Synthetic Biology Design of Engineered Probiotics for Short-Chain Fatty Acid Production: from Metabolic Enhancement to Smart Regulation

Short-chain fatty acids (SCFAs), as key metabolites produced by the intestinal microbiota from the fermentation of dietary fiber and other substrates, play a crucial role in maintaining intestinal barrier function, regulating immune balance, and promoting systemic health. This review explores strategies for utilizing engineered food microorganisms (particularly probiotics) as novel “bio-factories” to achieve efficient and precise synthesis of SCFAs. This review outlines the core selection criteria for ideal engineered chassis strains, including their safety for application, robustness in the intestinal environment, and genetic tractability. It then details strategies for significantly enhancing the efficiency of SCFA synthesis in food microorganisms such as discovery and engineering of rate-limiting enzymes, intelligent enzyme engineering modifications, and artificial intelligence-driven metabolic network optimization. Furthermore, this review discusses how to integrate biosensors and clustered regularly interspaced short palindromic repeats-based dynamic regulation systems to achieve on-demand and precise modulation of SCFAs within the intestinal microecology. The application prospects of engineered food microorganisms are discussed in two major directions: First, in vitro food industrial biomanufacturing, i.e., utilizing engineered strains to efficiently produce SCFAs in fermentation systems as food ingredients or additives; this pathway exhibits relatively high technical maturity and a relatively clear regulatory framework. Second, in vivo live biotherapeutics, i.e., direct ingestion of engineered probiotics to in situ synthesize SCFAs in the gut. This pathway holds significant potential for personalized nutritional intervention and gut health management, but faces greater challenges in safety assessment and regulation.