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个月内经历3次尿路感染时， 感染称为复发性尿路感染(RUTI)。Ruti严重降低了生活质量，已经成为最 女性难于处理的泌尿系统疾病。绝经前妇女的患病率为19%-36%， 在绝经后(PM)妇女中增加到50%。绝经后妇女中RUTI的发生率高于 绝经前妇女提示宿主环境在Ruti易感性中起作用。鲁蒂管理 依赖于抗生素治疗，但许多一线抗生素由于普遍存在而变得无效 抗菌素耐药性。为了对抗不断增加的抗生素耐药Ruti的发病率，新的治疗方法必须 发展起来的。新Ruti疗法的一个有希望的来源是尿液微生物组，在这里被称为尿菌组， 它最近被确定为泌尿环境的重要组成部分。关键的一步 益生菌疗法的开发正在确定生态位定植和维护要求。然而，为了 到目前为止，尿生物群的研究主要集中在成分分类上，还没有确定特定的尿生物群功能或代谢需求。此外，乳提和荷尔蒙的作用 PM妇女的尿菌群组成和功能的变化尚未得到评估。 我们已经完成了来自PM横断面队列的尿液的鸟枪式元基因组测序(MGS 女人。在这项工作中，我们发现没有RUTI的妇女尿中乳酸杆菌(Lb)的丰度 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 NO患者中枢性碳代谢途径的差异性丰富 尿路感染与活动性尿路感染的历史对比表明，健康女性的尿菌群在功能上是 与鲁蒂的不同。我们已经组建了一个多学科、协作的团队，以最终填补 通过以下具体目标在认识上存在根本差距：1)确定尿液和尿液之间的相关性 使用EHT的绝经后妇女的Lb丰度和雌激素浓度，2)定义代谢差异 健康女性和RUTI患者的尿菌群与尿路环境有关，以及3)建立 健康PM妇女和RUTI期间尿菌群组成和功能的时空动态。在……里面 为了实现这些目标，我们将对排出的eht代谢物进行量化，并确定它们与尿lb的相关性。 富足。我们将定义尿菌群之间关键的、相关的代谢差异，并确定代谢物分类群。 与鲁蒂有关的协会。最后，我们对尿元基因组和代谢产物进行了纵向分析。 匹配的患者样本将确定EHT对健康PM妇女和健康PM期间尿菌群动力学的影响 鲁蒂。这些发现将产生功能和时空动力学的基础知识 PM妇女的尿菌群对于合理设计Ruti的尿菌群靶向治疗是必要的。

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.