Noisy metabolism can drive the evolution of microbial cross-feeding

Cross-feeding, the exchange of nutrients between organisms, is ubiquitous in microbial communities. Despite its importance in natural and engineered microbial systems, our understanding of how cross-feeding arises is incomplete, with existing theories limited to specific scenarios. Here, we introduce a novel theory for the evolution of cross-feeding, which we term noise-averaging cooperation (NAC). NAC is based on the idea that, due to their small size, bacteria are prone to noisy regulation of metabolism which limits their growth rate. To compensate, related bacteria can share metabolites with each other to “average out” noise and improve their collective growth. This metabolite sharing among kin then allows for the evolution of metabolic interdependencies via gene deletions (this can be viewed as a generalization of the Black Queen Hypothesis). We first characterize NAC in a simple model of cell metabolism, showing that metabolite leakage can in principle substantially increase growth rate in a community context. Next, we develop a generalized framework for estimating the potential benefits of NAC among real bacteria. Using single-cell protein abundance data, we predict that bacteria suffer from substantial noise-driven growth inefficiencies, and may therefore benefit from NAC. Finally, we review existing evidence for NAC and outline potential experimental approaches to detect NAC in microbial communities. ### Competing Interest Statement The authors have declared no competing interest.