Predicting Function from Composition: A Synthetic Ecology Approach to Understand Butyrate Production By Human Gut Microbiome Communities

Microbial community functions arise from complex systems-level behavior based on microbial interactions and environmental context. Because of the complexity of these systems, model-guided, high-throughput methods are necessary to design optimal experiments to probe system behavior and to develop solutions to problems in the realms of health (i.e. modulating microbiome disease impacts), energy (i.e. efficient and robust bioprocesses), and environment (i.e. bioremediations that restore the native ecosystem). In this work, we used synthetic ecology methods to develop a model-guided experimental approach to predict how microbial community composition impacts function, in this case butyrate production by the human gut microbiome. We first characterized growth and metabolite production of 25 genotyped human gut bacterial isolates, 5 of whose genomes encode metabolic pathways required for butyrate production. We then characterized the impact of pairwise interactions from these 25 species on growth and butyrate production of each of the 5 butyrate-producing bacteria. Using this initial dataset, we built a minimally-parameterized predictive model using tools from dynamic ecological modeling and statistical modeling to predict species abundance and butyrate production by higher-order communities. For experimental validation, we used this model to design 165 communities of 3-5 species that spanned the entire range of predicted butyrate concentrations and included every combination of the 5 butyrate producing bacteria. The model was able to accurately predict the species abundance and butyrate production of these communities in most cases. The structure of this model identifies the pairwise interactions that have the largest impact on butyrate production in these synthetic communities and thus can be used to identify general principles of butyrate production within this synthetic ecology model. The knowledge and methodologies generated in this work will be useful for designing interventions to treat patients with butyrate-deficient gut microbiomes as well as for designing microbial communities with specified functional outputs in general.