Probiotics: From natural to artificial

Probiotics are live microorganisms that confer significant health benefits by maintaining gut homeostasis, regulating immune function, and producing beneficial metabolites including short-chain fatty acids (SCFAs), bioactive peptides, and extracellular polysaccharides (EPSs). Most naturally isolated probiotics are severely limited by poor functional specificity, insufficient stress tolerance, and suboptimal performance. Driven by advances in multi-omics, mutagenesis breeding, and synthetic biology, the field has shifted from conventional natural screening to rational design and construction of artificial probiotics. This review systematically summarizes core technologies for developing high-performance artificial probiotics, including artificial intelligence (AI), high-throughput screening (HTS), directed evolution, genetic engineering, as well as scarless gene editing and in situ engineering. Applications of artificial probiotics span gut-organ axis regulation, medicinal-edible homologous (MEH) fermentation, targeted disease treatment, drug delivery, and environmental bioremediation. We also discuss major challenges concerning biosafety assessment, regulatory policies, in vivo adaptability, and dosage regulation. Finally, we highlight future directions toward personalized probiotics, aiming to provide a theoretical roadmap for research, clinical translation, and industrial application of next-generation artificial probiotics.