Interrogating function, regulation, and interactions in a clade of prevalent human gut microbes

探究人类肠道微生物进化枝的功能、调节和相互作用

• 批准号: 10712228
• 负责人: Patrick Joseph Bradley
• 金额: $ 37.17万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712228
• 关键词: Affect; Atherosclerosis; Biochemical; Case/Control Studies; Communities; Data; Development; Distant; Environment; Future; Gene Expression; Genes; Growth; Health; Human; In Vitro; Intervention; Knowledge; Laboratories; Lead; Link; Mediating; Metabolic; Metabolic Control; Metabolism; Metagenomics; Microbe; Nutrient; Output; Pharmaceutical Preparations; Physiological; Process; Regulation; Research; dietary; diverse data; gene function; gut bacteria; gut microbes; immunoregulation; improved; in vivo; microbial; microbiome; microbiome research; microorganism interaction; model organism; pathogen; stressor; targeted treatment; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT Human-associated microbes are causally linked to processes as diverse as immunomodulation, protection against pathogens, and atherosclerosis. Many of these links are mediated through biochemical transformations of dietary, drug, or host compounds. This makes the microbiome a promising therapeutic target, especially as we could potentially affect downstream processes by controlling metabolic inputs. However, in order to effectively intervene, we must first understand how exactly changes in these inputs lead to differential regulation of growth, gene expression, and metabolism. This is challenging because our microbiomes are not only genetically and physiologically diverse, but are also highly diverged from the most common model organisms, with many genes of unknown function. Over the next five years, my research group will use a combined computational and experimental strategy to characterize gene function, metabolic regulation, and microbial interactions in one of the most prevalent and abundant clades of gut bacteria, the Bacteroidales. Specifically, we seek to determine 1) which Bacteroidales genes are involved in growth on different nutrients and stressors; 2) how Bacteroidales genes are regulated, and how this affects their metabolic outputs; and 3) how Bacteroidales interact with the other microbial inhabitants of the gut. We will accomplish this by gathering high-throughput in vitro data from diverse sets of microbiome isolates and synthetic communities, developing more powerful and specific statistical tools to analyze these data, and using these new data and tools to re-analyze metagenomics data gathered from in vivo case-control studies. I envision that this line of inquiry will provide missing fundamental knowledge about this clade of microbes, which will ultimately help us interpret case-control studies of the microbiome and support the development of more precise interventions.

项目总结/摘要 人类相关的微生物与免疫调节、保护和免疫应答等多种过程有因果关系。 抵抗病原体和动脉粥样硬化。这些联系中有许多是通过生化转化介导的 饮食、药物或宿主化合物的影响。这使得微生物组成为有希望的治疗靶点，特别是当 我们可以通过控制代谢输入来潜在地影响下游过程。但为了 为了有效地进行干预，我们必须首先了解这些投入的变化究竟是如何导致差异的， 调节生长、基因表达和代谢。这是一个挑战，因为我们的微生物组不是 只有遗传和生理上的多样性，但也高度偏离最常见的模式， 有许多功能未知的基因。 在接下来的五年里，我的研究小组将采用计算和实验相结合的策略 描述基因功能，代谢调节和微生物相互作用在一个最普遍的， 肠道细菌的丰富分支，拟杆菌目。具体来说，我们试图确定1）哪些拟杆菌 基因参与不同营养物和应激物的生长; 2）拟杆菌目基因如何被调节， 以及这如何影响它们的代谢产物;以及3）拟杆菌如何与其他微生物相互作用 肠道的居民。我们将通过从不同的组织中收集高通量的体外数据来实现这一点。 微生物组分离株和合成群落，开发更强大和具体的统计工具， 分析这些数据，并使用这些新的数据和工具来重新分析从 体内病例对照研究。我设想，这条调查路线将提供缺失的基本知识， 这支微生物，这将最终帮助我们解释微生物组的病例对照研究， 支持制定更精确的干预措施。