Cell Growth Model with Stochastic Gene Expression Helps Understand the Growth Advantage of Metabolic Exchange and Auxotrophy

During cooperative growth, microbes often experience higher fitness by sharing resources via metabolite exchange. How competitive species evolve to cooperate is, however, not known. Moreover, existing models (based on optimization of steady-state resources or fluxes) are often unable to explain the growth advantage for the cooperating species, even for simple reciprocally cross-feeding auxotrophic pairs. We present here an abstract model of cell growth that considers the stochastic burst-like gene expression of biosynthetic pathways of limiting biomass precursor metabolites and directly connect the amount of metabolite produced to cell growth and division, using a “metabolic sizer/adder” rule. Our model recapitulates Monod’s law and yields the experimentally observed right-skewed long-tailed distribution of cell doubling times. The model further predicts the growth effect of secretion and uptake of metabolites by linking it to changes in the internal metabolite levels. The model also explains why auxotrophs may grow faster when supplied with the metabolite they cannot produce and why two reciprocally cross-feeding auxotrophs can grow faster than prototrophs. Overall, our framework allows us to predict the growth effect of metabolic interactions in independent microbes and microbial communities, setting up the stage to study the evolution of these interactions. IMPORTANCE Cooperative behaviors are highly prevalent in the wild, but their evolution is not understood. Metabolic flux models can demonstrate the viability of metabolic exchange as cooperative interactions, but steady-state growth models cannot explain why cooperators grow faster. We present a stochastic model that connects growth to the cell’s internal metabolite levels and quantifies the growth effect of metabolite exchange and auxotrophy. We show that a reduction in gene expression noise can explain why cells that import metabolites or become auxotrophs can grow faster and why reciprocal cross-feeding of metabolites between complementary auxotrophs allows them to grow faster. Furthermore, our framework can simulate the growth of interacting cells, which will enable us to understand the possible trajectories of the evolution of cooperation in silico.