Phenotypic bistability in Escherichia coli 's central carbon metabolism

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. image Upon nutrient change, a homogeneous E. coli  population can split into a growing and a non‐growing persister phenotype. Stochastic variation in metabolic flux is responsible for this responsive diversification. Responsive diversification offers an explanation for lag phases in bacterial cultures Flux‐induced phenotypic bistability generalizes to central metabolism Conditional bet‐hedging balances fast glycolytic growth and ability for gluconeogenic growth Limited carbon influx is a major trigger for persistence