Diverse mechanisms of bioproduction heterogeneity in fermentation and their control strategies

: Microbial bioproduction often faces challenges related to populational heterogeneity, where cells exhibit varying biosynthesis capabilities. Bioproduction heterogeneity can stem from genetic and non-genetic factors, resulting in decreased titer, yield, stability, and reproducibility. Consequently, understanding and controlling bioproduction heterogeneity are crucial for enhancing the economic competitiveness of large-scale biomanufacturing. In this review, we provide a comprehensive overview of current understandings of the various mechanisms underlying bioproduction heterogeneity. Additionally, we examine common strategies for controlling bioproduction heterogeneity based on these mechanisms. By implementing more robust measures to mitigate heterogeneity, we anticipate substantial enhancements in the scalability and stability of bioproduction processes. ONE-SENTENCE SUMMARY: This review summarizes current understandings of different mechanisms of bioproduction heterogeneity and common control strategies based on these mechanisms.