Microbiome-based therapeutics for Clostridioides difficile infection: additive, subtractive, and modulatory strategies in modern clinical practice.

Microbiome-based therapeutics have rapidly evolved into a transformative field at the intersection of infectious diseases, microbial ecology, and precision medicine. Clostridioides difficile infection (CDI) represents the most extensively studied model, providing a framework for understanding microbiome-driven disease and ecological restoration. This review synthesizes three major therapeutic strategies, additive, subtractive, and modulatory, and integrates recent advances from basic, translational, and clinical research. Additive approaches, including fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and defined microbial consortia, aim to restore microbial diversity and colonization resistance. Subtractive strategies selectively target C. difficile or its ecological advantages through targeted antibiotics, bacteriocins, bacteriophages, and CRISPR-based antimicrobials. Modulatory therapies reshape host-microbe and microbe-microbe interactions, targeting toxin activity, bile acid metabolism, and spore germination. Together, these approaches reflect a paradigm shift from pathogen-centered treatment toward ecological therapeutics targeting the dysbiotic niche underlying CDI persistence and recurrence. Understanding the similarities and differences between these strategies can help guide the design of future microbiome-targeted interventions and explore their potential beyond CDI across microbiome-mediated diseases.