Collaborative Research: Scaling from single-cell physiology to community stability in a natural gut microbiome

微生物是无处不在的炼金术士，可以将分子转化为有用和有害的形式。它们有可能保护人类、动物和农作物的健康，也有可能分解温室气体来修复我们的气候。然而，微生物也会导致疾病，并产生地球大气、水和土壤的污染物。每个微生物细胞都根据自己的基因和所处的环境“决定”自己的功能，但基因相同的细胞如何做出不同的决定是一个重大的知识鸿沟。这项提议的目的是了解单个细胞如何根据基因和环境之间的联系做出这些决定。为了实现这一目标，主要研究人员将使用创新的高通量成像技术对单个细胞进行成像，以量化它们在精确环境条件下的决定。苍蝇微生物群的使用将使物种多样性和环境条件达到接近自然环境的现实水平。这些知识将有利于设计微生物群落的方法，以改善人类、动物、植物和环境的健康。在教育方面，将培养研究生和博士后学者。此外，这两个私人投资机构将与既定的计划合作，将科学带给来自低收入家庭的大量K-12学生。该项目实施了一种量化方法，将单细胞生理学与生态学中的消费资源理论相结合，以产生遗传途径对群落功能影响的可检验预测。该项目整合了计算显微镜和高通量连续培养实验，以明确地将单个细胞的反应与它们在生态系统中的适应性联系起来。本研究调查了一种自然、简单、易驯化的模式肠道微生物群，即野生果蝇肠道微生物群，该微生物群具有~5个稳定的伴生物种，对寄主适合性有明确的作用。通过理论和实验的循环，该项目将1)为果蝇肠道微生物群开发一个完全参数化的消费者资源模型，2)量化单细胞决策在群落动力学中的作用，3)应用该模型研究个体果蝇肠道微生物群的动态。通过揭示单细胞水平的生态适宜性特征的遗传基础并将单细胞决定与群落功能联系起来，这项工作将为基因工程奠定基础，这种基因工程结合了个体生物对环境的异质性反应，提供了一个控制旋钮，以合理地调整给定微生物群中工程微生物的生态稳定性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Microorganisms are ubiquitous alchemists that can convert molecules to both useful and harmful forms. They have the potential to protect human, animal, and crop plant health as well as to break down greenhouse gases to remediate our climate. However, microorganisms also cause disease and produce pollutants of Earth’s atmosphere, water, and soils. Each microbial cell “decides” its function based on its genes and the environment in which it is living, but how genetically identical cells make different decisions is a major knowledge gap. The aim of this proposal is to understand how individual cells make these decisions based on the connection between genes and the environment. To accomplish this aim, the principal investigators will employ innovative high-throughput imaging of individual cells to quantify their decisions when placed under precise environmental conditions. The use of the fly microbiome will allow a realistic level of species diversity and environmental conditions that approximate natural environments. Such knowledge will benefit approaches to engineer microbial communities to improve health of humans, animals, plants, and the environment. Educationally, graduate students and postdoctoral scholars will be trained. In addition, both PIs will work with established programs to bring science to a large number of K-12 students from low income families. This project implements a quantitative approach integrating single-cell physiology with consumer-resource theory from ecology to yield testable predictions of the impact of genetic pathways on community function. The project integrates computational microscopy and high-throughput continuous culture experiments to explicitly link the responses of individual cells to their fitness in the ecosystem. The research investigates a model gut microbiome that is natural, simple, and tractable, namely the wild fruit fly gut microbiome with ~5 stably associated species and a clear role in host fitness. Through cycles of theory and experiment, the project will 1) develop a completely parameterized consumer-resource model for the Drosophila gut microbiome, 2) quantify the role of single-cell decision-making in community dynamics, and 3) apply the model to study the dynamics of gut microbiomes in individual flies. By revealing the genetic basis of ecological fitness traits at the single-cell level and linking single-cell decisions to community function, this work will lay the foundation for genetic engineering that incorporates heterogeneity in individual organismal responses to their environment, providing a control knob to rationally tune the ecological stability of an engineered microbe in a given microbiome.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.