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

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.