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/总结:

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