Fecal Microbiota Transplantation Beyond Clostridioides difficile Infection: Expanding Indications, Mechanisms, and Future Directions

Fecal microbiota transplantation (FMT) has emerged as a transformative therapeutic approach to restore gut microbial homeostasis. The most established indication is recurrent Clostridioides difficile infection (CDI), demonstrating that restoring ecosystem-level microbiota has substantial clinical benefits. Building on this success, FMT is now being investigated across a broader range of indications associated with gut dysbiosis and altered microbiome-host signaling, including inflammatory bowel disease, irritable bowel syndrome, metabolic, and neurological disorders. Mechanistic insights into the gut-organ axes provide biological plausibility for this expansion; gut dysbiosis can function as a modifiable upstream driver of host metabolism, immune-neural signaling, and barrier function. However, the clinical benefits beyond CDI remain heterogeneous and often modest, highlighting the need for further research on patient stratification, standardized protocols, and mechanistic biomarkers. Furthermore, regulatory frameworks remain heterogeneous worldwide, and recent approvals of standardized microbiota-based products for recurrent CDI represent a transition toward treating microbiome therapeutics as regulated biologics. This review synthesizes the mechanistic rationale and current evidence for FMT beyond CDI and outlines future directions for personalized and next-generation microbiome therapeutics.