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

ABSTRACT 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.