Engineering bacterial behaviors to control microbiota invasion resistance

改造细菌行为以控制微生物群入侵抵抗力

• 批准号: 10227106
• 负责人: Raghuveer Parthasarathy
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227106
• 关键词: Address; Affect; Animals; Antibiotics; Bacteria; Behavior; Behavior Control; Biodiversity; Biological; Cells; Characteristics; Chemicals; Chemotaxis; Communities; Data; Disease; Dose; Engineering; Environment; Exposure to; Foundations; Genetic; Genetic Engineering; Gnotobiotic; Health; Human Microbiome; Image; In Situ; Individual; Intestines; Lead; Metagenomics; Microbe; Modeling; Morphology; Nature; Optics; Organ; Pathway interactions; Phenotype; Physiological Processes; Play; Population; Predisposition; Reporting; Resistance; Role; SOS Response; Series; Spatial Distribution; Stimulus; Structure; System; Testing; Time; Variant; Zebrafish; bacterial community; base; biological adaptation to stress; cell motility; experimental study; gut microbiota; human microbiota; in vivo; insight; microbial; microbiome composition; microbiota; response; synthetic biology; transmission process; virtual

PROJECT SUMMARY/ABSTRACT (PROJECT 1) The gastrointestinal microbiota of humans and other animals, composed of vast numbers of individual cells representing many different species, serves as a virtual organ contributing to a wide range of physiological processes. More than most organs, it is subject to strong and frequent perturbations due to its connectedness to the outside world and the inter-species competition inherent in its nature as a multi-species consortium. These perturbations may be chemical, e.g. from antibiotic drugs, or biological, e.g. from invasion by new species, and may couple to physical characteristics of microbes such as motility and spatial distribution. It is likely that the large variability in human microbiome composition, both within individuals over time and between individuals in populations, is due in part to responses to variations in externally driven stimuli. Despite this, our understanding of how specific perturbations influence gut microbial communities, and whether generic features might unify diverse responses, remains minimal. We propose a series of experiments that will address this, using larval zebrafish as a model host-microbe system. The amenability of larval zebrafish to gnotobiotic manipulation enables controlled experiments with large replicate populations, and their optical transparency allows imaging-based quantifications of microbial abundances, spatial distributions, and dynamics. We focus on two important classes of perturbations: invasion by new species and exposure to antibiotics. The introduction of new species is a constant feature of the intestinal environment, and behaviors such as motility and chemotaxis likely play important roles in interactions between resident and invasive microbes. Building on advances in synthetic biology, we will engineer genetic switches to report on and control these behaviors in situ, using the control afforded by gnotobiotic zebrafish to manipulate intestinal communities. Antibiotic use is known from metagenomic studies to dramatically affect the gastrointestinal microbiota, even at low (sub- lethal) doses, for reasons that remain to be discovered. Building on preliminary data, we hypothesize that even weak antibiotic perturbations can dramatically alter bacterial behaviors, spatial distributions, and persistence within the gut, altering both species abundances and dispersal to new hosts. Our proposed experiments will provide new insights into how common perturbations influence intestinal microbiota dynamics and will establish a foundation for understanding the dynamics of human microbiomes during both health and disease.

项目概要/摘要（项目 1） 人类和其他动物的胃肠道微生物群由大量单个细胞组成 代表许多不同的物种，作为一个虚拟器官，有助于广泛的生理 流程。由于与其他器官的联系，它比大多数器官更容易受到强烈而频繁的扰动。 外部世界和作为多物种联合体的本质所固有的物种间竞争。这些 扰动可能是化学的，例如来自抗生素药物或生物药物，例如免受新物种的入侵，以及 可能与微生物的物理特征（例如运动性和空间分布）耦合。这很可能是 人类微生物组组成的巨大变异性，无论是在个体内部还是在不同时间之间 群体中的个体的差异部分是由于对外部驱动刺激的变化的反应。尽管如此， 我们对特定扰动如何影响肠道微生物群落的理解，以及是否具有通用性 功能可能会统一不同的响应，但仍然很少。我们提出了一系列实验来解决 使用斑马鱼幼虫作为模型宿主微生物系统。斑马鱼幼虫对知生菌的适应性 操纵使得能够进行大量重复群体的受控实验及其光学透明度 允许对微生物丰度、空间分布和动态进行基于成像的量化。我们专注 关于两类重要的扰动：新物种的入侵和抗生素的暴露。这 新物种的引入是肠道环境的一个恒定特征，而蠕动等行为 趋化性可能在常驻微生物和入侵微生物之间的相互作用中发挥重要作用。建筑 随着合成生物学的进步，我们将设计基因开关来报告和控制这些行为 原位，利用知生斑马鱼提供的控制来操纵肠道群落。抗生素的使用是 宏基因组研究表明，即使在低（亚- 致死）剂量，其原因仍有待发现。根据初步数据，我们假设即使 微弱的抗生素扰动可以显着改变细菌的行为、空间分布和持久性 在肠道内，改变物种丰度和向新宿主的扩散。我们提出的实验将 提供关于常见扰动如何影响肠道微生物群动态的新见解，并将 为了解健康和疾病期间人类微生物组的动态奠定基础。