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.

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