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

• 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
• 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

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 扩展频谱β-内酰胺酶产生（ESBL）肠杆菌科的快速上升非常严重 威胁我们对待常见传染病的方式。肠杆菌科，例如大肠杆菌（E. 大肠杆菌是新生儿中感染的主要原因，例如细菌，脑膜炎和尿路感染。 ESBL大肠杆菌的肠道定植是这些侵入性感染的危险因素。此外，婴儿 用ESBL大肠杆菌殖民的不对称也有助于这些菌株的社区水库。 最近的几项研究表明，用Esbl E. Coli的肠道定植的获取和持久性可以 即使在没有抗生素暴露的情况下，传统上也被认为是关键危险因素。出生时新生儿 肠道只有稀疏的微生物，因此为获取的独特环境提供了 ESBL大肠杆菌由于其他微生物的竞争有限。收购的婴儿很大一部分 Esbl E. Coli的生命早期仍然与他们一起持续殖民。但是，早期习得的影响 在快速发育的婴儿肠道微生物组上，研究不好，尤其是在不同年龄的情况下 获取和营养摄入量。 使用早期生命大肠杆菌获取的鼠模型在Arshad实验室的先前工作表明， 几个Esbl E. Coli持续地在成年期间定居小鼠肠道，燃烧明显更高 与共同体非ESBL大肠杆菌相比，定植的殖民化。体外研究表明，一些菌株熟练 在肠道中，殖民化也能够在有限的营养生长培养基中竞争非ESBL大肠杆菌以及 动物模型中的体内。在我们的鼠模型中，至少一个ESBL大肠杆菌的围产期传播导致 大肠杆菌在婴儿肠道微生物组中的过度不足和通常的共生微生物的位移。 该建议旨在利用临床相关的ESBL大肠杆菌，基因组测序和动物模型为1） 确定与ESBL大肠杆菌定植相关的肠道微生物组特征 时期，以及2）评估肠道化的肠道化结肠，并根据年龄和对微生物组的影响 营养状况。这些目标将通过建立ARSHAD之间的现有合作来实现 实验室（细菌发病机理和动物模型的专业知识）和脱皮实验室（小鼠肠道营养方面的专业知识） 在Lurie儿童医院和西北大学的Hartmann实验室（细菌基因组学专业知识， 下一代测序）和威斯康星大学的Grobe Lab（热量评估专业知识 凳子）。 我们预计提出的实验的结果将提供长期的体内证据 用ESBL大肠杆菌对肠道定植对婴儿肠道微生物组的影响。此外，提议的结果 研究将有助于制定营养干预措施和/或可能是共生微生物的鉴定 用作益生菌，以防止用ESBL大肠杆菌长期定植。