Epidemiologic and molecular basis of the gut-urinary tract axis in urinary tract infection

尿路感染中肠道-尿路轴的流行病学和分子基础

• 批准号: 10392431
• 负责人: Ashlee Miriam Earl
• 金额: $ 66.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392431
• 关键词: Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Bacteria; Bladder; Chronic; Clinical; Collection; Data; Deterioration; Development; Diagnosis; Digestive System Disorders; Distal; Dose; Drug resistance; Epidemiology; Escherichia coli; Event; Feces; Female; Future; Gastrointestinal tract structure; Genetic; Genomics; Gnotobiotic; Goals; Habitats; Health Care Costs; Homeostasis; Human; Immune response; Immune system; Immunologic Markers; Immunologics; Impairment; Individual; Infection; Inflammation; Inflammatory; Invaded; Investigation; Knowledge; Link; Measures; Mediator of activation protein; Metagenomics; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Mutagenesis; Organ; Pathogenesis; Patients; Pattern; Physicians; Pilum; Predisposition; Prevalence; Process; Quality of life; Recurrence; Research; Resolution; Risk; Role; Sampling; Seeds; Streptomycin; Structure; Technology; Testing; Text; Therapeutic; Time; Tissues; United States; Urinary tract; Urinary tract infection; Urine; Urologist; Uropathogenic E. coli; Woman; base; cohort; colonization resistance; comparative genomics; dysbiosis; economic impact; experience; gut colonization; humanized mouse; immune function; indexing; longitudinal analysis; metatranscriptomics; microbiota; microorganism; mouse model; novel; pathogen; pathogenic bacteria; prevent; residence; therapeutic development; therapy development; transcriptomics; urinary

ABSTRACT/SUMMARY: Urinary tract infection (UTI): i) is caused by uropathogenic Escherichia coli (UPEC) in over 80% of uncomplicated cases in the United States; ii) primarily affects otherwise healthy females (the lifetime prevalence of UTI in women is 50%); iii) is associated with significant morbidity and economic impact; iv) can become chronically recurrent (20-30% of women diagnosed with a UTI will experience a recurrent UTI (rUTI) in the following months, with some suffering six or more per year). Over 1 million women in the US are referred to urologists each year because of rUTIs and treatment difficulties, which are rising due to the rapid spread of antibiotic resistance in UPEC. Further, 60% of rUTIs are due to the same strain of E. coli that caused the initial infection, arguing that there exist host-associated reservoirs that are recalcitrant to antibiotic treatment and can seed rUTIs. The gastrointestinal tract (GIT) is an important reservoir for E. coli in humans. At the time of UTI, the causal E. coli strain is often the predominant E. coli strain in the GIT, which can persist there even after antibiotic therapy. The healthy GIT microbiota (the collection of microorganisms in the GIT) is a key mediator of homeostasis with the host immune system and can prevent colonization by bacterial pathogens. Ironically, antibiotic treatments meant to clear pathogens can also disrupt the GIT microbiota and expose individuals to an increased risk of colonization by pathogens. This proposal seeks to transform UTI research by investigating the unexplored gut-bladder axis. Goals include elucidating the interplay between UPEC, the GIT microbiota, UPEC pathogenesis and rUTI susceptibility, much of which was previously not technologically feasible. High- resolution longitudinal analyses of the GIT microbiota from rUTI patients have revealed: i) striking differential patterns of UPEC colonization, persistence, and displacement in the GIT; and ii) differences in the GIT microbiota structure of rUTI patients and healthy controls. Further, rUTI patients had an elevated inflammation status, even at baseline. These data have led to the hypothesis that the altered GIT microbiota of women with frequent rUTI may be conducive for UPEC persistence and blooming in the GIT, predisposing to the seeding of UPEC into the bladder to cause rUTIs. We will study the impact of UPEC reservoirs in the GIT and an altered microbiota on mucosal and systemic immunologic changes and the susceptibility and/or host response to rUTIs. This proposal will use clinical samples from rUTI sufferers and healthy controls, newly developed genomic and transcriptomic technologies, and conventional and humanized gnotobiotic mouse models to: Aim 1) unveil factors critical for UPEC colonization of the GIT and the establishment of a reservoir capable of seeding rUTI; Aim 2) elucidate the effects of dysbiotic GIT microbiota found in rUTI patients on host immune functions and UTI susceptibility; and Aim 3) determine the role of the microbiota in controlling UPEC colonization of the GIT These studies will transform the development of antibiotic-sparing therapeutics urgently needed to treat and prevent rUTI.

摘要/总结： 尿路感染 (UTI)：i) 80% 以上是由尿路致病性大肠杆菌 (UPEC) 引起 美国境内的不复杂案件； ii) 主要影响其他方面健康的女性（一生 女性尿路感染患病率为 50%）； iii) 与显着的发病率和经济影响相关； iv) 可以 慢性复发（20-30% 被诊断患有尿路感染的女性会经历复发性尿路感染 (rUTI) 在接下来的几个月里，有些人每年遭受六次或更多）。美国有超过 100 万女性被转介 每年泌尿外科医生都会因鲁尿路感染和治疗困难而受到困扰，而这种情况由于该病的迅速蔓延而不断增加 UPEC 中的抗生素耐药性。此外，60% 的 rUTI 是由引起初始感染的同一大肠杆菌菌株引起的。 感染，认为存在与宿主相关的储存库，这些储存库难以接受抗生素治疗，并且可以 种子 rUTI。胃肠道（GIT）是人类大肠杆菌的重要储存库。在发生尿路感染时， 致病大肠杆菌菌株通常是胃肠道中的主要大肠杆菌菌株，即使在 抗生素治疗。健康的胃肠道微生物群（胃肠道中微生物的集合）是 与宿主免疫系统保持稳态，并可以防止细菌病原体的定植。讽刺的是， 旨在清除病原体的抗生素治疗也会破坏胃肠道微生物群，并使个体暴露于 病原体定植的风险增加。该提案旨在通过调查来改变尿路感染研究 未探索的肠-膀胱轴。目标包括阐明 UPEC、GIT 微生物群、 UPEC 发病机制和 rUTI 易感性，其中大部分以前在技术上不可行。高的- 对 rUTI 患者胃肠道微生物群的分辨率纵向分析揭示： i) 显着差异 UPEC 在 GIT 中的定殖、持久性和迁移模式； ii) GIT 的差异 rUTI 患者和健康对照者的微生物群结构。此外，rUTI 患者的炎症水平升高 状态，即使是在基线上。这些数据导致了这样的假设：患有此类疾病的女性胃肠道微生物群发生了改变 频繁的 rUTI 可能有利于 UPEC 在胃肠道中的持续存在和开花，从而容易播种 UPEC 进入膀胱引起 rUTI。我们将研究 UPEC 水库对 GIT 的影响以及变化 微生物群对粘膜和全身免疫变化以及易感性和/或宿主反应的影响 尿路感染。该提案将使用新开发的 rUTI 患者和健康对照的临床样本 基因组和转录组技术以及传统和人源化的限生小鼠模型： 1) 揭示 UPEC 在 GIT 定植和建立能够 播种 rUTI；目标 2) 阐明 rUTI 患者中发现的肠道菌群失调对宿主免疫的影响 功能和尿路感染易感性；目标 3) 确定微生物群在控制 UPEC 中的作用 胃肠道定植 这些研究将迫切改变抗生素节约疗法的发展 需要治疗和预防 rUTI。