Metabolic trade-offs and regulatory changes as drivers of metabolic cross-feeding interactions in simple microbial communities

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Microorganisms exist in complex, interdependent ecological communities. A prominent feature of these assemblages is the reciprocal exchange of essential metabolites between community members that has been shown to be key for determining the structure, function, and evolution of a given microbial community. In many cases, these metabolic interactions are obligate as evidenced by the fact that auxotrophic genotypes, which are unable to autonomously produce certain essential metabolites, are prevalent in such communities. Previous work has shown that auxotrophic genotypes can gain significant growth advantages when engaging in a reciprocal cross-feeding interaction with other genotypes. However, the biochemical and systems-level underpinnings of this effect remain completely unclear. To understand this metabolic division of labor on a broader scale, we will comparatively analyze a prokaryotic (bacteria) and a eukaryotic microbial system (yeast). By integrating systems-level approaches with mathematical models, we propose to quantitatively determine how an amino acid auxotrophy-causing mutation affects the allocation of cellular resources and thus, potentially, also the production levels of other amino acids or metabolites. In addition, we will establish the existence of metabolic trade-offs in these systems, and both theoretically and experimentally test whether the breaking of these trade-offs by metabolic cross-feeding provides growth advantages to interacting strains relative to autonomous genotypes. This work will provide fundamental insights into the biochemical and metabolic factors driving division of labor in microbial communities. Such a quantitative understanding of the rules governing community assembly and function is urgently required to rationally design microbial consortia for medical or biotechnological applications.