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

Background: Pre-diabetes 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 recently. As a promising hypoglycemic alternative drug, Nobiletin whether affect gut microbes will provide a scientific basis for its application. Methods: A hyperglycemia animal model was established using high-fat-fed ApoE-/- mice. After 24 weeks of Nobiletin intervention, the level of fasting blood glucose, glucose tolerance, insulin resistance, and glycosylated serum protein were measured; pancreas integrity was observed by HE staining and transmission electron microscopy. 16s RNA sequencing and untargeted metabolomics were to determine the changes of intestinal microbial composition and metabolic pathways. Findings: The levels of fasting blood glucose and glycosylated serum protein in hyperglycemic mice were effectively reduced after NOB treatment. The secretory function of pancreas was improved. Meanwhile, NOB treatment restored the intestinal flora composition and affected metabolic function. Furthermore, NOB treatment regulated the metabolic disorder mainly through lipid metabolism, amino acid metabolism, Secondary bile acid metabolism and bile secretion, etc. In addition, the mutual promotion between microbe and metabolites further promoted the improvement of micro-ecological function. Interpretation: NOB probably played a vital role in the hypoglycemic effect and pancreatic islets protection by improving microbiota composition and gut metabolism. Funding: This study was supported by National Natural Science Foundation of China [81973013]; Guangdong Key R&D Program [2019B020210002]; Guangdong Basic and Applied Basic Research Foundation [2018030310301, 2020A1515010594]; and Regular Institutions of Higher Learning Characteristic Innovation Projects of Guangdong Province [2018KTSCX030]. The funding mentioned above sponsored the research reagents and consumables, mice and feeding laboratory, and sequencing analysis. Declaration of Interest: The authors declare no conflict of financial interest Ethical Approval: The animal experimental protocol was inspected and supported by Southern Medical University ethics committee and Guangdong Medical Laboratory Animal Center (C202011-1).