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

阴道雌激素成功预防绝经后女性复发性尿路感染的机制：泌尿生殖微生物群和宿主免疫反应

• 批准号: 10516250
• 负责人: VICTORIA Lynn HANDA
• 金额: $ 33.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516250
• 关键词: 16S ribosomal RNA sequencing; Address; Affect; Allergic Reaction; Alternative Therapies; Animals; Antibiotics; Atopobium vaginae; Bacteria; Benign; Biological; Biological Markers; Bladder; Characteristics; Chronic; Clinical Trials; Clostridium difficile; Data; Development; Dose; Duct (organ) structure; Effectiveness; Elderly; Environment; Escherichia coli; Estrogen Therapy; Estrogens; Exhibits; Female; Funding Mechanisms; Genitourinary System Infection; Genitourinary system; Goals; Growth; Hospitalization; Human; Immune response; Individual; Infection prevention; Inflammation; Inflammation Mediators; Lactic acid; Lactobacillus; Lower urinary tract; Measures; Mediating; Medicare; Menopause; Modernization; Modification; Molecular; Morbidity - disease rate; NIH Program Announcements; Parents; Participant; Pathologic; Pathway interactions; Patients; Pilot Projects; Play; Population; Postmenopause; Predisposition; Prevention; Prevention strategy; Production; Prophylactic treatment; Recurrence; Research; Role; Sampling; Signal Pathway; Signal Transduction; Symptoms; Techniques; Time; Urinary Microbiome; Urinary tract infection; Urine; Uropathogen; Vagina; Woman; antibiotic resistant infections; bactericide; beneficiary; biomarker identification; cost; cytokine; evidence base; experience; human data; improved; macrophage; microbial; microbiota; neutrophil; novel; older women; open label; pathogen; prevent; recurrent infection; response; treatment response; urinary; urogenital tract; urologic; vaginal lactobacilli; vaginal microbiome; vaginal microbiota

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.

摘要/摘要 复发性尿路感染 (rUTI) 是老年女性的一个严重问题：13% 的女性 医疗保险受益人每年至少经历一次尿路感染，其中超过 40% 的人患有慢性复发性尿路感染。 尽管阴道雌激素疗法 (VET) 显着减少了尿路感染，但使用 VET 的患者中 50% 仍继续使用 经历尿路感染复发。目前尚不清楚为什么有些女性能从职业教育与培训中受益，而另一些女性则不能。这 应用程序的重点是询问两种可能对职业教育与培训有效性至关重要的机制。第一个 是泌尿生殖微生物群：阴道乳酸杆菌的增加是 VET 的据称机制 减少 rUTI。然而，最近的研究表明并非所有乳酸菌都同样有益：阴道微生物群 以卷曲乳杆菌为主的细菌可能更具保护性（可能通过产生 D-乳酸来抑制大肠杆菌）。 大肠杆菌生长）。重要且尚未解答的问题包括 VET 如何影响特定的乳杆菌属， 特定乳杆菌属的变化是否是成功预防的关键，以及 VET 如何影响 尿液微生物群可能在尿路感染易感性中发挥关键作用。本文解决的第二种机制 应用是宿主阴道和泌尿系统的免疫反应。雌激素似乎影响局部 泌尿生殖免疫反应，包括 Th17 和 Th1 与 Th2 通路信号传导。动物研究表明 这些区室化的免疫反应在尿路感染易感性中发挥着关键作用，但人类数据 缺乏。该应用程序将解决这些未解答的问题。患有 rUTI 的绝经后妇女将 接受 VET 治疗。 VET 之前和之后收集的样本将表征阴道和尿液微生物群 (16S rRNA 基因测序）、两个区室中的可溶性炎症介质以及阴道 D-乳酸。 该提案的目标 1 和 2 将调查 VET 对泌尿生殖微生物群和泌尿生殖系统的影响 分别产生免疫反应。目标 3 将描述参与者的泌尿生殖环境特征 与那些仍然没有尿路感染的人相比，在职业教育和培训期间继续经历尿路感染的人。这些目标的实现 将为更大规模、更明确的临床试验提供试点数据。因此，该应用程序响应 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规划严格、有力的试验所需的数据，以确定 与成功预防 rUTI 相关的特征。这些拟议的研究是我们迈向的关键一步 识别生物标志物的目标是可靠地预测对 rUTI 预防的成功反应并确定 成功预防尿路感染所需的生物学条件。最终，了解 rUTI 预防机制将有助于制定新颖有效的预防策略 患有 ruTI 的绝经后妇女。