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

社区获得性尿路感染（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个月内患有3次UTI时， 感染被称为复发性UTI（鲁蒂）。鲁蒂严重降低了生活质量，并已成为世界上最严重的 难治的泌尿系统疾病。绝经前妇女的发病率为19-36%， 在绝经后（PM）妇女中增加到50%。PM女性中鲁蒂的发生率较高， 绝经前妇女表明宿主环境在鲁蒂易感性中起作用。鲁蒂管理 依赖于抗生素治疗，但由于广泛的抗生素使用， 抗菌素耐药性为了对抗不断增加的难治性鲁蒂的发病率，必须开发新的治疗方法。 开发新的鲁蒂疗法的一个有希望的来源是尿微生物组，这里称为尿生物组， 其最近被鉴定为泌尿环境的重要组分。中的一个关键步骤 益生菌疗法的发展确定了小生境定殖和维持的要求。但要 迄今为止，尿生物群系的研究主要集中在组成分类上，尚未确定小生境特异性的尿生物群系功能或代谢要求。此外，鲁蒂和激素 在PM妇女中尚未评估尿生物群系组成和功能的变化。 我们已经完成了一个PM横断面队列的尿液鸟枪宏基因组测序（MGS） 妇女在这项工作中，我们发现，在没有鲁蒂的妇女中，尿乳酸杆菌（Lb）丰度是 与雌激素治疗（EHT）的特定方式相关。我们对MGS数据的函数分析 结果显示，在没有糖尿病的女性宏基因组中， UTI病史与活动性鲁蒂女性相比，提示健康女性的尿组在功能上 与鲁蒂患者不同。我们组建了一个多学科的协作团队， 通过以下具体目标，消除知识方面的根本差距：1）确定尿 使用EHT的PM妇女中的Lb丰度和雌激素浓度，2）定义 健康女性和鲁蒂患者与泌尿环境相关的尿生物组，以及3）建立 健康PM女性和鲁蒂期间尿生物群系组成和功能的时空动态。在 为了完成这些目标，我们将定量排泄的EHT代谢物，并确定它们与尿Lb的相关性 丰饶。我们将确定关键的，相关的代谢差异之间的尿路和确定代谢类群 与鲁蒂相关的组织最后，我们对尿宏基因组和代谢物的纵向分析表明， 匹配的患者样本将确定EHT对健康PM女性和PM期间尿生物群系动力学的影响。 鲁蒂。这些发现将产生的功能和时空动态的基础知识， PM女性的尿生物群系对于鲁蒂的尿生物群系靶向治疗的合理设计是必要的。

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.