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

项目总结 胃肠道是数以万亿计的微生物的家园，这些微生物在早期生命中发挥着至关重要的作用 发展和维护健康。出生后不久，新生儿很快就会被这种病毒殖民 具有丰富代谢潜力的复杂微生物群落。对组件的扰动 微生物区系可能会对健康产生重大的下游后果。然而，根本的生态 建立有益和稳定的微生物群落的原理和分子过程 在很大程度上是未知的。定义这个复杂生态系统中的多维相互作用已经证明 令人难以置信的挑战，并没有超越简单的联想。这在一定程度上是由于固有的 微生物区系的复杂性和相互关联性，以及在这方面缺乏基本的机制研究 界面。此外，用于空间映射和研究新陈代谢串扰的技术有限。 在微生物区系中的物种之间。在这里，我们提出了一种新的策略来生成分子蓝图 利用整合先进技术的创新管道在组装微生物区系中的代谢相互作用 影像代谢组学与全面的机制研究。我们的目标是生成一个高分辨率的 群落聚集和扰动过程中代谢产物的空间分布图。我们将利用这张分子图谱来 系统地确定微生物区系成员之间的代谢串扰机制和 定义这些互动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、灵知生物素和 连续流栽培制度。我们的目标是提供对空间定位和 微生物区系早期代谢相互作用的分子机制。此外，我们将定义 这些分子决定因素增加了早期生命移居生物的适合性。总而言之，这 提案将为理解#年社区集会的基本机制提供一个框架 并导致开发新的策略来操纵早期生命和 在与微生物区系相关的疾病期间。

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.