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: 10618218
• 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/10618218
• 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 Diseases; 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; 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; Streptomycin; Structure; Technology; Testing; Text; Therapeutic; Time; Tissues; United States; Urinary tract; Urinary tract infection; Urine; Urologist; Uropathogenic E. coli; Woman; cohort; colonization resistance; comparative genomics; dysbiosis; economic impact; experience; gut colonization; humanized mouse; immune function; indexing; longitudinal analysis; metatranscriptomics; microbiota; microorganism; mouse model; new technology; 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/摘要： 尿路感染（UTI）：i）是由超过80％以上的尿路病大肠杆菌（UPEC）引起的 美国简单的案件； ii）主要影响健康的女性（寿命 女性UTI的患病率为50％）； iii）与巨大的发病率和经济影响有关； iv）可以 长期复发（20-30％被诊断出患有UTI的妇女会经历复发性UTI（RUTI） 在接下来的几个月中，每年有六个或以上）。美国超过100万妇女被推荐 由于RUTI和治疗困难，每年致泌尿科医生，由于 UPEC中的抗生素抗性。此外，60％的Rutis是由于相同的大肠杆菌菌株引起的 感染，认为存在与宿主相关的储层，这些储层是抗生素治疗的顽固性的，并且可以 种子rutis。胃肠道（GIT）是人类大肠杆菌的重要储层。在UTI时， 因果大肠杆菌菌株通常是Git中主要的大肠杆菌菌株，即使在此之后也可以持续存在 抗生素疗法。健康的GIT微生物群（GIT中的微生物的收集）是 与宿主免疫系统的体内平衡，可以防止细菌病原体定植。具有讽刺意味的是 旨在清除病原体的抗生素治疗也会破坏GIT微生物群，并使个人暴露于 病原体定植的风险增加。该建议旨在通过调查UTI研究来改变UTI研究 未开发的肠裂轴。目标包括阐明UPEC，GIT微生物群之间的相互作用， UPEC发病机理和RUTI敏感性，其中许多以前在技术上不可行。高的- RUTI患者的GIT微生物群的分辨率纵向分析显示：i）打击差异 git中UPEC殖民，持久性和位移的模式； ii）git的差异 RUTI患者和健康对照组的微生物群结构。此外，鲁蒂患者的炎症升高 状态，即使在基线时也是如此。这些数据导致了以下假设： 频繁的ruti可能有利于upec持久性并在git中开花，易于播种 UPEC进入膀胱以引起rutis。我们将研究UPEC水库在GIT中的影响和变化 微生物群在粘膜和全身免疫学变化以及对易感性和/或宿主反应 鲁蒂斯。该建议将使用新开发的Ruti患者和健康控制的临床样本 基因组和转录组技术以及常规和人源化的小鼠模型：AIM 1）揭露对GIT殖民和建立能够建立的储层至关重要的因素 播种ruti; AIM 2）阐明RUTI患者发现宿主免疫的失调GIT GIT微生物群的影响 功能和UTI敏感性；目标3）确定菌群在控制UPEC中的作用 GIT的定殖这些研究将紧急改变抗生素治疗剂的发展 需要治疗和预防鲁蒂。

项目成果

The Role of Mobile Genetic Elements in Virulence Factor Carriage from Symptomatic and Asymptomatic Cases of Escherichia coli Bacteriuria.

移动遗传元件在有症状和无症状大肠杆菌菌尿病例毒力因子携带中的作用。

• DOI: 10.1128/spectrum.04710-22
• 发表时间: 2023-06-15
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections.

• DOI: 10.1186/s12866-021-02106-4
• 发表时间: 2021-02-18
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Straub TJ;Chou WC;Manson AL;Schreiber HL 4th;Walker BJ;Desjardins CA;Chapman SB;Kaspar KL;Kahsai OJ;Traylor E;Dodson KW;Hullar MAJ;Hultgren SJ;Khoo C;Earl AM
• 通讯作者: Earl AM

StrainGE: a toolkit to track and characterize low-abundance strains in complex microbial communities.

• DOI: 10.1186/s13059-022-02630-0
• 发表时间: 2022-03-07
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: van Dijk LR;Walker BJ;Straub TJ;Worby CJ;Grote A;Schreiber HL 4th;Anyansi C;Pickering AJ;Hultgren SJ;Manson AL;Abeel T;Earl AM
• 通讯作者: Earl AM