Population heterogeneity in microbial bioprocesses: origin, analysis, mechanisms, and future perspectives.

Population heterogeneity is omnipresent in all bioprocesses even in homogenous environments. Its origin, however, is only so well understood that potential strategies like bet-hedging, noise in gene expression and division of labour that lead to population heterogeneity can be derived from experimental studies simulating the dynamics in industrial scale bioprocesses. This review aims at summarizing the current state of the different parts of single cell studies in bioprocesses. This includes setups to visualize different phenotypes of single cells, computational approaches connecting single cell physiology with environmental influence and special cultivation setups like scale-down reactors that have been proven to be useful to simulate large-scale conditions. A step in between investigation of populations and single cells is studying subpopulations with distinct properties that differ from the rest of the population with sub-omics methods which are also presented here. Moreover, the current knowledge about population heterogeneity in bioprocesses is summarized for relevant industrial production hosts and mixed cultures, as they provide the unique opportunity to distribute metabolic burden and optimize production processes in a way that is impossible in traditional monocultures. In the end, approaches to explain the underlying mechanism of population heterogeneity and the evidences found to support each hypothesis are presented. For instance, population heterogeneity serving as a bet-hedging strategy that is used as coordinated action against bioprocess-related stresses while at the same time spreading the risk between individual cells as it ensures the survival of least a part of the population in any environment the cells encounter.