No abstract

Microbial communities have tremendous potential as therapeutics. However, a major bottleneck is manufacturing high-diversity microbial communities with desired species compositions. We develop a two-stage, model-guided framework to produce microbial communities with target species compositions. We apply this method to optimize the diversity of a synthetic human gut community. The first stage exploits media components to enable uniform growth responses of individual species and the second stage uses a design-test-learn cycle with initial species abundance as a control point to manipulate community composition. Our designed culture conditions yield 91% of the maximum possible diversity. Leveraging these data, we construct a dynamic ecological model to guide the design of lower-order communities with desired temporal properties over a longer timescale. In sum, a deeper understanding of how microbial community assembly responds to changes in environmental factors, initial species abundances, and inter-species interactions can enable the predictable design of community dynamics.

Polysaccharide utilization loci (PULs) in the human gut microbiome have critical roles in shaping human health and ecological dynamics. We develop a CRISPR-FnCpf1-RecT genome-editing tool to study 23 PULs in the highly abundant species B. uniformis (BU). We identify the glycan-degrading functions of multiple PULs and elucidate transcriptional coordination between PULs that enables the population to adapt to the loss of PULs. Exploiting a pooled BU mutant barcoding strategy, we demonstrate that the in vitro fitness and the colonization ability of BU in the murine gut is enhanced by deletion of specific PULs and modulated by glycan availability. We show that BU PULs can mediate complex glycan-dependent interactions with butyrate producers that depend on the mechanism of degradation and the butyrate producer glycan utilizing ability. In sum, PULs are major determinants of community dynamics and butyrate production and can provide a selective advantage or disadvantage depending on the nutritional landscape.