will allow the development of novel and effective prevention strategies for postmenopausal women suffering from rUTI.