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.

项目概要 胃肠道是数万亿微生物的家园，这些微生物在生命早期发挥着重要作用 的发展和健康的维护。出生后不久，新生儿就会迅速被这种细菌定植 复杂的微生物群落，具有丰富的代谢潜力。对组装的扰动 微生物群可能对健康产生重大的下游影响。然而，基本的生态 建立有益且稳定的微生物群落的原理和分子过程 很大程度上是未知的。事实证明，定义这个复杂生态系统中的多维相互作用 极具挑战性，而且还没有超出简单的联想范围。这部分是由于固有的 微生物群的复杂性和相互关联性以及缺乏基础机制研究 界面。此外，可用于空间映射和研究代谢串扰的技术有限 微生物群中的物种之间。在这里，我们提出了一种新的策略来生成分子蓝图 使用集成了先进技术的创新管道来组装微生物群中的代谢相互作用 成像代谢组学与综合机制研究。我们的目标是生成高分辨率 群落组装和扰动过程中代谢物的空间图。我们将使用这个分子图谱 系统地确定微生物群成员之间的代谢串扰机制 定义这些相互作用在社区集合中的作用。我们将研究殖民和解构 使用简单的联觉微生物群落、知生菌和微生物群落的群落组装机制 连续流栽培系统。我们的目标是提供对空间定位和 生命早期微生物群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体更强适应性的分子决定因素。在一起，这个 该提案将为理解社区集会的基本机制提供一个框架 婴儿并导致开发出在生命早期操纵微生物群落的新策略 在微生物群相关疾病期间。