Metabolic Heterogeneity and Cross-Feeding in Bacterial Multicellular Systems

Metabolic diversification in bacterial systems arises from innate stochasticity and can be further promoted by growth in chemical gradients and/or constrained spaces. Metabolic heterogeneity can enable metabolite cross-feeding, and cross-feeding itself can promote the development of metabolically differentiated subpopulations. New techniques for characterizing metabolically diversified subpopulations in situ include those that incorporate three-dimensional dynamic flux balance analysis, 13C-metabolic flux analysis, growth in microfluidic devices, and stimulated Raman scattering microscopy. Metabolic heterogeneity is an important factor to incorporate into models of infection because it influences virulence and antibiotic susceptibility. Cells in assemblages differentiate and perform distinct roles. Though many pathways of differentiation are understood at the molecular level in multicellular eukaryotes, the elucidation of similar processes in bacterial assemblages is recent and ongoing. Here, we discuss examples of bacterial differentiation, focusing on cases in which distinct metabolisms coexist and those that exhibit cross-feeding, with one subpopulation producing substrates that are metabolized by a second subpopulation. We describe several studies of single-species systems, then segue to studies of multispecies metabolic heterogeneity and cross-feeding in the clinical setting. Many of the studies described exemplify the application of new techniques and modeling approaches that provide insights into metabolic interactions relevant for bacterial growth outside the laboratory. Cells in assemblages differentiate and perform distinct roles. Though many pathways of differentiation are understood at the molecular level in multicellular eukaryotes, the elucidation of similar processes in bacterial assemblages is recent and ongoing. Here, we discuss examples of bacterial differentiation, focusing on cases in which distinct metabolisms coexist and those that exhibit cross-feeding, with one subpopulation producing substrates that are metabolized by a second subpopulation. We describe several studies of single-species systems, then segue to studies of multispecies metabolic heterogeneity and cross-feeding in the clinical setting. Many of the studies described exemplify the application of new techniques and modeling approaches that provide insights into metabolic interactions relevant for bacterial growth outside the laboratory.