Dihydromyricetin Promotes Glucagon‐Like Peptide‐1 Secretion and Improves Insulin Resistance by Modulation of the Gut Microbiota‐CDCA Pathway

Insulin resistance is a common metabolic disease, and its pathogenesis is still unclear. The decrease of glucagon-like peptide-1 (GLP-1) level mediated by the alteration of gut microbiota may be the pathogenesis. The study was to investigate the regulatory effect of dihydromyricetin (DHM) on GLP-1 level and insulin resistance induced by high-fat diet (HFD), and to further explore its possible molecular mechanism. Mice were fed an HFD to establish the model of insulin resistance to determine whether DHM had a protective effect. DHM could improve insulin resistance. DHM increased serum GLP-1 by improving intestinal GLP-1 secretion and inhibiting GLP-1 decomposition, associated with the alteration of intestinal intraepithelial lymphocytes (IELs) proportions and decreased expression of CD26 in IELs and TCRαβ⁺ CD8αβ⁺ IELs in HFD-induced mice. DHM could ameliorate GLP-1 level and insulin resistance by modulation of gut microbiota and the metabolites, particularly the regulation of chenodeoxycholic acid (CDCA) content, followed by the inhibition of farnesoid X receptor (FXR) expression in intestinal L cells and increased glucagon gene (Gcg) mRNA expression and GLP-1 secretion. This research demonstrates the role of "gut microbiota-CDCA" pathway in the improvement of intestinal GLP-1 levels in HFD-induced mice by DHM administration, providing a new target for the prevention of insulin resistance.