Envision a world where the trillions of bacteria that inhabit our bodies become the frontier of personalized medicine, having the ability to shape our health, performance and even influence behavior. When in harmony, this teeming world of bacteria offers numerous health benefits. However, a shift in this delicate balance can lead to substantial negative health effects due to contrasting evolutionary objectives. Precision engineering of the gut microbiome that can add, remove or modify functional capabilities of the system holds tremendous therapeutic potential for personalized and precision medicine. However, the complexity of this system that encompasses hundreds of species, unknown interaction networks and mechanisms driving these interactions have precluded our ability to effectively manipulate this system to our benefit. A detailed and quantitative understanding of this system would enable the discovery of molecular and ecological design principles of the system as well as novel control knobs for steering the gut microbiome to desired states.
By combining high-throughput bottom-up assembly of human gut communities with computational modeling, we explore large microbiome functional landscapes mapping species abundance to health-relevant microbiome functions. Our data-driven models guide the discovery of communities with tailored metabolite profiles or inhibition of the major human gut pathogen Clostridioides difficile in vitro and in the mammalian gut. Complex dietary fibers/pre-biotics can be used to promote health-relevant metabolic functions and resistance to environmental perturbations. Finally, we demonstrate that control of specialized metabolic pathways is an effective control knob for predictably manipulating health-relevant metabolites. In sum, our work provides a foundation for exploring and exploiting the interaction networks driving the human gut microbiome as precision therapeutics.