Harnessing microbial division of labor for biomanufacturing: a review of laboratory and formal modeling approaches

Bioprocess industries aim to meet the increasing demand for product complexity by designing enhanced cellular and metabolic capabilities for the host. Monocultures, standard biomanufacturing workhorses, are often restricted in their capability to meet these demands, and the solution often involves the genetic modification of the host. Synthetic microbial communities are a promising alternative to monocultures because they exhibit division of labor, enabling efficient resource utilization and pathway modularity. This specialization minimizes metabolic burden and enhances robustness to perturbations, providing a competitive advantage. Despite this potential, their utilization in biotechnological or bioprocessing applications remains limited. The recent emergence of new and innovative community design tools and strategies, particularly those harnessing the division of labor, holds promise to change this outlook. Understanding the microbial interactions governing natural microbial communities can be used to identify complementary partners, informing synthetic community design. Therefore, we particularly consider engineering division of labor in synthetic microbial communities as a viable solution to accelerate progress in the field. This review presents the current understanding of how microbial interactions enable division of labor and how this information can be used to design synthetic microbial communities to perform tasks otherwise unfeasible to individual organisms. We then evaluate laboratory and formal modeling approaches specifically developed to: elucidate microbial community physiology, guide experimental design, and improve our understanding of complex community interactions assisting synthetic community design. By synthesizing these insights, we aim to present a comprehensive framework that advances the use of microbial communities in biomanufacturing applications.