Inducible Cooperation in a Synthetic Gut Bacterial Consortium Introduces Population Balance and Stability

Commensal microbes in the gut do not act alone but instead as cooperative consortia to conduct their myriad functions. Cooperative interactions and feedback mechanisms are key to consortia performance, yet are often ignored in current synthetic biology efforts to engineer the microbiota. To this end, we engineered mutual metabolic dependencies between four heterogeneous gut-dwelling bacterial species. Each species was made auxotrophic for three amino acids and an overproducer for one amino acid to share with the other species. By performing dynamical systems inference from time-series measurements, we show that our engineering introduced positive interactions that either reversed or neutralized pre-existing competitive interactions and improved stability of the consortium. We further demonstrate that we can induce population balance in the engineered consortia, both in vitro and in the mouse gut, through nutrient and dietary manipulations. Our findings indicate that induced cooperation can introduce evenness and stability in a synthetic microbial ecosystem, and have implications for development of synthetic approaches to manipulate the microbiome.