Population genomic analysis of gut microbial colonization in premature infants.

早产儿肠道微生物定植的群体基因组分析。

• 批准号: 9176569
• 负责人: Jillian Banfield
• 金额: $ 75.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176569
• 关键词: Address; Affect; Age; Antibiotic Resistance; Antibiotics; Appearance; Back; Bacteria; Bacterial Genome; Bacteriophages; Behavior; Cesarean section; Childhood; Clinical; Communities; DNA; DNA Sequence Alteration; Data; Development; Ecosystem; Elements; Environment; Equipment and supply inventories; Event; Funding; Gene Expression; Genetic; Genetic Heterogeneity; Genetic Variation; Genome; Genomics; Gestational Age; Growth; Health; Health Sciences; Hospitalization; Hospitals; Human; Human Microbiome; Immigrant; Immigration; Immune system; In Situ; Individual; Infant; Infant Development; Infant Health; Investigation; Life; Measures; Medical; Metabolic; Metagenomics; Methods; Microbe; Mobile Genetic Elements; Monitor; Mothers; Mutation; Nature; Necrotizing Enterocolitis; Newborn Infant; Organism; Outcome; Pattern; Phenotype; Plasmids; Population; Premature Infant; Process; Regimen; Research; Resolution; Risk; Role; Sampling; Sepsis; Series; Structure; Testing; Time; Translating; Uncertainty; Variant; Work; deep sequencing; disorder prevention; disorder risk; feeding; fitness; gut microbiome; improved; improved outcome; in vivo; medical complication; microbial; microbial colonization; microbial community; microbiome; microbiota; novel; premature; reconstruction

Many studies of the human microbiome underemphasize the complexity of strain-level genetic diversity, partly due to computational challenges. This is an important problem because subtle genomic alterations can sharply impact microbial behavior, e.g. antibiotic resistance. Strain-level investigations are needed to understand how genomes change over time, and also to accurately characterize how microbial communities assemble, respond to perturbations, and vary among individuals. Our work focuses on the infant gut microbiome to address these fundamental biologic questions and to identify connections between infant health and early patterns of colonization. The objective of this project is to use strain-resolved metagenomic analyses to monitor microbial colonization in the infant gut during the first three years of life. We will test the hypothesis that early configurations of the infant microbiome can negatively impact maturation of the gut microbiome later in childhood. If this hypothesis is true, then manipulation of the microbiome in at-risk individuals, particularly premature infants, may provide opportunities to improve health outcomes. Our proposed work will characterize the population structure of microbial communities that develop during colonization of the infant gut and examine the roles of strain persistence, strain immigration, in situ genome diversification, and mobile genetic elements. To understand major temporal changes in strain or species abundance, we will utilize a novel method to infer microbial growth rates as well as community wide gene expression. We will conduct strain- level analyses of fecal samples from 100 newborn infants and their mothers during the first three years of life. We will include 40 preterm infants with no major medical problems, half born via caesarean section; 40 preterm infants that develop either necrotizing enterocolitis (NEC) or late-onset sepsis (LOS), half born via caesarean section; and 20 full term infants, half born via caesarean section. Deep sequencing of microbial DNA will enable genome reconstruction from coexisting bacterial, archaeal (if present), phage, and plasmid populations. This will allow us to track species membership, community structure, metabolic potential, and population-level genetic heterogeneity. We will use these data to test the hypothesis that some early-establishing strains persist beyond the initial colonization period (Aim 1); to test the hypothesis that stable gut microbial communities possess higher strain-level diversity than unstable gut microbial communities (Aim 2); and to test the hypothesis that clinical variables in the newborn period impact patterns of strain acquisition in the first three years of life (Aim 3). Improved understanding of community assembly and diversification in the infant gut could translate to improved outcomes by uncovering strategies for disease prevention and treatment. This research will also reveal universal principles of microbial community dynamics that will have implications for other aspects of human health and science.

许多人类微生物组的研究都低估了菌株水平遗传多样性的复杂性，部分原因是 由于计算挑战。这是一个重要的问题，因为细微的基因组改变可能会急剧改变 影响微生物行为，例如抗生素耐药性。需要进行应变水平的研究来了解如何 基因组随着时间的推移而变化，并且还可以准确地描述微生物群落如何组装、反应 扰动，并且因人而异。我们的工作重点是婴儿肠道微生物组，以解决这些问题 基本的生物学问题，并确定婴儿健康与早期模式之间的联系 殖民化。该项目的目标是利用菌株解析宏基因组分析来监测微生物 在生命的前三年在婴儿肠道中定植。我们将检验早期的假设 婴儿微生物组的配置会对以后肠道微生物组的成熟产生负面影响 童年。如果这个假设成立，那么对高危个体的微生物组进行操纵，特别是 早产儿，可能提供改善健康结果的机会。我们提出的工作将特点 在婴儿肠道定植期间形成的微生物群落的种群结构以及 检查菌株持久性、菌株迁移、原位基因组多样化和移动遗传的作用 元素。为了了解菌株或物种丰度的主要时间变化，我们将利用一种新颖的方法 推断微生物生长速率以及群落范围基因表达的方法。我们将进行应变- 对 100 名新生儿及其母亲在出生后头三年的粪便样本进行水平分析。 我们将纳入 40 名没有重大健康问题的早产儿，其中一半是剖腹产出生的； 40 早产 患有坏死性小肠结肠炎 (NEC) 或迟发性败血症 (LOS) 的婴儿，半数是剖腹产出生的 部分;以及 20 名足月婴儿，其中一半是剖腹产出生的。微生物 DNA 深度测序将 能够从共存的细菌、古菌（如果存在）、噬菌体和质粒群体中重建基因组。 这将使我们能够跟踪物种成员、群落结构、代谢潜力和种群水平 遗传异质性。我们将使用这些数据来检验一些早期建立的菌株的假设 持续超过初始定植期（目标 1）；检验稳定肠道微生物的假设 群落比不稳定的肠道微生物群落具有更高的菌株水平多样性（目标 2）；并测试 新生儿期临床变量影响前三个时期应变获得模式的假设 寿命（目标 3）。提高对婴儿肠道群落组装和多样化的理解可以 通过揭示疾病预防和治疗策略来转化为改善结果。这项研究 还将揭示微生物群落动态的普遍原理，这将对其他领域产生影响 人类健康和科学的各个方面。