Astragaloside IV Exhibited Antidiabetic Effects by Improving Glucose Metabolism, Repairing Damaged Gut Barrier and Regulating Intestinal Microbiota

ABSTRACT Astragaloside IV (AS‐IV), a main active ingredient derived from Astragali Radix , displays a favorable effect in treating type 2 diabetes mellitus (T2DM). This study was aimed to figure out its antidiabetic mechanisms. The db/db mice were treated with AS‐IV, and the metabolism phenotype and epithelial barrier permeability were tested. Trans‐epithelial resistance assay was performed in Caco‐2 cells. Metagenomic sequencing was used to determine the gut microbiota composition and function. The content of short‐chain fatty acid (SCFA) in feces was determined using Agilent 8890‐5977B GC–MS. Despite increasing mice body weight, AS‐IV significantly reduced hyperglycemia in the db/db mice, decreased the ratio of liver weight/body weight, alleviated hepatic total cholesterol and triglyceride levels. AS‐IV reduced inflammation through suppressing pro‐inflammatory genes ( Il1b, Tnf, Ccl2 ) and elevating anti‐inflammatory genes ( Il10, Il4, Il13, Il33 ) in the colonic epithelium. AS‐IV also reversed the increased intestinal permeability and decreased expression of tight junction (TJ) proteins Claudin‐1, ZO‐1 in the db/db mice and Claudin‐1, Occludin in Caco‐2 cells. Additionally, metagenomic sequencing showed AS‐IV altered composition and function of gut microbiota. The 80 species of gut microbiota were markedly changed, e.g., boosting of Alistipes spp. and Prevotella copri , decreasing of relative abundance of Ruminococcus gnavus and Enterocloster bolteae . AS‐IV upregulated the SCFA related pathway, increased the content of SCFA, upregulated the transcription levels of SCFA receptors (i.e., GPR41, GPR43 and GPR109a), thereby improved glucose metabolism in the db/db mice. These findings demonstrate that AS‐IV exhibited favorable antidiabetic effects by improving glucose metabolism and altering intestinal microbiota symbiosis via repairing the damaged gut barrier. This study will provide valuable reference for the development of new antidiabetic drugs and medication of T2DM.