Introduction

Low-carbon and sustainable manufacturing has become the topical subject of global economic development and environmentally friendly microbial manufacturing has developed rapidly in the fields of food, medicine and energy, which bring huge economic effects and social value to the world (Bi et al. 2021; Hu et al. 2021; Shi et al. 2022).

Recent advances have been made in many commercial cases of microbial manufacturing using high-performance strains in artemisinin (Kung et al. 2018), farnesene (Liu et al. 2022), 1,3-propanediol (Zhu et al. 2021), succinic acid (Ahn et al. 2016) and other products. During the common process optimization, traditional methods and experimental design such as single factor experiment, orthogonal experiment, Plackett–Burman and Box–Behnken designs are extensively used to optimize the medium components and environmental factors directly. However, the intrinsic connection of cell metabolism and culture condition is not clear, and the optimization methods are often “black box” and time-consuming.

With the rapid development of omics technologies, the process optimization of microbial manufacturing also can be guided by omics, including genomics, transcriptomics, proteomics, metabolomics and the metabolic network model constructed on this basis. These technologies allow the overall analysis of transcription, translation and metabolism from the molecular level (Xu et al. 2018; Amer and Baidoo 2021).Through the omics analysis of different microbial phenotypes, we can truly gain insight into the changes of overall metabolism caused by the microenvironment changes, which help us explore the macro factors that affect the performance of microbial manufacturing from multiscale of molecular-cell–microenvironment and facilitate the realization of accurate and rapid optimization (Fig. 1).

Fig. 1
figure 1

Comparison of microbial manufacturing process optimization using traditional methods and omics technologies

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In this paper, we have summarized the current strategies and successful cases of microbial manufacturing process optimization based on the long used experimental design and that guided by omics technologies, and then looked forward to the future trend of process optimization with greater productivity and lower cost.

The development of microbial manufacturing

At present, many pharmaceutical intermediates, food additives and natural products are mainly produced by animal and plant extracts or chemical synthesis. The unsustainable production processes bring a lot of problems, such as waste of natural resources and serious environmental pollution (Sun et al. 2022; Ko et al. 2020). With the strengthening of human awareness of environmental protection, green and sustainable microbial manufacturing using microbial cell factories as production units and renewable resources as raw materials has been widely studied in the production of various kinds of natural and bulk chemicals (Zhu et al. 2020).

Actually, human beings have a long history of using microorganisms for daily life and production since 9000 years ago (Mcgovern et al. 2004). With the birth of modern microbiology and the maturity of fermentation technology, microbial manufacturing appeared at the beginning of the twentieth century. Due to research on glycolysis intermediates and the demand for explosives with the outbreak of World War I, the use of microorganisms to produce various organic acids, short-chain alcohols and ketones were developed. From 1920 to 1940, the discovery of penicillin and the great demand for antibiotics during the outbreak of World War II opened a new chapter in the history of microbial manufacturing with fast development in all aspects. Then, in 1980s, genetic engineering started to be used for modifying microorganisms at the genetic level to achieve the desired phenotypes, such as producing a variety of heterologous proteins, drugs and industrial enzymes. In the twenty-first century, the rapid development of synthetic biology facilitates the use of microbial cell factories to produce biofuels and chemicals and causes a new round of scientific and technological revolution in the world for green and sustainable development. Up to now, microbial cell factories have been used to produce various compounds including fuels, bulk chemicals, enzymes and natural products (Fig. 2) (Amer and Baidoo 2021; Buchholz and Collins 2013; Zhang et al. 2017, 2022a; Srinivasan and Smolke 2020).

Fig. 2
figure 2

Main development history of microbial manufacturing

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Although microbial manufacturing can bring great social and economic benefits, but the output of many microbial products is still too low to meet the need of commercial production. Thus, the performance of microbial manufacturing needs to be improved and process optimization is a key factor, by which the optimization and scale-up of fermentation processes could improve the performance of high-performance strains with better productivity and lower cost (Son et al. 2023).

