Crt-miR166a, a Citrus-Derived MicroRNA, Modulates the Gut Microbiota-Metabolites under High-Fat Diet

High-fat diet (HFD) induces dysregulation of gut microbiota-derived metabolites, including short-chain fatty acids, bile acids, and indole derivatives. Although microRNAs (miRNAs) are known to regulate gut microbiota composition, the effects of plant miRNAs on microbiota-derived metabolite outcomes remain poorly understood. This study aimed to investigate the regulatory effects of crt-miR166a, a citrus-derived miRNAs, on HFD-induced gut microbiota-metabolite dysbiosis. Our results demonstrated that crt-miR166a significantly increased the beneficial bacterial abundance (e.g., Bacteroides and Acetatifactor ) and elevated the levels of acetic acid, butyric acid, and valeric acid in HFD-fed mice. Additionally, crt-miR166a markedly reduced the cholic acid (CA) content while increasing the levels of primary (except CA) and secondary bile acids. Furthermore, crt-miR166a promoted the production of tryptophan-derived indole derivatives, especially indole-3-aldehyde, indole-3-propionic acid, and indole-3-acetamide. Collectively, these findings suggest that crt-miR166a alleviates HFD-induced dysbiosis of gut microbiota metabolites, providing novel insights into the potential of plant-derived miRNAs as dietary modulators to improve host metabolic health.