Jiang-Tang-San-Huang pill alleviates type 2 diabetes mellitus through modulating the gut microbiota and bile acids metabolism

Jiang-Tang-San-Huang (JTSH) pill, a traditional Chinese medicine (TCM) prescription, has long been applied to clinically treat type 2 diabetes mellitus (T2DM), while the underlying antidiabetic mechanism remains unclarified. Currently, it is believed that the interaction between intestinal microbiota and bile acids (BAs) metabolism mediates host metabolism and promotes T2DM.To elucidate the underlying mechanisms of JTSH for treating T2DM with animal models.In this study, male SD rats received high-fat diet (HFD) and streptozotocin (STZ) injection to induce T2DM and were treated with different dosages (0.27, 0.54 and 1.08 g/kg) of JTSH pill for 4 weeks; metformin was given as a positive control. Alterations of gut microbiota and BA profiles in the distal ileum were assessed by 16S ribosomal RNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Additionally, we conducted quantitative Real Time-PCR and western blotting to determine the mRNA and protein expression levels of intestinal farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), Takeda G-protein-coupled receptor 5 (TGR5) and glucagon-like peptide 1 (GLP-1) as well as hepatic cytochrome P450, family 7, subfamily a, poly-peptide 1 (CYP7A1) and cytochrome P450, family 8, subfamily b, poly-peptide 1 (CYP8B1), which are involved in BAs metabolism and enterohepatic circulation.Here, the results revealed that JTSH treatment significantly ameliorated hyperglycaemia, insulin resistance (IR), hyperlipidaemia, and pathological changes in the pancreas, liver, kidney and intestine and reduced the serum levels of pro-inflammatory cytokines in T2DM model rats. 16S rRNA sequencing and UPLC-MS/MS showed that JTSH treatment could modulate gut microbiota dysbiosis by preferentially increasing bacteria (e.g., Bacteroides, Lactobacillus, Bifidobacterium) with bile-salt hydrolase (BSH) activity, which might in turn lead to the accumulation of ileal unconjugated BAs (e.g., CDCA, DCA) and further upregulate the intestinal FXR/FGF15 and TGR5/GLP-1 signaling pathways.The study demonstrated that JTSH treatment could alleviate T2DM by modulating the interaction between gut microbiota and BAs metabolism. These findings suggest that JTSH pill may serve as a promising oral therapeutic agent for T2DM.