A study of antibiotics usage on early gut microbiome colonization and establishment in young children

抗生素使用对幼儿早期肠道微生物定植和建立的研究

• 批准号: 10113538
• 负责人: Weizhong Li
• 金额: $ 17.5万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113538
• 关键词: Acute; Address; Affect; Aftercare; Amoxicillin; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Azithromycin; Bacterial Antibiotic Resistance; Child; Clavulanate; Clinical; Clinical Medicine; Cohort Studies; Communities; Comparative Study; Complex; Development; Elements; Enrollment; Exhibits; Exposure to; Genome; Genomics; Guidelines; Human; Human Microbiome; Hypersensitivity; Infant; Institutional Review Boards; Intestines; Invaded; Machine Learning; Microbe; Modeling; Otitis Media; Pathogenicity; Pathway interactions; Patient observation; Pattern; Plasmids; Play; Preventive measure; Primary Health Care; Protocols documentation; Public Health; Recombinant DNA; Respiratory Tract Infections; Role; Sampling; Technology; Time; Universities; antimicrobial; antimicrobial drug; base; beta-Lactams; clinical care; colonization resistance; design; emerging antimicrobial resistance; fecal microbiome; genetic variant; gut colonization; gut microbiome; insight; metagenomic sequencing; microbiome; microbiome alteration; microbiome research; nanopore; novel; novel strategies; predictive marker; prevent; prospective; randomized controlled study; recruit; resistance gene; stool sample; three dimensional structure; transmission process; treatment arm; treatment choice; treatment group

PROJECT SUMMARY The emergence and transmission of antimicrobial resistance (AMR) is currently one of the most critical public health threats. As such there is an urgent need to identify new ways to reduce AMR transmission. In recent years, several studies have started to reveal the complex relations and interactions between antibiotics, antimicrobial resistance genes (ARGs) and the human microbiome. The human microbiome plays profound roles in responding to antibiotic treatment and the transmission of ARGs. The altered microbiome, especially in children, may have a distinct resistome (the entire ARGs in the microbiome community). Infants and young children receive frequent antimicrobial courses for common respiratory infections and are thought to spread ARGs effectively in the community. Otitis media is the most common reason for antimicrobial treatment in children. The antibiotic treatment that is selected for use in young children may significantly influence AMR spread in the communities. To date, there are a limited number of prospective, controlled comparative studies on how selected antibiotics affect the development of antibiotic resistance in the microbiome in young children. It is not possible to investigate children in an experimental way and expose them to antibiotics without an indication for the treatment. Non-severe acute otitis media, however, is an excellent clinical model to investigate the impact of different antimicrobial agents, since clinical guidelines suggest several alternative approaches to treat children, including watchful waiting without antibiotics. In this study, we will investigate the impact of the most commonly used antibiotics on the intestinal microbiome, and in particular the resistome in children with otitis media. The Oulu University study is IRB approved and has started enrolling infants and young children with non-severe otitis media in a study cohort and plan to finish the enrollment within the first few months of this project. Children are randomly allocated in four antibiotic treatment groups to compare the impact of amoxicillin, amoxicillin-clavulanate, azithromycin, or no treatment on the intestinal microbiome and ARGs. We will solicit the antibiotic exposure during lifetime and collect stool samples before (day 0) and three days after the antibiotic course (day 10). We will apply quantitative PCR, 16S rDNA and metagenomic sequencing on different platforms to characterize the microbiome and resistome over time. De novo genome assembly based on Oxford Nanopore long reads technology, combined with high depth Illumina sequencing will reveal the details of ARGs and gene variants between species, and between microbiome communities, and show us novel mobile elements containing ARGs, which may be potentially transferred horizontally between species. We will apply machine learning approaches to quantitatively study how each bacterial species responds to and survives under antibiotic exposure, by analyzing genomic variants in ARGs, changes in three dimensional structure of the key ARGs, ARG network and pathways.

项目概要 抗菌素耐药性（AMR）的出现和传播是目前公众最关注的问题之一 健康威胁。因此，迫切需要找到减少抗菌素耐药性传播的新方法。近来 多年来，一些研究已经开始揭示抗生素之间复杂的关系和相互作用， 抗菌素耐药基因（ARG）和人类微生物组。人类微生物组发挥着深远的作用 响应抗生素治疗和 ARG 的传播。改变的微生物组，尤其是 儿童可能具有独特的抗药性组（微生物群落中的整个 ARG）。婴儿和青少年 儿童经常接受针对常见呼吸道感染的抗菌课程，并被认为会传播 ARG 在社区中有效。中耳炎是抗生素治疗最常见的原因 孩子们。选择用于幼儿的抗生素治疗可能会显着影响 AMR 在社区中传播。迄今为止，前瞻性、对照比较研究的数量有限 关于所选抗生素如何影响幼儿微生物组中抗生素耐药性的发展。 不可能以实验的方式对儿童进行研究，并让他们接触抗生素而不经过实验。 治疗的指征。然而，非严重急性中耳炎是一个很好的临床模型来研究 不同抗菌药物的影响，因为临床指南提出了几种替代方法 治疗儿童，包括在不使用抗生素的情况下观察等待。在这项研究中，我们将调查 最常用的抗生素对肠道微生物组，特别是儿童的耐药组 中耳炎。奥卢大学的研究已获得 IRB 批准，并已开始招募患有以下疾病的婴幼儿： 研究队列中的非严重中耳炎，并计划在本研究的头几个月内完成入组 项目。儿童被随机分配到四个抗生素治疗组，以比较阿莫西林的影响， 阿莫西林克拉维酸、阿奇霉素或不治疗肠道微生物组和 ARG。我们将征集 一生中接触抗生素并在使用抗生素前（第 0 天）和使用后三天收集粪便样本 课程（第 10 天）。我们将在不同的平台上应用定量PCR、16S rDNA和宏基因组测序 随着时间的推移来表征微生物组和抗性组。基于牛津纳米孔的从头基因组组装 长读长技术结合Illumina高深度测序将揭示ARG和基因的细节 物种之间以及微生物群落之间的变异，并向我们展示了新颖的移动元素 含有 ARG，可能在物种之间水平转移。我们将应用机器 定量研究每种细菌在抗生素下如何反应和生存的学习方法 暴露，通过分析ARG的基因组变异，关键ARG的三维结构的变化， ARG 网络和途径。