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.

总结/摘要 复发性尿路感染（鲁蒂）是老年妇女的一个重要问题：13%的女性 医疗保险受益人每年至少经历一次UTI，其中>40%发展为慢性复发性UTI。 尽管阴道雌激素治疗（VET）可显著减少UTI，但50%的使用VET的患者仍继续使用 复发性尿路感染不知道为什么有些妇女从职业教育和培训中受益，而另一些妇女则没有。这 应用程序的重点是询问两个机制可能是中心的有效性VET。 是泌尿生殖道微生物群：阴道乳酸杆菌的增加是VET 降低鲁蒂。然而，最近的研究表明，并非所有的乳酸杆菌都是同样有益的：阴道微生物群 由L.卷曲肠杆菌可能更具保护性（可能通过产生D-乳酸，其抑制E. 大肠杆菌生长）。重要和未回答的问题包括VET如何影响特定的乳杆菌属， 特定乳杆菌的变化是否是成功预防的关键，以及VET如何影响 泌尿微生物群，这可能在UTI易感性中起关键作用。第二种机制是， 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 泌尿生殖系统免疫反应，包括Th 17和Th 1与Th 2通路信号传导。动物研究表明 这些区室化的免疫反应在UTI易感性中起着关键作用，但人类数据 缺乏这个应用程序将解决这些悬而未决的问题。患有鲁蒂的绝经后女性将 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（16 S rRNA基因测序）、两个隔室中的可溶性炎症介质和阴道D-乳酸。 本提案的目的1和2将研究VET对泌尿生殖道微生物群和泌尿生殖道的影响。 免疫反应。目标3将描述参与者的泌尿生殖环境， 在VET期间继续经历鲁蒂与那些保持UTI自由的人相比。这些目标的实现 将为更大更明确的临床试验提供初步数据。因此，本申请响应于 PAS-20-160计划公告，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计划一项严格的、有充分把握的试验所需的数据，以确定 与成功预防鲁蒂相关的特征。这些拟议中的研究是迈向我们的关键一步。 目的是鉴定可靠预测鲁蒂预防成功应答的生物标志物， 成功预防UTI所需的生物条件。最后，要理解 鲁蒂预防机制将允许开发新的有效的预防策略， 患有鲁蒂的绝经后妇女。