PMID- 36870307 OWN - NLM STAT- MEDLINE DCOM- 20230327 LR - 20230327 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 113 DP - 2023 May TI - Jiang-Tang-San-Huang pill alleviates type 2 diabetes mellitus through modulating the gut microbiota and bile acids metabolism. PG - 154733 LID - S0944-7113(23)00091-0 [pii] LID - 10.1016/j.phymed.2023.154733 [doi] AB - BACKGROUND: 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. PURPOSE: To elucidate the underlying mechanisms of JTSH for treating T2DM with animal models. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CI - Copyright (c) 2023 Elsevier GmbH. All rights reserved. FAU - Tawulie, Dina AU - Tawulie D AD - The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. FAU - Jin, Lulu AU - Jin L AD - Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Shang, Xin AU - Shang X AD - The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. FAU - Li, Yimei AU - Li Y AD - The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. FAU - Sun, Le AU - Sun L AD - The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. FAU - Xie, Haixue AU - Xie H AD - Yunnan Provincial Hospital of Chinese Medicine, Kunming 650021, China. FAU - Zhao, Jie AU - Zhao J AD - Yunnan Provincial Hospital of Chinese Medicine, Kunming 650021, China. FAU - Liao, Jiabao AU - Liao J AD - Department of Emergency, Jiaxing Hospital of Traditional Chinese Medicine, Hangzhou 310003, China; Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314033, China. FAU - Zhu, Zhangzhi AU - Zhu Z AD - The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. Electronic address: zhuangi@vip.sina.com. FAU - Cui, Huantian AU - Cui H AD - Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China. Electronic address: 1762316411@qq.com. FAU - Wen, Weibo AU - Wen W AD - Yunnan Provincial Hospital of Chinese Medicine, Kunming 650021, China. Electronic address: wenweibo2020@163.com. LA - eng PT - Journal Article DEP - 20230226 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (San-Huang) RN - 0 (RNA, Ribosomal, 16S) RN - 0 (Bile Acids and Salts) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Rats MH - Male MH - Animals MH - *Gastrointestinal Microbiome MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Chromatography, Liquid MH - RNA, Ribosomal, 16S MH - Bile Acids and Salts/metabolism MH - Rats, Sprague-Dawley MH - Tandem Mass Spectrometry MH - Liver/metabolism MH - Cytochrome P-450 Enzyme System/metabolism MH - Glucagon-Like Peptide 1/metabolism OTO - NOTNLM OT - Bile acids metabolism OT - FXR/FGF15 signaling OT - Gut microbiota OT - Jiang-Tang-San-Huang pill OT - TGR5/GLP-1 signaling OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The authors declare no conflict of interest. EDAT- 2023/03/05 06:00 MHDA- 2023/03/28 06:00 CRDT- 2023/03/04 18:19 PHST- 2022/07/12 00:00 [received] PHST- 2023/02/18 00:00 [revised] PHST- 2023/02/22 00:00 [accepted] PHST- 2023/03/05 06:00 [pubmed] PHST- 2023/03/28 06:00 [medline] PHST- 2023/03/04 18:19 [entrez] AID - S0944-7113(23)00091-0 [pii] AID - 10.1016/j.phymed.2023.154733 [doi] PST - ppublish SO - Phytomedicine. 2023 May;113:154733. doi: 10.1016/j.phymed.2023.154733. Epub 2023 Feb 26.