When and why spatial structure favors metabolic cross-feeding

Metabolic cross-feeding is central to microbial life. Theory predicts that spatial structure favors cross-feeding by affording cells preferential access to the exchanged metabolites. Yet recent evidence shows that spatial structure can, in some contexts, disfavor cross-feeding. Here, we resolve this contradiction by structuring cross-feeding interactions into three dimensions: (i) directionality, (ii) investment, and (iii) metabolic dependency. We then investigated their combined effects using a spatially explicit individual-based model. We find that the effect of spatial structure on cross-feeding is determined not by physical proximity alone, but by how microbial growth depends on exchanged metabolites. Metabolic dependence shapes the spatial organization of cells and metabolite fluxes, and this emergent organization, in turn, reshapes the ecological outcome of cross-feeding. Our results reconcile previously conflicting observations and provide a general framework for predicting and engineering metabolically interdependent microbial communities.