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.

项目摘要/摘要（项目1） 人类和其他动物的胃肠道菌群，由大量单个细胞组成 代表许多不同的物种，是一种虚拟器官，有助于广泛的生理 过程。比大多数器官多，由于它与 外界和种族间的竞争本质上固有的多物种财团。这些 扰动可能是化学的，例如来自抗生素药物或生物学，例如来自新物种的入侵，以及 可能会将运动性和空间分布等微生物的物理特征融入。很可能 随着时间的时间和之间的个人，人类微生物组组成的差异很大 人口中的个体部分归因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，以及是否通用 功能可能会统一多样化的响应，保持最低。我们提出了一系列实验，以解决 这是使用幼虫斑马鱼作为型号宿主微型机系统的。幼虫斑马鱼对gnotobiotic的舒适性 操纵可以具有大量重复人群及其光学透明度的受控实验 允许基于成像的微生物丰度，空间分布和动力学的定量。我们集中精力 在两种重要的扰动类别中：新物种的侵袭和暴露于抗生素。这 引入新物种是肠道环境的恒定特征，诸如运动之类的行为 趋化性可能在居民和侵入性微生物之间的相互作用中起重要作用。建筑 关于合成生物学的进步，我们将设计遗传转换以报告和控制这些行为 现场，使用gnotobiotic斑马鱼提供的控制来操纵肠道群落。抗生素使用是 从宏基因组研究已知，以极大地影响胃肠道微生物群，即使在低（亚下） 致命的剂量，出于尚待发现的原因。在初步数据的基础上，我们假设即使 弱抗生素扰动可以极大地改变细菌行为，空间分布和持久性 在肠道内，改变了两种物种的丰度，并散布到新宿主。我们提出的实验将 提供有关常见扰动如何影响肠道菌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建立基础。