Abstract
Fluctuations in intracellular molecule abundance can lead to distinct, coexisting phenotypes in isogenic populations. Although metabolism continuously adapts to unpredictable environmental changes, and although bistability was found in certain substrate-uptake pathways, central carbon metabolism is thought to operate deterministically. Here, we combine experiment and theory to demonstrate that a clonal Escherichia coli population splits into two stochastically generated phenotypic subpopulations after glucose-gluconeogenic substrate shifts. Most cells refrain from growth, entering a dormant persister state that manifests as a lag phase in the population growth curve. The subpopulation-generating mechanism resides at the metabolic core, overarches the metabolic and transcriptional networks, and only allows the growth of cells initially achieving sufficiently high gluconeogenic flux. Thus, central metabolism does not ensure the gluconeogenic growth of individual cells, but uses a population-level adaptation resulting in responsive diversification upon nutrient changes.
Highlights
Since the early studies of bacterial physiology, inoculation of a bacterial population into a new medium has been known to result in a period lacking apparent growth prior to growth on the new carbon source (Monod, 1949)
Metabolism continuously adapts to unpredictable environmental changes, and certain substrateuptake pathways have been found to exhibit phenotypic bistability (Ozbudak et al, 2004; Acar et al, 2005), central carbon metabolism as a whole is thought to operate deterministically
We found that the subpopulation-generating mechanism resides at the core of central metabolism, overarches the metabolic and transcriptional networks, and only allows the growth of cells achieving sufficiently high gluconeogenic metabolic flux
Summary
Since the early studies of bacterial physiology, inoculation of a bacterial population into a new medium has been known to result in a period lacking apparent growth prior to growth on the new carbon source (Monod, 1949). This lag phase is classically attributed to the duration of the requisite biochemical adaptation processes in individual cells, which are thought to switch homogeneously and responsively to the new substrate (Fig 1A and B). The possible emergence of multiple coexisting phenotypes within an isogenic cell population provides an alternative, but untested, hypothesis that the apparent lag time is caused by the exclusive growth of an initially small phenotypic subpopulation (Fig 1C)
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