Synthetic biology for high-performance strains

High-performance strain is the core of microbial manufacturing, and synthetic biology is an important tool for building high-performance strains. Although different cells, such as Actinomycetes, Bacillus subtilis, Saccharomyces cerevisiae, cyanobacteria and microalgae could be selected for microbial manufacturing, the synthetic biology strategies generally focus on the rational design of biosynthetic pathways for products, the construction and optimization of biosynthetic pathways, and the heterogenic expression of biosynthetic pathways. These strategies can be summarized as follows: new enzymes mining and synthesis pathways design, precursors enhancement and cofactors regeneration, protein engineering, weakening competitive pathways, balancing cell growth and production, and transport engineering to reduce the feedback inhibition and product cytotoxicity (Zhu et al. 2020; Bu et al. 2020; Gao et al. 2016).

Since the metabolic situation in cells under different fermentation scales will change drastically due to the changes in the microenvironment. Thus, the comparative omics analysis of different fermentation scales could help understand the relationship between the microenvironment and internal metabolism of cells in the fermenter during the scale-up of fermentation process and explore the metabolic bottlenecks that affecting cell growth and product synthesis due to microenvironment changes, so as to achieve a reasonable scale-up of fermentation (Zou et al. 2020). Tang et al. designed a metabolic model by coupling computational fluid dynamics with cell reaction dynamics to simulate the fermentation performance of Penicillium chrysogenum at different fermentation scales, and provided a rational strategy for the scale-up fermentation (Tang et al. 2017).

The oxygen uptake rate is an important parameter in the scale-up of fermentation process. Gao et al. studied the significant difference of Chinese hamster ovary (CHO) cells productivity between a 20-L bench-top scale bioreactor and a 5-KL production scale under seemingly identical process parameters. The integrated metabolomics and proteomics data revealed that the excess ROS produced in the 5-kL compared to the 20-L scale due to intermittent hypoxia in the industrial scale, which may lead to CHO cells apoptosis and affect productivity (Gao et al. 2016). Thus, it is necessary to ensure a sufficient supply of oxygen when scale-up of fermentation to improve the microbial manufacturing performance. Zou et al. simulated the oxygen uptake and oxygen transfer effects on the erythromycin production under the fermentation scales of 50 L and 132 m3 by computational fluid dynamics and found that a relatively high oxygen uptake rate (OUR) in the early phase of fermentation favored the biosynthesis of erythromycin, and the decrease of oxygen transfer rate (OTR) in 132 m3 fermenter was the main reason affecting the physiological metabolism of cells and biosynthesis of erythromycin (Zou et al. 2012). By optimizing oxygen uptake and oxygen transfer rate, the fermentation process could be scaled up effectively.

Conclusions and prospects

As the world pays more and more attention to environmental protection and greenness development, microbial manufacturing plays an increasingly important role in human life and production for the advantages of environmental protection and sustainable production. However, the lack of ideal fermentation process remains a major obstacle to reducing cost and boosting the capacity of microbial manufacturing for the eventual commercial production.

The traditional experience-based process optimization often is "black box" and time-consuming. With the rapid development of omics technologies, the use of multi-omics technologies to analyze the fermentation processes from different levels, including transcription, protein and metabolism, is helpful to understand the response relationship between the internal metabolism of microorganisms and the extracellular microenvironment during the fermentation processes, which provides clear direction for microbial manufacturing optimization. However, the metabolic bottleneck gained by diving into different levels of omics data in process optimization is still at its nascent stage, and the omics analysis will bring massive amounts of data, including the uptake and utilization of nutrients, cell growth, synthesis of product, efflux of product and so on. Hence, how to quickly and accurately capture the metabolic bottleneck from the sea of data by machine learning would be an important direction for future research in the process optimization of microbial manufacturing.

In addition, in terms of optimizing microbial manufacturing process to improve the yield and reduce cost, the selection and design of fermentation reactors, pretreatment of substrates, wastewater treatment, and downstream separation and purification should also be considered, so that the performance of microbial manufacturing can be fully improved and benefit human beings.