Cellular Economics of Exchanged Metabolites Alter Ratios of Microbial Trading Partners in a Predictable Manner
Most microorganisms exist in interacting consortia, yet the principles behind consortia assembly, including trading partner structure, still require deciphering, despite being central to understanding, building, and controlling consortia. This study tests a cellular-economy-based hypothesis that pro...
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2025
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| Summary: | Most microorganisms exist in interacting consortia, yet the principles behind consortia assembly, including trading partner structure, still require deciphering, despite being central to understanding, building, and controlling consortia. This study tests a cellular-economy-based hypothesis that proposes consortia engaged in obligate metabolite exchange will assemble at ratios where the metabolic burden associated with the exchanges is predictably shared. The metabolic burden was quantified using ATP equivalents, the quantity of high-energy ATP phosphoanhydride bonds that could be produced if the exchanged metabolites were instead retained and catabolized for cellular energy. The hypothesis was tested using Escherichia coli cocultures engineered for obligatory exchange of pyruvate and l-arginine. The burden of metabolite exchange was manipulated by changing the availability of O<sub>2</sub>, which altered the bioavailability of substrate energy, and by deactivating the ATP synthase enzyme, which prevented oxidative phosphorylation. Three synthetic cocultures assembled at predicted strain ratios as a function of perturbations. The strain ratios represented an equivalent metabolic burden between the trading partners even though the exchanged metabolites varied substantially in flux magnitude (300+ fold), molecular weight (174 vs 88 g mol<sup>–1</sup>), enzyme requirements (8 specialized enzymes vs none), and biological energy density (27.5 vs 9 ATP molecule<sup>–1</sup>). The strain ratios could be rationally altered up to 20-fold using O<sub>2</sub> availability and cellular phenotype. The metabolic burden theory was applied to seven additional published cocultures and was found to accurately predict trading partner ratios. Quantifying exchanged metabolites on an ATP-equivalent basis provides a theory for interpreting natural consortia and a toolbox for controlling bioprocess consortia. |
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