Microbial Engineering to Control the Structure and Function of the Gut Microbiome.

控制肠道微生物群结构和功能的微生物工程 摘要 人类的微生物区系，即生活在体内的微生物的集合，与人类完全整合。 生理学，并被广泛地牵涉到健康和疾病。与所有微生物群落一样， 环境、细菌间和界间相互作用的总和既控制着成分，也控制着 微生物区系的功能。到目前为止，自上而下的方法在很大程度上被用于研究微生物组。 功能，使用多组学技术得出微生物分类群、基因和代谢物之间的关联 在不同的环境条件下具有功能特性。虽然这些研究贡献了一套丰富的 假设，需要自下而上的方法来因果地查明分子机制，通过这些机制 微生物与它们的环境、彼此和宿主相互作用。这些力学研究的综合 可以进一步实现可用于设计微生物群的预测性模型。通过 新技术的开发和应用，这里描述的研究计划旨在预测性地 设计肠道微生物组的生态反应和代谢功能。明确的微生物群落 这反映了自然群落的系统发育和功能多样性，将作为模型的试验床 由于细菌间的相互作用而产生的紧急现象。利用来自自然的灵感 微生物群落为合成生物学提供燃料，我们将创造新的工具来允许基因 在之前难以处理的肠道共生体中的操纵和表达控制。这些遗传工具将被应用于 将微生物基因和相关功能与微生物群落的新特性联系起来，包括 小鼠肠道对环境扰动和代谢网络的适应能力。这些研究将提供一个 对构成微生物群落的核心功能进行调查的实验框架 制定合理的微生物工程设计规则。

Microbial Engineering to Control the Structure and Function of the Gut Microbiome SUMMARY The human microbiota, the collection of microbes that live on and in the body, is fully integrated with human physiology and has been extensively implicated in health and disease. As with all microbial communities, the summation of environmental, interbacterial, and interkingdom interactions governs both the composition and function of the microbiota. To date, top-down approaches have been largely used to study microbiome function, using multi-omics techniques to draw correlations between microbial taxa, genes, and metabolites with functional properties in different environmental conditions. While these studies contribute a rich set of hypotheses, bottom-up approaches are required to causally pinpoint the molecular mechanisms through which microbes interact with their environment, one another, and the host. Synthesis of these mechanistic studies can further enable predictive models that can be leveraged to engineer microbiomes. Through the development and application of novel technologies, the research program described herein aims to predictively engineer ecological responses and metabolic functions in the gut microbiome. A defined microbial community that mirrors the phylogenetic and functional diversity of natural communities will be used as a testbed to model the emergent phenomena that arise as a result of interbacterial interactions. Using inspiration from natural microbial communities to fuel synthetic biology approaches, we will create new tools to allow for genetic manipulation and expression control in previously intractable gut symbionts. These genetic tools will be applied to link microbial genes and associated functions with emergent properties of microbial communities, including resilience to environment perturbations and metabolic networks in the mouse gut. These studies will provide an experimental framework to pursue investigations into the core functions that structure microbial communities and to establish design rules for rational microbiome engineering.