Mixed carbon substrates: a necessary nuisance or a missed opportunity?

Although fermentation with single carbon sources is the preferred mode of operation in current industrial biotechnology, the use of multiple substrates has been continuously investigated throughout the years. Generally, microbial metabolism varies significantly when cells are presented with mixed carbon substrates compared to a single carbon-energy source, as different nutrients interact in complex ways within the metabolic network. By exploiting these distinct modes of interaction, researchers have identified unique opportunities to optimize metabolism using mixed carbon sources. Here we review situations where process yield and productivity are markedly improved through the judicious introduction of substrate mixtures. Our goal is to illustrate that with proper design of the choice of substrates and the way they are introduced to cultures, metabolic optimization with mixed substrates can be a unique strategy that complements genetic engineering techniques to enhance cell performance beyond what is accomplished in single substrate fermentations.