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: 10733489
• 负责人: Nicole Janell De Nisco
• 金额: $ 8.66万
• 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/10733489
• 关键词: 3-Dimensional; Address; Affect; Anatomy; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bladder; Carbohydrates; Carbon; Chemicals; Classification; Data; Development; Disease; Disease remission; Environment; Estrogen Therapy; Estrogens; Excretory function; Genetic; Goals; Health; Healthcare; Hormonal Change; Human; Hypersensitivity; Incidence; Infection; Knowledge; Lactobacillus; Longitudinal Studies; Maintenance; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methods; Modality; Modeling; Oral; Outcome; Pathway interactions; Patients; Persons; Population; Postmenopause; Predisposition; Premenopause; Quality of life; Recording of previous events; Recovery; Recurrence; Refractory; Relapse; Role; Sampling; Shotguns; Source; Structure; Techniques; Testing; Time; Urethra; Urinary Microbiome; Urinary tract infection; Urine; Urologic Diseases; Uropathogen; Vagina; Woman; Work; biobank; care burden; cohort; combat; community-acquired UTI; dosage; infection management; longitudinal analysis; member; metagenome; metagenomic sequencing; microbiome; microbiome analysis; microbiota; multidisciplinary; novel therapeutics; probiotic therapy; rational design; 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.

社区获得性尿路感染（UTI）是全球最常见的细菌感染之一， 每年影响至少 1.5 亿人。当患者在 12 个月内出现 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，并已成为最严重的疾病之一 女性难以治疗的泌尿系统疾病。绝经前妇女的比率范围为 19-36% 绝经后 (PM) 女性的这一比例增加至 50%。与 PM 女性相比，rUTI 发生率更高 绝经前女性表明宿主环境在 rUTI 易感性中发挥着作用。尿路感染管理 依赖抗生素治疗，但由于广泛使用，许多一线抗生素已变得无效 抗菌素耐药性。为了应对不断增加的抗生素难治性 rUTI 发病率，必须采用新疗法 发达。新的 rUTI 疗法的一个有前途的来源是泌尿微生物组，这里称为尿微生物组， 最近被确定为泌尿环境的重要组成部分。的关键一步 益生菌疗法的发展正在定义利基定植和维持要求。然而，为了 迄今为止，尿生物组研究主要集中在成分分类上，尚未确定特定的尿生物组功能或代谢需求。此外，rUTI 和荷尔蒙的影响 尚未在 PM 女性中评估尿生物组组成和功能的变化。 我们已经完成了 PM 横断面队列的尿液鸟枪法宏基因组测序 (MGS) 女性。在这项工作中，我们发现，没有 rUTI 的女性尿液中乳酸杆菌 (Lb) 的丰度是 与雌激素治疗（EHT）的特定方式相关。我们对 MGS 数据的功能分析 揭示了女性宏基因组中中央碳代谢途径的差异富集 UTI 病史与患有活动性 rUTI 的女性相比，表明健康女性的尿路生物组在功能上 与 ruUTI 患者不同。我们组建了一支多学科协作团队来最终填补 通过以下具体目标来弥补知识上的基本差距： 1) 定义泌尿系统之间的相关性 使用 EHT 测定 PM 女性的 Lb 丰度和雌激素浓度，2) 定义之间的代谢差异 健康女性和患有 rUTI 的女性与泌尿环境相关的尿微生物组，以及 3) 建立 健康 PM 女性和 rUTI 期间尿生物组组成和功能的时空动态。在 为了完成这些目标，我们将量化排泄的 EHT 代谢物并确定它们与尿 Lb 的相关性 丰富。我们将定义尿生物组之间关键的相关代谢差异，并确定代谢物分类群 与 rUTI 相关的协会。最后，我们对尿液宏基因组和代谢物的纵向分析 匹配的患者样本将确定 EHT 对健康 PM 女性和 尿路感染。这些发现将产生有关功能和时空动力学的基础知识 PM 女性的尿生物组对于合理设计针对 rUTI 的尿生物组靶向疗法至关重要。

项目成果

Complete Genome Sequences of Three Lactobacillus gasseri Urine Isolates Obtained from Postmenopausal Women.

从绝经后妇女尿液中分离出的三种加氏乳杆菌的完整基因组序列。

• 发表时间: 2022-09-15
• 影响因子: 0.8
• 作者: Shipman, Braden M;Nguyen, Amber;Sharon, Belle M;Zimmern, Philippe E;De Nisco, Nicole J
• 通讯作者: De Nisco, Nicole J

Urinary Glycosaminoglycans Are Associated with Recurrent UTI and Urobiome Ecology in Postmenopausal Women.

尿糖胺聚糖与绝经后女性复发性尿路感染和尿生物组生态相关。

• 发表时间: 2023-04-14
• 影响因子: 5.3
• 作者: Neugent, Michael L;Hulyalkar, Neha V;Kumar, Ashwani;Xing, Chao;Zimmern, Philippe E;Shulaev, Vladimir;De Nisco, Nicole J
• 通讯作者: De Nisco, Nicole J

Genetic and functional enrichments associated with Enterococcus faecalis isolated from the urinary tract.

与从泌尿道分离的粪肠球菌相关的遗传和功能富集。

• 发表时间: 2023-11-14
• 影响因子: 6.4
• 作者: Sharon, Belle M;Arute, Amanda P;Nguyen, Amber;Tiwari, Suman;Reddy Bonthu, Sri Snehita;Hulyalkar, Neha V;Neugent, Michael L;Palacios Araya, Dennise;Dillon, Nicholas A;Zimmern, Philippe E;Palmer, Kelli L;De Nisco, Nicole J
• 通讯作者: De Nisco, Nicole J

Aging-associated augmentation of gut microbiome virulence capability drives sepsis severity.

与衰老相关的肠道微生物组毒力能力的增强会导致脓毒症的严重程度。

• 发表时间: 2023-01-11
• 作者: Colbert, James F;Kirsch, Joshua M;Erzen, Christopher L;Langouët;Thompson, Grace E;McMurtry, Sarah A;Kofonow, Jennifer M;Robertson, Charles E;Kovacs, Elizabeth J;Sullivan, Ryan C;Hippensteel, Joseph A;Sawant, Namrata V;De N
• 通讯作者: De N

Gut-bladder axis enters the stage: Implication for recurrent urinary tract infections.

肠-膀胱轴进入阶段：对复发性尿路感染的影响。

• DOI: 10.1016/j.chom.2022.07.008
• 发表时间: 2022-08-10
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Salazar, Arnold M.;Neugent, Michael L.;De Nisco, Nicole J.;Mysorekar, Indira U.
• 通讯作者: Mysorekar, Indira U.