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: 10634654
• 负责人: Gautam Dantas
• 金额: $ 77.67万
• 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/10634654
• 关键词: 9 year old; Acute; Address; Adult; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Basic Science; Bioinformatics; Birth; Carbohydrates; Child; Childhood; Communities; Complement; Data; Development; Diet; Disease; Educational process of instructing; Environmental Exposure; Evolution; Exposure to; Feces; Future; Genetic Transcription; Genomics; Germ-Free; Health; Heterogeneity; Horizontal Gene Transfer; Human; Human Milk; Individual; Infant; Interdisciplinary Study; 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; 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; cohort; conflict resolution; de novo mutation; dietary; early life exposure; early onset; 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 在生命的前三年（YOL）婴儿肠道微生物组（GM）在结构和 功能，与饮食和环境过渡有关。至关重要的是，通用汽车对特定外部的响应 刺激是患者特异性的，使个性化风险预测复杂化。健康的通用汽车成熟包括应计 相同物种的多种菌株在关键功能上经常有所不同。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 具有健康和疾病的同一物种。我们提议背后的理由是，应变和物种 - 细菌功能的水平变化驱动对早期饮食和抗生素的异质GM反应 扰动，部分解释了个性化的发展轨迹。该提议高度追求 互补目的：1）定义小儿肠道微生物组的应变分辨功能成熟 2）研究EL抗生素（ELA）扰动对应变动力学，HGT和微型 - 早产新生儿和微生物群体中的生物群体成熟。 AIM 1将检验以下假设 El环境暴露会影响肠道物种的基因组多样化，从而导致GM COM的持久变化 城市结构和微生物功能。我们将利用我们在第一台收集的2,436个凳子的独特集 来自婴儿的9个YOL会多样地暴露于饮食和环境刺激。通过结合富含培养的元 基因组学，元文字组学和代谢组学，我们将确定子Spe- CIES水平和功率统计模型，这些模型预测EL暴露对应变多样化的影响，微生物 功能关联和转录活动。 AIM 2将检验elas急性应变的假设 动力学并刺激HGT，并且可以从基线组成和 功能。在这里，我们将在第一个早产儿中询问160个粪便侧面变量的ELA暴露 4个月的生命，将富含培养的宏基因组学与选择性培养和分离构造与炭化相结合 对早产质体”和轮廓后菌株菌株动力学和HGT进行构成。确定微生物组 - SIC对ELA的响应，我们将利用一种创新的跨代小鼠模型，无菌水坝接收 人，早产，垂直转移到幼崽的人，用肠胃外抗体治疗 ICS。我们将使用结果数据来预测基于组成的特定抗生素的单个反应， 抗性基因含量和细菌功能。我们的建议具有创新性，因为我们的跨学科重新 搜索团队将表征应变水平的细菌功能，以了解GM响应的异质性 在两套现有的人类标本集上扰动；这很重要，因为它将识别功能 这可以预测物种分辨的转基因特异性反应对EL选择。我们的工作将推进小儿微生物 通过全面表征应变的功能成熟和GM破坏来进行研究 了解导致个性化微生物组医学未来的个人变化。

项目成果

Genomic Surveillance of Clinical Pseudomonas aeruginosa Isolates Reveals an Additive Effect of Carbapenemase Production on Carbapenem Resistance.

• DOI: 10.1128/spectrum.00766-22
• 发表时间: 2022-06-29
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Diorio-Toth, Luke;Irum, Sidra;Potter, Robert F.;Wallace, Meghan A.;Arslan, Muhammad;Munir, Tehmina;Andleeb, Saadia;Burnham, Carey-Ann D.;Dantas, Gautam
• 通讯作者: Dantas, Gautam

A Tunable and Expandable Transactivation System in Probiotic Yeast Saccharomyces boulardii.

• DOI: 10.1021/acssynbio.1c00384
• 发表时间: 2022-01-21
• 期刊: ACS SYNTHETIC BIOLOGY
• 影响因子: 4.7
• 作者: Kwak, Suryang;Mahmud, Bejan;Dantas, Gautam
• 通讯作者: Dantas, Gautam