Research review paperButyric acid: Applications and recent advances in its bioproduction
Introduction
Butyric acid (CH3CH2CH2COOH) is a short-chain volatile fatty acid naturally produced by anaerobic bacteria with important applications in chemical, food, pharmaceutical, and animal feed industries (Brändle et al., 2016; Dwidar et al., 2012; Yang et al., 2013). Current industrial butyric acid production is exclusively via chemical synthesis, with a worldwide market of approximately 80,000 metric tons per year at a price of ~$1.8/kg (Wang et al., 2016a). However, bioproduction of butyric acid from renewable biomass is an inevitable trend as demand from food and pharmaceutical manufacturers, who generally prefer biologically produced products, increases. For economic production of bio-based butyric acid in fermentation, research efforts have focused on strain development using metabolic engineering and process development using low-cost biomass feedstocks (Dwidar et al., 2012; Jha et al., 2014; Luo et al., 2018; Zhang et al., 2009b; Zigova and Sturdik, 2000).
In this review paper, industrial applications of butyric acid and its current and future production status are introduced first, followed by a review on current challenges and recent advances in bioproduction of butyric acid, focusing on technical issues and approaches related to improvements in bioprocess efficiency and economics. This review highlights the metabolic regulation and its effect on butyric acid biosynthesis, and the genome editing and adaptive evolutionary engineering strategies applied to the development of a robust butyrate-producing strain. The information discussed in this review should provide a deeper understanding of clostridial fermentation and its intrinsic weakness, and inspire future synthetic biology strategy. Furthermore, techniques to improve process efficiency and achieve economical bio-based butyric acid production are discussed, namely low-cost biomass feedstocks with relevant pretreatments, novel bioreactors, and fermentation integrated with in situ product recovery. We hope this review will facilitate the development and expansion of engineered strains and integrated bioprocesses for large-scale production of bio-based butyrate for industrial applications in the near future.
Section snippets
Applications of butyric acid
Butyric acid, an important C4 chemical, and its derivatives have many applications in chemical, food, pharmaceutical, perfume, and animal feed industries (Brändle et al., 2016; Dwidar et al., 2012) (Fig. 1). Although butyric acid itself has an unpleasant odor, it is widely used as a pure acid to intensify butter-like notes in food flavors (Armstrong and Yamazaki, 1986). Esters of butyric acid, such as methyl, ethyl, and amyl butyrate, are used as additives to enhance fruit fragrance and as
Current industrial production and future needs
Current industrial production of butyric acid is almost exclusively by chemical synthesis using petrochemical feedstocks, with the “Oxo” process being predominant (Billig and Bryant, 1991). Chemical synthesis from a propylene feedstock is utilized due to availability, low cost, and historical connections to the petrochemical industry. For example, one mainstream commercial butyric acid production process involves the hydroformylation of propylene derived from crude oil, with the addition of
Butyric acid producing bacteria
Many microorganisms, mainly in the genera of Clostridium, Butyrivibrio, and Butyribacterium, can produce butyric acid as the major fermentation product (Zhang et al., 2009b; Zigova and Sturdik, 2000). Some species in the genera of Coprococcus, Eubacterium, Fusobacterium, Megasphaera, Roseburia, and Sarcina can also produce butyric acid (Duncan et al., 2002). Among them, the genus Clostridium, which are anaerobic, Gram-positive and spore-forming bacteria, can produce butyric acid with a high
Strain engineering for butyric acid production
The main challenges associated with the bioproduction of butyric acid are low product yield and low productivity, respectively arising due to the co-production of acetic acid and CO2 in fermentation and butyric acid toxicity to cells, which also limits the achievable butyric acid titer. Therefore, development of a robust strain with significantly improved butyric acid yield and tolerance is prerequisite for butyric acid production to be economically competitive with chemical synthesis routes (
Fermentation process development
Conventional butyric acid production by batch fermentation suffers from low final product concentration, yield and productivity. The low product concentration also results in uneconomical downstream processing due to difficult product recovery and costly purification (Yang et al., 2013). Consequently, many studies have aimed to increase cell density, final product concentration, product yield and overall reactor productivity using different process operating modes, immobilized cell bioreactors,
Conclusions and future perspectives
Recent advances in cell and process engineering have made fermentation an attractive route for butyric acid production from renewable, low-cost biomass feedstocks. Compared to other carboxylic acids, such as acetic, propionic, lactic and citric acids, currently produced by fermentation, butyric acid fermentation needs further improvements in final product titer, productivity, and yield, which have been accomplished primarily by cell engineering through metabolic and evolutionary engineering and
Acknowledgments
This work was supported in part by the Department of Energy (DE-EE0007005), Advanced Research Projects Agency–Energy (DE-AR0000095), the National Science Foundation STTR program (IIP-1026648), the Ohio Department of Development-Third Frontier Advanced Energy Program (Tech 08-036), the National Science Foundation of China (21676098, U1603112), and the Natural Science Foundation of Jiangsu Province (BK20171461).
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