Impact of early-life perturbations on pediatric microbiome maturation

早期生活扰动对儿科微生物组成熟的影响

• 批准号: 10424578
• 负责人: Gautam Dantas
• 金额: $ 75.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-08 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424578
• 关键词: 9 year old; Acute; Address; Adult; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Basic Science; Bioinformatics; Birth; Carbohydrates; Child; Childhood; Communities; Complement; Conflict (Psychology); Data; Development; Diet; Disease; Environmental Exposure; Evolution; Exposure to; Feces; Future; Genetic Transcription; Genomics; Germ-Free; Health; Heterogeneity; Horizontal Gene Transfer; Human; Human Milk; Individual; Infant; Life; Maintenance; Maps; Medicine; Metadata; Metagenomics; Microbe; Mission; Mobile Genetic Elements; Neonatal; Patients; Plasmids; Process; Property; Public Health; Recommendation; Recording of previous events; Research; Resolution; Risk; Salvelinus; Shapes; Specimen; Statistical Models; Stimulus; Structure; Taxonomy; Testing; Training; Twin Multiple Birth; United States National Institutes of Health; Variant; Vitamins; Weaning; Work; amino acid metabolism; bacterial community; base; cohort; de novo mutation; dietary; early life exposure; gut bacteria; gut microbiome; gut microbiota; humanized mouse; improved; improved outcome; individual variation; infant gut microbiome; innovation; machine learning model; metabolomics; metatranscriptomics; microbial; microbial community; microbiome; microbiome composition; microbiome research; microbiota; mouse model; multiple omics; personalized predictions; personalized risk prediction; predictive modeling; preterm newborn; pup; repository; resistance gene; response; risk prediction

ABSTRACT During the first 3 years of life (YOL) the infant gut microbiome (GM) rapidly diversifies both in structure and function, concomitant with dietary and environmental transitions. Critically, the GM response to specific external stimuli is patient-specific, complicating individualized risk predictions. Healthy GM maturation includes accruing multiple strains of the same species, which frequently differ in key functions. These functional differences, ac- centuated by horizontal gene transfer (HGT) and de novo mutations, could resolve conflicting associations of the same species with both health and disease. The rationale behind our proposal is that strain- and species- level variation in bacterial functions drives heterogenous GM responses to early-life (EL) dietary and antibiotic perturbations, which explains, in part, individualized developmental trajectories. This proposal pursues two highly complementary Aims: 1) Define strain-resolved functional maturation of the pediatric gut microbiome and 2) Investigate the acute effects of EL antibiotic (ELA) perturbation on strain dynamics, HGT, and micro- biome maturation in preterm neonates and microbiota-humanized mice. Aim 1 will test the hypothesis that EL environmental exposures shape genomic diversification of gut species, causing lasting changes in GM com- munity structure and microbial functions. We will leverage our unique set of 2,436 stools collected over the first 9 YOL from infants variably exposed to dietary and environmental stimuli. By combining culture-enriched meta- genomics, metatranscriptomics, and metabolomics, we will determine taxa-function relationships at the sub-spe- cies level and power statistical models that predict the impact of EL exposures on strain diversification, microbe- function associations, and transcriptional activity. Aim 2 will test the hypothesis that ELAs acutely alter strain dynamics and stimulate HGT and that the GM response to ELA can be predicted from baseline composition and function. Here, we will interrogate 160 stools flanking variable ELA exposure in 80 preterm neonates in the first 4 months of life, combining culture-enriched metagenomics with selective culture and isolate sequencing to char- acterize the preterm `plasmidome' and profile post-ELA strain dynamics and HGT. To identify microbiome-intrin- sic responses to ELA, we will utilize an innovative transgenerational mouse model where germ-free dams receive human, preterm, microbiota that is vertically transferred to their pups, which are treated with parenteral antibiot- ics. We will use the resulting data to predict individual GM responses to specific antibiotics based on composition, resistance gene content, and bacterial functions. Our proposal is innovative because our interdisciplinary re- search team will characterize strain-level bacterial functions to understand the heterogeneity of GM responses to EL perturbations on two pre-existing sets of human specimens; it is significant because it will identify features that predict species-resolved GM-specific responses to EL selection. Our work will advance pediatric microbi- ome research by comprehensively characterizing strain-resolved functional maturation and GM disruption to understand individual variation leading towards a future of personalized, microbiome medicine.

抽象的 在生命的前 3 年 (YOL)，婴儿肠道微生物群 (GM) 在结构和功能上迅速多样化 功能，伴随饮食和环境的转变。至关重要的是，通用汽车对特定外部因素的反应 刺激是针对患者的，使个体化风险预测变得复杂。健康的 GM 成熟包括累积 同一物种的多个菌株，其关键功能经常不同。这些功能差异，ac- 以水平基因转移（HGT）和从头突变为中心，可以解决相互冲突的关联 同一物种同时具有健康和疾病。我们建议背后的基本原理是菌株和物种 细菌功能的水平变化驱动异质性 GM 对生命早期 (EL) 饮食和抗生素的反应 扰动，这在一定程度上解释了个体化的发展轨迹。本提案高度追求两个目标 补充目标：1) 定义儿科肠道微生物组的应变解决功能成熟和 2) 研究 EL 抗生素 (ELA) 扰动对菌株动力学、HGT 和微量的急性影响 早产新生儿和微生物群人源化小鼠的生物群系成熟。目标 1 将检验以下假设： EL 环境暴露塑造肠道物种的基因组多样性，导致 GM 成分发生持久变化 群落结构和微生物功能。我们将利用我们在第一轮收集的 2,436 个凳子的独特组合 9岁的婴儿受到不同程度的饮食和环境刺激。通过结合丰富的文化元 基因组学、宏转录组学和代谢组学，我们将在子特定领域确定分类单元与功能的关系 城市水平和功率统计模型，预测 EL 暴露对菌株多样化、微生物的影响 功能关联和转录活性。目标 2 将检验 ELA 急剧改变应变的假设 动力学并刺激 HGT，并且 GM 对 ELA 的反应可以从基线成分和 功能。在这里，我们将首先询问 80 名早产儿的 160 份粪便，这些粪便的侧翼有不同的 ELA 暴露情况。 4 个月的生命，将培养富集的宏基因组学与选择性培养和分离测序相结合，以表征 表征早产“质粒组”并分析 ELA 后菌株动力学和 HGT。识别微生物组内在 为了回应 ELA，我们将利用创新的跨代小鼠模型，其中无菌水坝接受 人类、早产儿的微生物群被垂直转移到它们的幼崽身上，这些幼崽接受了肠外抗生素治疗 ICS。我们将使用所得数据根据成分预测个体 GM 对特定抗生素的反应， 抗性基因含量和细菌功能。我们的建议是创新的，因为我们的跨学科重新 研究小组将表征菌株水平的细菌功能，以了解转基因反应的异质性 对两组预先存在的人类标本进行电致发光扰动；它很重要，因为它将识别特征 预测物种解决的 GM 特异性对 EL 选择的反应。我们的工作将推动儿科微生物 一些研究通过全面表征菌株解决的功能成熟和 GM 破坏来 了解个体差异，从而实现个性化微生物医学的未来。