Harnessing Lactobacillus-derived SCFAs for food and health: Pathways, genes, and functional implications

Short-chain fatty acids (SCFAs) are crucial microbial metabolites that mediate host-microbiota interactions, regulate immune responses, and maintain gut homeostasis. While most studies focus on SCFA production by obligate anaerobes, recent evidence highlights Lactobacillus spp. as potential SCFA-producing microorganisms that remain understudied in terms of SCFA-based health and food-related effects. This research review compiles what is currently known about species- and strain-specific biosynthetic capabilities of Lactobacillus for SCFA production, particularly acetate, and lactate, which, while produced by Lactobacillus, is not classified as a SCFA but plays similar metabolic roles (e.g., activation of G-protein-coupled receptors, inhibition of histone deacetylases, and immune cell metabolism). We additionally assess new synthetic biology and metabolic engineering approaches to improving SCFA yield in Lactobacillus, including gene circuit design, CRISPR editing, and co-culture optimization. Importantly, we discuss translational opportunities not only in inflammatory, metabolic, and neuroimmune diseases but also in the development of functional foods, synbiotics, and nutraceutical applications. Finally, we highlight key challenges-strain variability, delivery strategies, and regulatory oversight-that preclude both clinical and food system translation. By integrating perspectives from microbiology, immunology, food science, and bioengineering, this review provides a broad framework for the rational design of SCFA-producing Lactobacillus strains as next-generation probiotics and food-grade biotherapeutics.