Insights into microbiome-based therapeutics: Engineered probiotics, bacteriophages, and microbiome-derived metabolites

The human microbiome is increasingly recognized as a key regulator of immunity, metabolism, and disease progression; however, conventional interventions such as probiotics, prebiotics, and fecal microbiota transplantation remain limited by their precision and yield inconsistent outcomes. Recent advances in biotechnology have catalyzed the development of engineered probiotics, bacteriophage therapy, and microbiome-derived metabolites as next-generation therapeutics. Engineered probiotics can now be reprogrammed via synthetic biology to sense disease states, secrete therapeutic molecules, and modulate host responses. Bacteriophages, including engineered variants, provide highly selective antibacterial activity and may help address antimicrobial resistance. Microbial metabolites—including short-chain fatty acids and bile-acid derivatives—function as systemic modulators and constitute emerging drug candidates. This review critically examines these three modalities, emphasizing both their individual advances and their potential for synergistic integration into multimodal, precision-tailored therapies. We further highlight translational challenges, including biosafety concerns, inter-individual microbiome variability, manufacturing scalability, and unresolved regulatory issues, and outline future directions that could transform the microbiome from a disease biomarker into a therapeutic frontier for precision medicine.