Spatially-resolved metabolic cooperativity within dense bacterial colonies

John A. Cole, Lars Kohler, Jamila Hedhli, Zaida Luthey-Schulten

Research output: Contribution to journalArticlepeer-review


Background: The exchange of metabolites and the reprogramming of metabolism in response to shifting microenvironmental conditions can drive subpopulations of cells within colonies toward divergent behaviors. Understanding the interactions of these subpopulations-their potential for competition as well as cooperation-requires both a metabolic model capable of accounting for a wide range of environmental conditions, and a detailed dynamic description of the cells' shared extracellular space. Results: Here we show that a cell's position within an in silico Escherichia coli colony grown on glucose minimal agar can drastically affect its metabolism: "pioneer" cells at the outer edge engage in rapid growth that expands the colony, while dormant cells in the interior separate two spatially distinct subpopulations linked by a cooperative form of acetate crossfeeding that has so far gone unnoticed. Our hybrid simulation technique integrates 3D reaction-diffusion modeling with genome-scale flux balance analysis (FBA) to describe the position-dependent metabolism and growth of cells within a colony. Our results are supported by imaging experiments involving strains of fluorescently-labeled E. coli. The spatial patterns of fluorescence within these experimental colonies identify cells with upregulated genes associated with acetate crossfeeding and are in excellent agreement with the predictions. Furthermore, the height-to-width ratios of both the experimental and simulated colonies are in good agreement over a growth period of 48 hours. Conclusions: Our modeling paradigm can accurately reproduce a number of known features of E. coli colony growth, as well as predict a novel one that had until now gone unrecognized. The acetate crossfeeding we see has a direct analogue in a form of lactate crossfeeding observed in certain forms of cancer, and we anticipate future application of our methodology to models of tissues and tumors.

Original languageEnglish (US)
Article number15
Pages (from-to)1-17
Number of pages17
JournalBMC Systems Biology
Issue number1
StatePublished - Mar 18 2015


  • Colony modeling
  • Crossfeeding
  • Flux balance analysis
  • Metabolic cooperativity
  • Reaction-diffusion modeling

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics


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