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.

项目摘要 抗生素耐药性（AMR）的产生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AMR传播的新方法。近几 多年来，一些研究已经开始揭示抗生素之间的复杂关系和相互作用， 抗菌素耐药基因（ARG）和人类微生物组。人类微生物组在人类的生活中 对抗生素治疗和ARG传播的反应。改变的微生物组，特别是在 儿童，可能有一个独特的耐药基因组（微生物群落中的整个ARG）。婴幼儿 儿童经常接受针对常见呼吸道感染的抗生素课程， 在社区中有效地使用ARG。中耳炎是最常见的原因，抗菌治疗， 孩子选择用于幼儿的抗生素治疗可能会显着影响抗生素耐药性 在社区中传播。到目前为止，只有有限数量的前瞻性对照比较研究 关于选定的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，并在没有充分研究的情况下将他们暴露于抗生素。 治疗的适应症。非严重急性中耳炎，然而，是一个很好的临床模型进行调查 不同抗菌药物的影响，因为临床指南建议了几种替代方法， 治疗儿童，包括在没有抗生素的情况下观察等待。在这项研究中，我们将调查的影响， 最常用的抗生素对肠道微生物组的影响，特别是儿童的耐药性 中耳炎欧卢大学的这项研究获得了IRB的批准，并已开始招募患有以下疾病的婴幼儿： 非严重中耳炎的研究队列，并计划在本研究的前几个月内完成入组 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-克拉维汀、阿奇霉素或不对肠道微生物组和ARG进行治疗。我们将征求 一生中的抗生素暴露，并收集抗生素前（第0天）和抗生素后3天的粪便样本 课程（第10天）。我们将在不同的平台上应用定量PCR、16 S rDNA和宏基因组测序 来表征微生物组和耐药组随时间的变化。基于Oxford Nanopore的从头基因组组装 长读段技术结合高深度Illumina测序将揭示ARGs和基因的细节， 物种之间和微生物群落之间的变异，并向我们展示了新的移动的元素 含有精氨酸，这可能是潜在的物种之间的水平转移。我们将应用机器 学习定量研究每种细菌如何对抗生素产生反应并在抗生素下生存的方法 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网络和路径。