Defining the dynamics of urobiome structure and function in postmenopausal women and its role in recurrent UTI susceptibility

定义绝经后女性尿生物组结构和功能的动态及其在复发性尿路感染易感性中的作用

• 批准号: 10346595
• 负责人: Nicole Janell De Nisco
• 金额: $ 28.8万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346595
• 关键词: 3-Dimensional; Address; Affect; Amino Acids; Anatomy; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bladder; Carbohydrates; Carbon; Chemicals; Classification; Cross-Sectional Studies; Data; Development; Disease; Disease remission; Environment; Estradiol; Estrogen Therapy; Estrogens; Estrone; Foundations; Genetic; Goals; Health; Healthcare; Hormonal Change; Human; Hypersensitivity; Incidence; Infection; Knowledge; Lactobacillus; Longitudinal Studies; Maintenance; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Methods; Modality; Modeling; Oral; Outcome; Pathway interactions; Patients; Play; Population; Postmenopause; Predisposition; Premenopause; Quality of life; Recording of previous events; Recovery; Recurrence; Refractory; Relapse; Role; Sampling; Shotguns; Source; Structure; Techniques; Testing; Time; Urinary Microbiome; Urinary tract infection; Urine; Urologic Diseases; Uropathogen; Vagina; Variant; Woman; Work; base; biobank; cohort; combat; community-acquired UTI; design; dosage; hormone therapy; longitudinal analysis; member; metabolomics; metagenome; metagenomic sequencing; microbial; microbiome; microbiome analysis; microbiota; multidisciplinary; novel therapeutics; probiotic therapy; response; spatiotemporal; targeted treatment; urethral microbiome; urinary; vaginal microbiome; vaginal microbiota

Community-acquired urinary tract infection (UTI) is among the most common bacterial infections worldwide, affecting at least 150 million people annually. When a patient suffers 3 UTIs within a 12-month period, the infection is termed recurrent UTI (rUTI). rUTI severely diminishes quality of life and has become one of the most difficult urologic diseases to manage in women. Rates of range from 19-36% in premenopausal women and increasing to 50% in postmenopausal (PM) women. The higher incidence of rUTI in PM women compared to premenopausal women suggests that the host environment plays a role in rUTI susceptibility. rUTI management relies on antibiotic therapy but many front-line antibiotics have become ineffective due to widespread antimicrobial resistance. To combat the increasing rates of antibiotic-refractory rUTI, new therapies must be developed. A promising source of new rUTI therapies is the urinary microbiome, termed here the urobiome, which has been recently identified as an important component of the urinary environment. A critical step in the development of probiotic therapies is defining niche colonization and maintenance requirements. However, to date, urobiome studies have been largely focused on compositional classification and have not identified nichespecific urobiome functions or metabolic requirements. Furthermore, the effect of rUTI and the hormonal changes on urobiome composition and function has not been assessed in PM women. We have completed shotgun metagenomic sequencing (MGS) of urine from a cross-sectional cohort of PM women. In this work we have discovered that urinary lactobacilli (Lb) abundance in women without rUTI was associated with specific modalities of estrogen hormone therapy (EHT). Our functional analysis of the MGS data revealed differential enrichment in central carbon metabolism pathways in the metagenomes of women with no history of UTI versus women with active rUTI suggesting that urobiomes of healthy women are functionally different than those with rUTI. We have assembled a multidisciplinary, collaborative team to conclusively fill fundamental gaps in knowledge through the following specific aims: 1) Define the correlation between urinary Lb abundance and estrogen concentration in PM women using EHT, 2) Define metabolic differences between the urobiomes of healthy women and those with rUTI relevant to the urinary environment, and 3) Establish the spatiotemporal dynamics of urobiome composition and function in healthy PM women and during rUTI. In completing these aims, we will quantify excreted EHT metabolites and define their correlation with urinary Lb abundance. We will define key, relevant metabolic differences between urobiomes and identify metabolite-taxa associations related to rUTI. Finally, our longitudinal analysis of urinary metagenomes and metabolites in matched patient samples will define the effect of EHT on urobiome dynamics in healthy PM women and during rUTI. These findings will generate foundational knowledge of the function and spatiotemporal dynamics of the urobiome of PM women necessary for the rational design of urobiome-targeted therapies for rUTI.

社区获得的尿路感染（UTI）是全球最常见的细菌感染之一， 每年至少影响1.5亿人。当患者在12个月内遭受3个UTI时， 感染称为复发性UTI（RUTI）。鲁蒂严重降低了生活质量，并已成为最多的人之一 妇女难以管理的困难泌尿科疾病。绝经前妇女的19-36％范围 绝经后（PM）女性增加到50％。与 绝经后妇女建议，宿主环境在ruti的敏感性中起作用。 RUTI管理 依靠抗生素疗法，但由于广泛的范围，许多一线抗生素已无效 抗菌耐药性。为了打击抗生素难治性ruti的增长速率，必须是新疗法 发达。新的Ruti疗法的一个有前途的来源是尿液微生物组，在这里称为尿虫组， 最近被确定为尿环境的重要组成部分。在 益生菌疗法的发展正在定义利基定植和维护要求。但是，要 日期，尿样剂研究主要集中在组成分类上，并且没有确定尿叶室功能或代谢需求。此外，鲁蒂和荷尔蒙的影响 PM女性尚未评估尿样蛋白组成分和功能的变化。 我们已经从PM的横截面队列完成了尿液的shot弹枪元基因组测序（MGS） 女性。在这项工作中，我们发现没有ruti的女性尿乳杆菌（LB）丰富 与雌激素疗法（EHT）的特定方式有关。我们对MGS数据的功能分析 揭示了中央碳代谢途径的差异富集 UTI与活跃的RUTI女性的历史表明健康女性的尿生物症在功能上是 与鲁蒂的人不同。我们组建了一个多学科的协作团队，以最终填补 通过以下特定目的在知识中的基本差距：1）定义尿之间的相关性 使用EHT，PM女性的LB丰度和雌激素浓度，2）定义代谢差异 健康妇女的尿虫和与尿环境相关的鲁蒂妇女的尿素组，3）建立 健康PM女性和鲁蒂期间的尿样组组成和功能的时空动力学。在 完成这些目标，我们将量化排出的EHT代谢物并定义其与尿LB的相关性 丰富。我们将定义尿叶中的密钥，相关的代谢差异，并识别代谢物核心 与鲁蒂有关的协会。最后，我们对泌尿宏基因组和代谢产物的纵向分析 匹配的患者样本将定义EHT对健康PM女性和期间的尿生物组动力学的影响 鲁蒂。这些发现将产生对功能和时空动力学的基础知识 PM妇女的尿素对Ruti的理性设计必不可少的女性。