csi-miR166e, A Microribonucleic Acid of Considerable Abundance in Plant Food, Ameliorates High-Fat Diet/Streptozotocin-Induced Type 2 Diabetes in Mice via Oral Administration

Diet regimes rich in fruits and vegetables have been adopted as effective strategies for the management of type 2 diabetes mellitus (T2DM). Here, we identified miR166e, a plant miRNA abundantly present in fruits and vegetables, as a functional agent that ameliorates T2DM in a mouse model. Orally administered miR166e oligomers passed through digestion, accumulated in the intestines at 14.1 ± 6.1 fM, and significantly improved glycemic parameters, including fasting blood glucose, HbA1c, and insulin resistance. Mechanistically, miR166e ameliorated liver dyslipidemia, maintained intestinal barrier integrity, suppressed systemic oxidative stress and inflammation, and restored gut microbiota composition by promoting the abundance of probiotics such as Muribaculaceae, Akkermansia, and Bifidobacterium. The coculturing assays showed that miR166e entered the bacterial cells, with the potential to target bacterial genes in a sequence-dependent manner. This study provided a new perspective on the inverse relationship between T2DM and plant food, suggesting the potential of miRNA-based strategies for T2DM management.