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

摘要/总结： 尿路感染（UTI）：i）由尿路致病性大肠杆菌（UPEC）引起， 在美国的不复杂的情况下; ii）主要影响其他健康女性（终身 女性中UTI的患病率为50%）; iii）与显著的发病率和经济影响相关; iv）可以 成为慢性复发性（20-30%诊断为UTI的女性将经历复发性UTI（鲁蒂）） 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100万女性被推荐 由于rUTI和治疗困难，每年都有泌尿科医生，由于rUTI的快速传播， UPEC的抗生素耐药性。此外，60%的rUTI是由于相同的E.大肠杆菌引起了最初的 感染，认为存在与宿主相关的水库，这些水库对抗生素治疗无效， 种子rUTI。胃肠道（GIT）是大肠杆菌的重要贮存库。大肠杆菌感染。在UTI的时候， 因果E.大肠杆菌菌株通常是主要的E.大肠杆菌菌株在胃肠道，它可以坚持有，即使在 抗生素治疗健康的GIT微生物群（GIT中微生物的集合）是GIT的关键介质。 在某些实施方案中，该方法可以维持与宿主免疫系统的稳态，并且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GIT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改变UTI研究 未被探索的肠道-膀胱轴。目标包括阐明UPEC，GIT微生物群， UPEC发病机制和鲁蒂易感性，其中大部分以前在技术上不可行。高- 来自鲁蒂患者的GIT微生物群的分辨率纵向分析已经揭示：i）显著差异 UPEC在GIT中的定殖、持久性和位移模式;以及ii）GIT中的差异 鲁蒂患者和健康对照的微生物群结构。此外，鲁蒂患者的炎症水平升高， 甚至在基线上。这些数据导致了一种假设，即患有乳腺癌的女性的GIT微生物群改变了。 频繁的鲁蒂可能有助于UPEC在GIT中的持续存在和开花， UPEC进入膀胱导致rUTI。我们将研究GIT中UPEC水库的影响， 微生物群对粘膜和全身免疫学变化以及对以下的易感性和/或宿主应答的影响 RUTI。该提案将使用来自鲁蒂患者和健康对照的临床样本， 基因组学和转录组学技术，以及常规和人源化的致菌小鼠模型，以：目的 1)揭示了UPEC在GIT定植的关键因素，并建立了一个能够 接种鲁蒂;目的2）阐明在鲁蒂患者中发现的生态失调的GIT微生物群对宿主免疫的影响 功能和UTI易感性;以及目的3）确定微生物群在控制UPEC中的作用 这些研究将迫切地改变保乳疗法的发展 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.