Leveraging synthetic gut microbiomes to understand the host and microbial determinants that promote dysbiosis

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The human gastrointestinal tract represents one of the most dense microbial ecosystems and, although likely underestimated. By providing unique enzymes and biochemical pathways, the gut microbiota regulates multiple aspects of host physiology, including metabolism, development and function of the immune and nervous system, as well as resistance to infection by pathogens. Adverse alterations of the structure and metabolic capacity of the microbiota, often referred to as dysbiosis, have been linked to numerous diseases, including inflammatory bowel disease (IBD), cancer, autoimmune diseases and metabolic disorders. However, defining what dysbiosis means on a compositional and functional level has proven to be difficult since disease-specific taxonomic signatures are not always consistently detected across multiple cohorts. Indeed, given the complexity of inter-microbe and microbe-host interaction networks within the gut ecosystem, it is difficult to decipher the physiological roles of individual members in natural communities. This is further complicated by the fact that multiple taxa possess similar metabolic capacities and are thereby functionally redundant. On the other hand, technical and practical constraints in culturing a proportion of gut bacteria have hindered the functional characterization of not-yet culturable or unknown taxa, which could play an important biological role in the complex microbial community. In addition, experimental animal studies of microbe-host crosstalk have shown limited reproducibility because of the inherent variability of the gut microbiota that can cause phenotypic variations. For these reasons, there is an emerging interest in developing standardized microbiota communities of reduced and known complexity, generally referred to as synthetic or defined microbial communities. In this project, we plan to leverage the use of synthetic microbiomes in order to delineate how the gut environment impacts the microbial ecosystem as well as how microbial factors from a perturbed community impact the host. Synthetic microbiomes representing human- or mouse-derived communities, either in conditions of health or disease, will be constructed in chemostat bioreactors where host-simulated environments encourage the stable growth of these communities. These communities will then be gavaged into germ-free mice, which provide the means to test the effectiveness of how well the bioreactors reflect composition and function of a given microbial community once within the gut environment as well as to determine what host factors impact the microbial ecosystem and which microbial factors contribute to host outcomes in a controlled and tractable system.