Shifting from Systemic Absorption to Local Interactions: The Bidirectional Role of Gut Microbiota in Curcumin’s Health Benefits

Curcumin, a natural polyphenol, has garnered considerable attention owing to the paradox between its low oral bioavailability and reported pharmacological effects. Traditional paradigms centered on systemic absorption and plasma exposure may not fully explain its broad actions in inflammation, metabolic disorders, and multi-organ diseases. Emerging evidence highlights the gastrointestinal tract as a crucial interface for local exposure, microbiota interactions, and host responses. Curcumin-related interventions are associated with context-dependent changes in gut microbial ecology and metabolism, including changes in short-chain fatty acids and bile acids. Reciprocally, the gut microbiota modulates curcumin’s molecular forms, local stability, and effective exposure through biotransformations. These reciprocal interactions may contribute to intestinal barrier protection, endotoxin-related and immune regulation, microbial metabolite signaling, and gut–organ communication. However, current evidence is dominated by preclinical and correlational studies, whereas human findings remain limited, heterogeneous, and formulation-specific. Delivery research is shifting from increasing systemic bioavailability to optimizing local gut interactions through site-specific and responsive release. Yet carrier materials and excipients may themselves affect the microbiota, requiring appropriate formulation controls. Future studies should integrate compartment-resolved pharmacokinetics, longitudinal microbiome and metabolome profiling, causal validation, and adequately powered clinical trials to support formulation-specific, microbiome-informed translation.