2. Academic Validation
  3. Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway

Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway

  • J Ethnopharmacol. 2025 Jan 30;337(Pt 2):118910. doi: 10.1016/j.jep.2024.118910.
Xiaoyan Cui 1,  Ronghua Zhang 1,  Yufeng Li 2,  Ping Li 3,  Yankun Liu 2,  Xiaohan Yu 3,  Jing Zhou 1,  Luyao Wang 1,  Xuetao Tian 3,  Hongjie Li 1,  Shukun Zhang 4,  Tao Lan 5,  Xin Li 5,  Guangling Zhang 6,  Jingwu Li 7,  Zhiyong Liu 8
Affiliations

Affiliations

  • 1 Hebei Provincial Key Laboratory for Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
  • 2 The Cancer Institute, Hebei Key Laboratory of Molecular Oncology, Tangshan People's Hospital, Tangshan, 063001, China.
  • 3 Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, School of Clinical Medicine, North China University of Science and Technology, Tangshan, 063000, China.
  • 4 Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China.
  • 5 Hepatobiliary Pancreatic Surgery Department, Cangzhou People's Hospital, Cangzhou, 061000, China.
  • 6 Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, School of Clinical Medicine, North China University of Science and Technology, Tangshan, 063000, China. Electronic address: zhanggl@ncst.edu.cn.
  • 7 The Cancer Institute, Hebei Key Laboratory of Molecular Oncology, Tangshan People's Hospital, Tangshan, 063001, China. Electronic address: tslijingwu@163.com.
  • 8 Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, School of Clinical Medicine, North China University of Science and Technology, Tangshan, 063000, China. Electronic address: macromicro@126.com.
PMID: 39369915 DOI: 10.1016/j.jep.2024.118910
Abstract

Ethnopharmacological relevance: As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown.

Aim of the study: To explore the role and potential mechanism of BJJP involved in treating HF.

Materials and methods: HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA Sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.

Results: BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/Akt signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/Akt signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/Akt pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/Akt signal pathway by BJJP.

Conclusion: These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/Akt pathway mediated by TMAO.

Keywords

Bie Jia Jian pill; Hepatic fibrosis; Intestinal microbiota; PI3K/AKT pathway; Trimethylamine N-Oxide.

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