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

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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.