Effects of Guanxinning tablet on the gut microbiota and bile acid metabolism in mice with hyperlipidemia.

INTRODUCTION: Guanxinning tablet (GXNT), a traditional Chinese medicine preparation, has been found to improve lipid metabolism in patients with cardiovascular disease. However, the underlying mechanisms are still poorly understood. This study aims to determine whether the gut microbiota and bile acid (BA) metabolism is involved in the mechanisms by which GXNT ameliorates hyperlipidemia. METHODS: The chemical composition of GXNT was characterized using UPLC-Q-TOF/MS. A mouse model of hyperlipidemia was established by feeding an high-fat diet (HFD), and GXNT or simvastatin was administered by gavage for 6 weeks. The impact of GXNT on hyperlipidemia was assessed by measuring markers related to lipid metabolism, liver injury and inflammation. Furthermore, 16S rDNA sequencing, targeted metabolomics, immunohistochemistry, molecular docking and western blot were used to investigate the underlying mechanisms. RESULTS: GXNT treatment reduced blood lipid levels, improved liver injury, and mitigated hepatic inflammation in HFD-fed mice. GXNT also ameliorated the dysfunction of the intestinal barrier by upregulating the expression of zonula occludens-1 (ZO-1), occludin and claudin-1. Importantly, GXNT remodeled the gut microbiota in mice with hyperlipidemia, which was manifested by an increase in the abundance of Bacteroidota and Rikenellaceae_RC9_gut_group, as well as a decrease in the abundance of Desulfovibrio, Monoglobus, and Streptococcus. In addition, GXNT intervention altered the composition of fecal BAs and regulated BA metabolism by mediating the hepatic farnesoid X receptor (FXR)/small heterodimer partner (SHP) and intestinal FXR/fibroblast growth factor 15 (FGF15) axis. CONCLUSION: GXNT improved hyperlipidemia by altering the gut microbiota and regulating BA metabolism in HFD-fed mice. Our results provide a theoretical basis for the application of GXNT.