From Inclusion Complexes to Metabolic Signaling: The Emerging Role of γ-Cyclodextrin in Gut Microbiota and Metabolic Regulation.

γ-Cyclodextrin (γ-CD) is a cyclic oligosaccharide with high aqueous solubility, low toxicity, and a large internal cavity that enables inclusion complex formation with selected bioactive compounds. Beyond its established role as a pharmaceutical and food excipient, emerging evidence suggests that γ-CD may influence metabolic regulation through interactions with the gut microbiota, microbial fermentation products, and host metabolic signaling pathways. This review synthesizes current evidence on the effects of γ-CD on short-chain fatty acid production, lipid homeostasis, glycemic control, and obesity- and type 2 diabetes-related metabolic disturbances. Particular attention is given to the gut-metabolism axis, SCFA-mediated GPCR signaling, microbial taxa potentially involved in γ-CD fermentation, and the relative contribution of prebiotic-like effects versus lipid-binding mechanisms. Available data indicate that γ-CD may modulate microbial composition and metabolic outcomes, but most evidence derives from in vitro experiments, animal models, and limited human studies. Therefore, the clinical relevance of γ-CD remains insufficiently established. Future studies should include well-designed human trials, standardized doses, multi-omics analyses, and direct comparisons between native and modified cyclodextrins to clarify whether γ-CD can be translated into nutritional or therapeutic strategies for metabolic disorders.