Hypoglycemic Effect of Nobiletin via Gut Microbiota‐Metabolism Axis on Hyperglycemic Mice

Prediabetes and diabetes are major public health problems worldwide without specific cure currently. Gut microbes have been recognized as one of the vital therapeutic targets for diabetes. The exploration that nobiletin (NOB) whether affects gut microbes provides a scientific basis for its application.A hyperglycemia animal model is established using high-fat-fed ApoE-/- mice. After 24 weeks of NOB intervention, the level of fasting blood glucose (FBG), glucose tolerance, insulin resistance, and glycosylated serum protein (GSP) are measured. Pancreas integrity is observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. 16s RNA sequencing and untargeted metabolomics are to determine the changes of intestinal microbial composition and metabolic pathways. The levels of FBG and GSP in hyperglycemic mice are effectively reduced. The secretory function of pancreas is improved. Meanwhile, NOB treatment restored the gut microbial composition and affected metabolic function. Furthermore, NOB treatment regulates the metabolic disorder mainly through lipid metabolism, amino acid metabolism, and Secondary bile acid metabolism, etc. In addition, it is possibly existed mutual promotion between microbe and metabolites.NOB probably plays a vital role in the hypoglycemic effect and pancreatic islets protection by improving microbiota composition and gut metabolism.