Abstract Syntrophic interactions based on reciprocal metabolite exchange are widespread in microbial communities, yet the factors determining their stability remain unclear. Using synthetic Escherichia coli consortia composed of lysine and arginine auxotrophs, we show that lower initial metabolite production promotes, rather than limits, syntrophic stability. During serial propagation, replicate cocultures diverged sharply: a minority maintained sustained growth, whereas most became extinct. This divergence was associated with phenotypic differences in metabolite production among founding isolates. Consortia founded by low-producing strains recovered reliably after dilution and were more resistant to invasion by non-producing mutants. By contrast, high-producing founder generated diminishing returns for consortium growth, and increased extracellular metabolite availability that favored exploitation by non-producer. Although we detected no consistent coding-region variations between high- and low-producing isolates, expression differences suggest that outside coding regions may influence these production traits. These results identify constrained initial metabolite production as a key determinant of syntrophic stability.
Ye et al. (2026) studied this question.