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

项目摘要 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。 发展和维护健康。出生后不久，新生儿迅速被这种 复杂的微生物群落，具有丰富的代谢潜力。对装配的扰动 微生物群可能对健康产生重大的下游后果。然而，基本的生态 建立有益和稳定的微生物群落的基本原理和分子过程 大部分都是未知的。在这个复杂的生态系统中定义多维交互已经证明 非常具有挑战性，并没有超越简单的联想。这部分是由于固有的 微生物群的复杂性和相互联系，以及缺乏基本的机制研究， 接口.此外，可用于空间映射和研究代谢串扰的技术有限 微生物群落中的物种之间。在这里，我们提出了一种新的策略，以产生一个分子蓝图， 使用创新的管道，整合先进的代谢相互作用的组装微生物群 代谢组学成像与全面的机制研究。我们的目标是生成一个高分辨率 群落组装和扰动过程中代谢物空间分布图。我们将用这张分子图谱 系统地确定微生物群成员之间的代谢串扰机制， 确定这些互动在社区集会中的作用。我们将研究殖民和解构 使用简单的联觉微生物群落，gnotobiotics，和 连续流动栽培系统。我们的目标是提供空间定位的详细了解， 生命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 赋予早期生命殖民生物体增加适应性的分子决定因素。在一起，这 建议将提供一个框架，了解社区大会的基本机制， 并导致开发新的策略来操纵早期生命中的微生物群落， 与微生物群相关的疾病。

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.