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

摘要 产超广谱β-内酰胺酶（ESBL）肠杆菌科细菌的迅速增加， 威胁着我们治疗常见传染病的方式。肠杆菌科如大肠杆菌（E. 大肠杆菌）是新生儿感染如菌血症、脑膜炎和尿路感染的主要原因。 ESBL E肠道定植。大肠杆菌是这些侵袭性感染的危险因素。此外， ESBL E无症状定植。大肠杆菌也有助于这些菌株的社区水库。 最近的一些研究表明，ESBL-E肠道定植的获得和持久性。大肠杆菌罐 即使在没有抗生素暴露的情况下也会发生，传统上认为这是一个关键的风险因素。出生时，新生儿 肠道中只有稀疏的微生物，因此提供了一个独特的环境， ESBL E.大肠杆菌，这是由于来自其他微生物的竞争有限。很大一部分婴儿 ESBL E.在生命早期的大肠杆菌中仍然持续地定植有它们。然而，早期生命收购的影响 对快速发育的婴儿肠道微生物组的影响还没有得到很好的研究，特别是在不同年龄段的情况下， 获取和营养摄入。 阿尔沙德实验室先前的工作是使用早期生命E.大肠杆菌的获得表明， 几种ESBL E.大肠杆菌在成年期持续定植于小鼠肠道， 与非ESBL-E大肠埃希菌相比，杆菌体外研究表明， 在肠道定殖中也能够胜过非ESBL E。大肠杆菌在有限的营养生长培养基以及 in vivo体内in the animal动物model模型.围产期传播至少一种ESBL E。在我们的小鼠模型中， 过量的E.婴儿肠道微生物组中的大肠杆菌和常见肠道微生物的替代。 该提案旨在利用临床相关的ESBL E。大肠杆菌，基因组测序和动物模型，以1） 确定与ESBL E相关的肠道微生物组特征。早期生活中的大肠杆菌定植 2）评估ESBL E的肠道定植。大肠杆菌和根据年龄对微生物组的影响， 营养状况这些目标将通过建立在阿尔沙德与 实验室（细菌发病机理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） Lurie儿童医院和西北大学的Hartmann实验室（细菌基因组学方面的专业知识， 下一代测序），以及威斯康星州大学的Grobe实验室（ 凳子）。 我们预计，从拟议的实验结果将提供体内证据的长期 大肠埃希菌肠道定植影响大肠杆菌对婴儿肠道微生物组的影响此外，建议的结果 这项研究将有助于开发营养干预措施和/或鉴定可能 用作益生菌，防止ESBL E长期定植。杆菌

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.