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: 10696251
• 负责人: VICTORIA Lynn HANDA
• 金额: $ 32万
• 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/10696251
• 关键词: 16S ribosomal RNA sequencing; Address; Affect; Allergic Reaction; Alternative Therapies; Animals; Antibiotic Resistance; Antibiotics; Atopobium vaginae; Bacillus; Bacteria; Benign; Biological; Bladder; Characteristics; Chronic; Clinical Trials; Data; Development; Dose; Effectiveness; Elderly; Environment; Escherichia coli; Estrogen Therapy; Estrogens; Exhibits; Female; Funding Mechanisms; Genitourinary system; Goals; Growth; Hospitalization; Human; Immune response; Individual; Infection prevention; Inflammation; Inflammation Mediators; Lactic acid; Lactobacillus; Lower urinary tract; Macrophage; Measures; Mediating; Medicare; Menopause; Modernization; Modification; Molecular; Morbidity - disease rate; NIH Program Announcements; Outcome; Participant; Pathologic; Pathway interactions; Patients; Pilot Projects; Play; Population; Postmenopause; Predisposition; Prevention; Prevention strategy; Production; Prophylactic treatment; Pseudomembranous Colitis; Recurrence; Research; Role; Sampling; Signal Pathway; Signal Transduction; Symptoms; Techniques; Urinary Microbiome; Urinary tract infection; Urine; Uropathogen; Vagina; Woman; antibiotic resistant infections; bactericide; beneficiary; biomarker identification; cost; cytokine; design; evidence base; experience; human data; improved; microbial community; microbiota; mortality; neutrophil; novel; older women; open label; pathogen; prevent; recurrent infection; relapse prevention; 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）是老年女性的重大问题：13％的女性 Medicare受益人每年至少有一个UTI，其中> 40％>其中40％发展慢性重复的UTI。 尽管阴道雌激素疗法（VET）显着降低了UTI，但使用兽医的人中有50％继续 体验UTI复发。尚不清楚为什么有些妇女从兽医那里受益，而另一些女性则不知道。这 应用的重点是审问两种可能是兽医有效性核心的机制。第一个 是泌尿生殖器菌群：阴道乳酸杆菌的增加是兽医的所谓机制 减少鲁蒂。但是，最近的研究表明，并非所有乳酸杆菌都同样有益：阴道菌群 以脆性乳杆菌为主可能更具保护作用（可能是通过抑制E. E.的D-乳酸的产生 大肠杆菌的生长）。重要和未解决的问题包括兽医如何影响特定的乳酸杆菌。 对特定乳酸杆菌的变化是否是成功预防的关键，以及兽医如何影响 尿菌群，可能在UTI易感性中起关键作用。解决这个问题的第二种机制 应用是宿主的阴道和尿液免疫反应。雌激素似乎会影响局部 泌尿生殖器免疫反应，包括TH17和TH1与Th2途径信号传导。动物研究表明 这些分隔的免疫反应在UTI敏感性中起着至关重要的作用，但是人类数据是 缺乏。该应用程序将解决这些未解决的问题。鲁蒂的绝经后妇女将 用兽医处理。兽医之前和之后收集的样品将表征阴道和尿菌群（16s rRNA基因测序），两个隔室炎症的可溶性介体和阴道D-乳酸。 该提案的目标1和2将研究兽医对泌尿生殖器微生物和泌尿生殖的影响 免疫反应。 AIM 3将表征参与者的泌尿生殖环境 在兽医期间与那些保持不含UTI的人一起继续体验Ruti。这些目标的成就 将为更大，更明确的临床试验提供试验数据。因此，此应用程序对 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需要计划的数据，以计划严格，充分的动力试验来确定 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关键一步 确定生物标志物的目标可靠地预测对Ruti预防的成功反应并确定 成功预防UTI所需的生物条件。最终，对 RUTI预防机制将允许制定新颖有效的预防策略 绝经后妇女患有鲁蒂。