Investigating the impact of ESBL E. coli colonization on infant microbiome

研究 ESBL 大肠杆菌定植对婴儿微生物组的影响

基本信息

批准号：
10727040
负责人：
Mehreen Arshad
金额：
$ 24.76万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727040
关键词：
Adult Age Animal Model Antibiotics Antimicrobial Resistance Bacteremia Biological Birth Calorimetry Characteristics Childhood Collaborations Communicable Diseases Communities Culture Media Development Dietary Intervention Disease Enterobacteriaceae Environment Escherichia coli Extended-spectrum β-lactamase Feces Genomics Growth Health Care Costs Immune system In Vitro Infant Infant Development Infant Health Infection Intake Integration Host Factors Knowledge Laboratories Length of Stay Life Malnutrition Meningitis Metabolic Metabolism Metagenomics Methods Microbe Microbial Physiology Molecular Morbidity - disease rate Multi-Drug Resistance Mus Neonatal Nutrient Nutritional Nutritional status Pathogenesis Pediatric Hospitals Perinatal transmission Physiology Prevalence Probiotics Public Health Research Personnel Resistance development Ribosomal RNA Risk Risk Factors Role Shotguns Testing Time Universities Urinary tract infection Vulnerable Populations Wisconsin Work age related clinically relevant colonization resistance commensal bacteria commensal microbes dysbiosis experimental study fitness gut colonization gut microbiome gut microbiota high risk high risk infant in vivo infancy infant gut microbiome infant nutrition infant outcome insight microbiome microbiome alteration modifiable risk mortality mouse model neonatal period neonate next generation sequencing nutrition pathogenic Escherichia coli postnatal prevent pup rRNA Genes

项目摘要

ABSTRACT The rapid rise of extended spectrum beta-lactamase-producing (ESBL) Enterobacteriaceae is severely threatening the way we treat common infectious diseases. Enterobacteriaceae such as Escherichia coli (E. coli) are a major cause of infections such as bacteremia, meningitis, and urinary tract infections in neonates. Gut colonization with ESBL E. coli is a risk factor for these invasive infections. Additionally, infants who are asymptomatically colonized with ESBL E. coli also contribute to the community reservoir of these strains. Several recent studies have shown that acquisition and persistence of gut colonization with ESBL E. coli can occur even in the absence of antibiotic exposure, traditionally considered a key risk factor. At birth the neonatal gut is only sparsely populated with microbes, and therefore provides a unique environment for acquisition of ESBL E. coli due to the limited competition from other microbes. A significant proportion of infants who acquire ESBL E. coli early in life remain persistently colonized with them. However, the impact of early life acquisition on the rapidly developing infant gut microbiome is not well studied, especially in the setting of varying age of acquisition and nutritional intake. Previous work in the Arshad laboratory using a murine model of early life E. coli acquisition has shown that several ESBL E. coli persistently colonize the mouse gut through adulthood with a significantly higher burden of colonization compared to commensal non-ESBL E. coli. In vitro studies show that some of the strains adept in gut colonization are also able to out compete non-ESBL E. coli in a limited nutrient growth media as well as in vivo in the animal model. Perinatal transmission of at least one ESBL E. coli in our murine model results in an overabundance of E. coli in the infant gut microbiome and a displacement of usual commensal microbes. This proposal aims to utilize clinically relevant ESBL E. coli, genomic sequencing, and animal models to 1) determine the gut microbiome characteristics associated with ESBL E. coli colonization during the early life period, and 2) assess gut colonization with ESBL E. coli and impact on microbiome according to age and nutritional status. These objectives will be achieved by building on existing collaborations between the Arshad lab (expertise in bacterial pathogenesis and animal models) and DePlaen lab (expertise in mouse gut nutrition) at Lurie Children’s Hospital, and Hartmann lab at Northwestern University (expertise in bacterial genomics, next-generation sequencing), and Grobe lab at University of Wisconsin (expertise in caloric assessment of stool). We anticipate that the results from the proposed experiments will provide in vivo evidence of the long-term impact of gut colonization with ESBL E. coli on the infant gut microbiome. Further, the results of the proposed study will aid in developing nutritional interventions and/or identification of commensal microbes that may be used as probiotics, to prevent long-term colonization with ESBL E. coli.

抽象的产超广谱 β-内酰胺酶 (ESBL) 肠杆菌科细菌的迅速增加严重影响了威胁着我们治疗大肠杆菌等常见传染病的方式。大肠杆菌）是新生儿菌血症、脑膜炎和尿路感染等感染的主要原因。 ESBL 大肠杆菌的肠道定植是这些侵袭性感染的危险因素。无症状定植的 ESBL 大肠杆菌也有助于形成这些菌株的群落储存库。最近的几项研究表明，ESBL 大肠杆菌肠道定植的获得和持续存在可以即使在没有接触抗生素的情况下也会发生这种情况，传统上认为这是新生儿出生时的一个关键危险因素。肠道中的微生物数量很少，因此为获取微生物提供了独特的环境由于与其他微生物的竞争有限，相当一部分婴儿感染了 ESBL 大肠杆菌。生命早期的 ESBL 大肠杆菌仍然持续定植，然而，生命早期获得的影响仍然存在。关于快速发展的婴儿肠道微生物组的研究尚未得到充分研究，特别是在不同年龄的环境中获取和营养摄入。 Arshad 实验室先前使用早期生命大肠杆菌采集的小鼠模型进行的研究表明，几种 ESBL 大肠杆菌在成年后持续定植于小鼠肠道，负担显着增加与共生非 ESBL 大肠杆菌相比，体外研究表明，一些菌株擅长定植。在肠道定植中也能够在营养有限的生长培养基中击败非 ESBL 大肠杆菌在我们的小鼠模型中，至少一种 ESBL 大肠杆菌在围产期传播。婴儿肠道微生物组中大肠杆菌过多，常见共生微生物被取代。该提案旨在利用临床相关的 ESBL 大肠杆菌、基因组测序和动物模型来：1) 确定生命早期与 ESBL 大肠杆菌定植相关的肠道微生物组特征 2) 根据年龄和年龄评估 ESBL 大肠杆菌的肠道定植情况以及对微生物组的影响这些目标将通过加强阿尔沙德之间的现有合作来实现。实验室（细菌发病机制和动物模型方面的专业知识）和 DePlaen 实验室（小鼠肠道营养方面的专业知识）卢里儿童医院和西北大学哈特曼实验室（细菌基因组学专业知识，下一代测序），以及威斯康星大学的 Grobe 实验室（热量评估方面的专业知识）凳子）。我们预计所提出的实验结果将提供长期的体内证据 ESBL 大肠杆菌肠道定植对婴儿肠道微生物组的影响此外，还提出了结果。研究将有助于制定营养干预措施和/或鉴定可能与用作益生菌，防止 ESBL 大肠杆菌长期定植。