The benefit of cooperation: Identifying growth-efficient interacting strains of Escherichia coli using metabolic flux balance models

Cross-feeding, where two or more strains of an organism coexist on a single limiting resource, has been observed to emerge in long-term evolution experiments of E. coli in continuous culture. Here, we describe a computational method to model and systematically identify synergistic strains that have superior growth by exploiting their metabolic by-products with mutual benefit. A mutual flux balance simulation considers all possible single gene deletions growing on various substrates. Several synergistic strains are found to have higher growth than any single-strain cultures given the same limiting substrates. As the method is based on a detailed genome scale metabolic flux balance model of the organism, the results are not only consistent with several observed cross-feeding E. coli strains, but can also explain the exact mechanism of the synergy. We expect a broad range of applications for this method in metabolic engineering.