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

摘要/摘要： 尿路感染(UTI)：I由尿路致病性大肠杆菌(UPEC)引起，超过80%的人 美国不复杂的病例；二)主要影响其他健康的女性(终生 妇女的尿路感染患病率为50%)；三)与严重的发病率和经济影响有关；四)可以 变得慢性复发(20%-30%被诊断为尿路感染的女性将经历尿路感染复发(RUTI)) 在接下来的几个月里，一些人每年遭受六次或更多的痛苦)。美国有100多万女性被推荐 由于尿路感染和治疗困难，尿路感染和治疗困难每年都会增加，这是由于尿路感染的快速传播 UPEC对抗生素耐药性的研究此外，60%的尿路感染是由引起最初感染的同一种大肠杆菌引起的 感染，认为存在与宿主相关的宿主相关的宿主，这些宿主对抗生素治疗顽固，并且可以 种子RUTI。胃肠道(GIT)是人类体内大肠杆菌的重要储存库。在UTI的时候， 致病的大肠杆菌菌株通常是GIT中的主要大肠杆菌菌株，即使在 抗生素治疗。健康的Git微生物区系(Git中的微生物集合)是 与宿主免疫系统保持动态平衡，并能防止细菌病原体的定植。具有讽刺意味的是， 旨在清除病原体的抗生素治疗也会扰乱胃肠道微生物区系，使个人暴露在 被病原体殖民的风险增加。这项提议寻求通过调查来改变UTI的研究 未被探索的肠膀胱轴。目标包括阐明UPEC、GIT微生物区系、 UPEC的发病机制和RUTI易感性，其中许多以前在技术上是不可行的。高- RUTI患者胃肠道微生物区系的纵向分辨率分析显示：i)显著的差异 UPEC在胃肠道中的定植、持久性和移位的模式；以及ii)胃肠道内的差异 RUTI患者和健康对照的微生物区系结构。此外，RUTI患者的炎症水平升高。 状态，即使是在基线上。这些数据导致了一种假设，即患有癌症的女性的胃肠道微生物区系发生了变化 频繁的Ruti可能有利于UPEC的持久和在Git中开花，有利于播种 UPEC进入膀胱导致尿路感染。我们将研究UPEC水库在GIT和一个改造后的影响 微生物区系对黏膜和系统免疫变化以及对肺炎易感性和/或宿主反应的影响 RUTIS。这项提议将使用新开发的Ruti患者和健康对照的临床样本。 基因组和转录组技术，以及常规和人源化的灵知生菌小鼠模型：目标 1)揭示UPEC在GIT的殖民和建立一个能够 目的2)阐明在Ruti患者体内发现的非生物Git微生物区系对宿主免疫的影响 功能和尿路感染敏感性；以及目的3)确定微生物区系在控制UPEC中的作用 Git的定植这些研究将迫切改变节省抗生素的治疗方法的发展 需要治疗和预防鲁蒂。

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.