Molecular interactions in the gut microbiota during early life colonization and perturbation

生命早期定植和扰动过程中肠道微生物群的分子相互作用

• 批准号: 10028814
• 负责人: Joseph Paul Zackular
• 金额: $ 44万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028814
• 关键词: Binding; Birth; Communities; Complex; Development; Disease; Ecosystem; Event; Gastrointestinal tract structure; Gnotobiotic; Goals; Health; Home environment; Image; Infant; Lead; Life; Maintenance; Maps; Mediating; Metabolic; Molecular; Newborn Infant; Organism; Play; Process; Resolution; Role; System; Technology; fitness; gut microbiota; innovation; member; metabolic abnormality assessment; metabolomics; microbial community; microbiota; microorganism; novel strategies

PROJECT SUMMARY The gastrointestinal tract is home to trillions of microorganisms that play an essential role in early life development and the maintenance of health. Shortly after birth, newborns are rapidly colonized by this complex microbial community that possesses a rich metabolic potential. Perturbation to assembly of the microbiota can have major downstream consequences to health. However, the fundamental ecological principles and molecular processes that underlie establishment of a beneficial and stable microbial community are largely unknown. Defining the multidimensional interactions in this complex ecosystem has proven incredibly challenging and has not moved far beyond simple associations. This is in part due to the inherent complexity and interconnectedness of the microbiota and a lack of fundamental mechanistic studies at this interface. Moreover, there are limited technologies available to spatially map and study metabolic cross talk between species in the microbiota. Here, we propose a novel strategy to generate a molecular blueprint of the metabolic interactions in the assembling microbiota using an innovative pipeline that integrates advanced imaging metabolomics with comprehensive mechanistic studies. Our objective is to generate a high-resolution spatial map of metabolites during community assembly and perturbation. We will use this molecular map to systematically determine the mechanisms of metabolic cross talk between members of the microbiota and define the role of these interactions in assembly of communities. We will study colonization and deconstruct mechanisms of community assembly using simple synesthetic microbial communities, gnotobiotics, and continuous flow cultivar systems. Our goal is to provide a detailed understanding of the spatial localization and molecular mechanisms of metabolic interactions in the microbiota during early life. Furthermore, we will define the molecular determinants that confer increased fitness for early life colonizing organisms. Together, this proposal will provide a framework for understanding the fundamental mechanisms of community assembly in infants and lead to the development of novel strategies for manipulating microbial communities in early life and during microbiota-associated disease.

项目摘要 胃肠道是数万亿微生物的家园，在早期生命中起着至关重要的作用 发展和健康维护。出生后不久，新生儿被此迅速殖民 具有丰富代谢潜力的复杂微生物社区。扰动 微生物群可以对健康产生重大的下游后果。但是，基本的生态学 建立有益和稳定的微生物社区的原理和分子过程 在很大程度上未知。在这个复杂的生态系统中定义多维互动已证明 令人难以置信的挑战，并没有远远超出简单的关联。这部分是由于固有的 在此，微生物群的复杂性和相互联系性以及缺乏基本的机械研究 界面。此外，有限的技术可用于空间映射和研究代谢横切 微生物群中的物种之间。在这里，我们提出了一种新的策略，以产生分子蓝图 使用创新的管道集成高级的菌群中的组装菌群中的代谢相互作用 与全面的机械研究成像代谢组学。我们的目标是产生高分辨率 社区组装和扰动期间代谢物的空间图。我们将使用此分子图 系统地确定菌群成员与 定义这些相互作用在社区集会中的作用。我们将研究殖民化和解构 使用简单的合成微生物群落，gnotobiotics和 连续流品种系统。我们的目标是对空间本地化和 早期微生物群中代谢相互作用的分子机制。此外，我们将定义 赋予早期生命定植生物适应性的分子决定因素。一起，这个 提案将为理解社区集会的基本机制提供一个框架 婴儿并导致制定新的策略，以在早期生活中操纵微生物群落和 在微生物群相关疾病期间。