Mechanistic basis of urinary Lactobacillus enrichment by estrogen hormone therapy

雌激素治疗增加尿乳酸菌的机制基础

• 批准号: 10537389
• 负责人: Michael Lee Neugent
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537389
• 关键词: Adherence; Affect; Age; Antibiotic Therapy; Bacterial Vaginosis; Biological Assay; Biological Models; Biomedical Research; Bladder; Cell Line; Cells; Chemical Models; Clinical; Clinical Research; Coculture Techniques; Communities; Confocal Microscopy; Data; Deposition; Estradiol; Estrogens; Exposure to; Fellowship; Female; Fluorescence; Future; Gastrointestinal tract structure; Genitourinary system; Glucose; Glycogen; Glycosaminoglycans; Goals; Hela Cells; Human; Image; Immunohistochemistry; In Vitro; Incidence; Infection; Knowledge; Lactobacillus; Link; Maintenance; Measures; Mediating; Medical; Menopause; Mentors; Metabolic; Metabolism; Metagenomics; Methods; Molecular; Mucous Membrane; Mus; Nutrient; Patients; Polysaccharides; Postmenopause; Production; Proteoglycan; Recording of previous events; Recurrence; Reporting; Research; Risk; Role; Scientist; Site; Source; Sterility; Structure; Surface; System; Techniques; Testing; Therapeutic; Thick; Tissues; Training; United States; Urinary Microbiome; Urinary tract; Urinary tract infection; Urine; Urothelial Cell; Urothelium; Vagina; Visit; Woman; Work; bacterial genetics; base; biobank; career; cohort; effective therapy; experience; extracellular; global health; glucose metabolism; hormone therapy; host microbiome; improved; in vitro Model; in vivo; insight; metagenomic sequencing; microbial community; microbiome; microbiota; preservation; programs; restoration; scaffold; therapeutic target; treatment strategy; urethral microbiota; urinary; urogenital tract; vaginal lactobacilli; vaginal microbiome; vaginal microbiota; vaginal mucosa; whole genome

Proposal Summary/Abstract The medical burden of urinary tract infection (UTI) is significant as they directly contribute to 1% of all clinical visits in the United States. Annual medical expenses attributed to UTI currently exceed $3.5 billion. As a global health concern, UTIs mainly affect women and commonly progress into recurrent UTI (rUTI) when a patient experiences 3 or more UTIs in a 12 month period. The risk of rUTI increases with age, leading to disproportionately high incidence rates in postmenopausal (PM) women. Effective therapies for rUTI are severely limited as most treatment strategies rely on long-term antibiotic therapy with the goal of achieving sterility within the urinary tract. However, even healthy urine is not sterile, and it has been confirmed that a microbial community resides in the healthy urinary tract of PM women, termed here the urobiome. To date, most therapeutic strategies for rUTI do not consider the preservation or restoration of the resident microbiota of the urinary or urogenital tract. Interestingly, the urobiome has been shown to be interconnected with the vaginal microbiome and vaginal D(-)Lactate-producing lactobacilli, such as Lactobacillus crispatus, have been shown to protect against bacterial vaginosis. Vaginal lactobacilli have been associated with circulating estrogen levels and early clinical studies found that estrogen hormone therapy (EHT) is strongly associated with vaginal lactobacilli enrichment in PM women. Interestingly, EHT is now widely becoming recognized as an effective treatment option for rUTI in PM women, but the mechanism behind this observation is unknown. We have observed a strong association between EHT use and urinary L. crispatus enrichment in our metagenomic analysis of the urobiome of a controlled cross-sectional cohort of PM women (n=75). These observations have led me to ask a fundamental question: How does estrogen enrich for Lactobacillus communities in the urobiome? This proposal centers around the following hypothesis: EHT, as a treatment for rUTI, enhances Lactobacillus colonization of the urinary tract by stimulating host production of nutrient sources and scaffolding attachment sites needed for colonization. To test these hypotheses, I will characterize the effect of EHT treatment on the metabolism of cultured primary urothelial cells and use a curated biobank of bacterial isolates from our de-identified human cohorts to study colonization of co-cultures of urothelial cells and L. crispatus in the presence and absence of estrogen. The long-term goal of this proposal is to leverage the insight gained from testing these hypotheses to identify alternate therapeutic targets for effective and safe adjunct therapies for rUTI. A central theme of this proposal is to use the scientific goals as a vehicle to achieve critical training goals I and my sponsors believe will greatly help in my future independent research career.

提案摘要/摘要 尿路感染（UTI）的医疗负担很大，因为它们直接贡献了所有临床的1％ 在美国访问。归因于UTI的年度医疗费用目前超过35亿美元。作为全球 健康问题，尿路感染主要影响妇女，并且通常会在患者时逐渐发展成为反复发作的UTI（RUTI） 在12个月内体验3个或更多UTI。鲁蒂的风险随着年龄的增长而增加，导致 绝经后（PM）妇女的发病率不成比例。 RUTI的有效疗法严重 受到限制，因为大多数治疗策略都依赖于长期抗生素疗法，目的是在 尿路。但是，即使是健康的尿液也不是无菌的，并且已经证实了微生物群落 居住在PM妇女的健康尿道中，在这里称为尿射剂。迄今为止，大多数治疗策略 对于ruti，请勿考虑保存或恢复尿液或泌尿生殖器的居民菌群 道。有趣的是，尿叶组已被证明与阴道微生物组和阴道相互联系 D（ - ）产生乳酸乳酸菌（例如乳酸乳杆菌）已被证明可以预防细菌 阴道病。阴道乳酸杆菌与循环的雌激素水平和早期临床研究有关 发现雌激素疗法（EHT）与PM中的阴道乳酸富集密切相关 女性。有趣的是，EHT现在已被广泛地被公认为是PM中RUTI的有效治疗选择 妇女，但是这种观察背后的机制尚不清楚。我们已经观察到了牢固的关联 在我们对A的核生组分析中，EHT使用和尿液中的尿。 PM妇女受控的横截面队列（n = 75）。这些观察结果使我问一个基本 问题：雌激素如何富含尿虫组中的乳杆菌群落？该建议中心 围绕以下假设：EHT作为RUTI的治疗，增强了乳酸菌定植 尿路通过刺激营养源的宿主产生和脚手架附件所需的宿主产生 殖民化。为了检验这些假设，我将表征EHT治疗对代谢的影响 培养的原发性尿路上皮细胞，并使用我们去识别的人类的细菌分离株的策划生物库 研究尿路上皮细胞和克里斯帕图斯氏乳杆菌共培养的人群在存在和不存在的情况下 雌激素。该提议的长期目标是利用从检验这些假设到的洞察力到 确定用于RUTI有效且安全的辅助疗法的替代治疗靶标。一个中心主题 建议是将科学目标用作实现关键训练目标的工具，我和我的赞助商认为 在我未来的独立研究生涯中极大地有助于。