Systems-level analysis of the metabolism and ecology of genetically intractable gut bacteria

遗传难治性肠道细菌的代谢和生态学的系统级分析

• 批准号: 10359071
• 负责人: Cecilia Noecker
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359071
• 关键词: Acetates; Actinobacteria class; Address; Age; Autoimmune Diseases; Awareness; Bacteremia; Biochemical Pathway; Biology; Characteristics; Chemicals; Coculture Techniques; Collection; Communicable Diseases; Communities; Complex; Computer Models; Data; Data Set; Dependence; Development; Disease; Ecology; Ecosystem; Environment; Equilibrium; Family; Fellowship; Formulation; Future; Gene Expression; Genes; Genome; Genomics; Geography; Growth; Health; Human; In Vitro; Institution; Intervention; Knowledge; Mentors; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Methods; Microbe; Modeling; Modification; Nutrient; Nutritional; Nutritional Requirements; Outcome; Pharmacology; Physiology; Play; Population; Production; Property; Regulation; Research; Resources; Role; Sampling; System; Technology; Testing; Training Programs; Variant; Work; Xenobiotics; bacterial metabolism; cohesion; comparative; comparative genomics; computerized tools; data resource; experimental study; genome-wide; genomic predictors; genomic variation; gut bacteria; gut microbes; gut microbiome; gut microbiota; improved; in vivo; insight; metabolic profile; metabolomics; metagenome; microbial; microbiome; microbiome composition; microbiome research; novel; nutrition; public database; reconstruction; skill acquisition; skills; trait

Project Summary/Abstract Despite the fundamental importance of the human gut microbiome in health and disease, a cohesive understanding of the core metabolic pathways of many human gut bacterial species is lacking. The Actinobacterium Eggerthella lenta is a notable example: it is highly prevalent, associated with bacteremia and the development of autoimmune disease, and capable of diverse transformations of endogenous and xenobiotic compounds, yet little is known about its nutrient requirements, metabolic regulation, and ecological niche. This project will investigate metabolic and ecological properties of E. lenta across multiple scales. It will use a combination of experimental and computational approaches to evaluate these properties across strains and species in the family Eggerthellaceae, taking advantage of a new resource of strain isolates and genomes. Preliminary experiments established defined minimal media formulations that support the growth of Eggerthellaceae and identified key growth determinants, including an unexpected growth benefit from acetate. Pilot metabolomics analysis of E. lenta cultured in minimal media revealed context-specific metabolism and production of host-relevant metabolites. This project will first quantify growth, metabolite fluxes, and gene expression of Eggerthellaceae strains across minimal nutrient contexts. The resulting data resource will be used to construct and analyze computational genome-scale metabolic models of these taxa. Next, co-culture studies of E. lenta strains with other gut microbial taxa will elucidate their ecological interactions and possible metabolite exchanges. Lastly, newly available collections of Eggerthellaceae genomes assembled from public metagenomic datasets will be analyzed to evaluate associations of genomic and metabolic features with host disease, geography, age, and microbiome composition. Overall, this work will provide insights into the metabolic, ecological, and evolutionary properties of this clade and its role in human health and disease. Moreover, the integration of in vitro profiling, cross-strain comparative analyses, and computational modeling demonstrated here is a generalizable framework for expanding scientific understanding of the metabolism of poorly characterized gut microbes. The fellowship training program will include skill development in experimental biology, research mentoring, and professional skills; supported by a collaborative and successful microbiome research community at a top-ranked institution.

项目总结/摘要 尽管人类肠道微生物组在健康和疾病中具有根本的重要性， 对许多人类肠道细菌物种的核心代谢途径缺乏了解。的 慢蛋放线杆菌（Eggerthella lenta）是一个值得注意的例子：它非常普遍，与菌血症有关， 自身免疫性疾病的发展，并能够内源性和 外源性化合物，但很少有人知道它的营养需求，代谢调节，生态 利基本项目将研究大肠杆菌的代谢和生态学特性。lenta lenta across多scale规模.它将 使用实验和计算方法相结合的方法来评估这些属性跨应变 和种在家庭Eggerthellaceae，利用菌株分离和基因组的新资源。 初步实验建立了支持微囊藻生长的限定的基本培养基配方。 并确定了关键的生长决定因素，包括一个意想不到的增长效益乙酸。 初步代谢组学分析E.在基本培养基中培养的lenta揭示了环境特异性代谢， 宿主相关代谢物的产生。该项目将首先量化生长，代谢物通量和基因 在最低限度的营养环境中表达Eggerthellaceae菌株。生成的数据资源将是 用于构建和分析这些分类群的计算基因组规模的代谢模型。接下来，共同培养 研究E. lenta菌株与其他肠道微生物类群将阐明它们的生态相互作用， 代谢物交换最后，从公众收集的新的茄子科基因组集合 将分析宏基因组数据集，以评估基因组和代谢特征与宿主的关联。 疾病、地理、年龄和微生物组组成。总的来说，这项工作将提供深入了解 代谢，生态和进化特性及其在人类健康和疾病中的作用。 此外，体外分析、跨菌株比较分析和计算建模的集成 这里展示的是一个可推广的框架，用于扩大对代谢的科学理解。 肠道微生物特征不明显。奖学金培训计划将包括以下方面的技能发展： 实验生物学，研究指导和专业技能;由合作和成功的支持 微生物组研究社区在一个顶级机构。