Ciwujianoside B alleviates cholestatic liver injury by regulating TMAO synthesis via remodeling of the gut microbiota

  • Phytomedicine. 2026 Jun 11:159:158426. doi: 10.1016/j.phymed.2026.158426.
Dongsheng Yu  1 ,  Benli Jia  2 ,  Fuqiang Zu  2 ,  Wen Zhang  3 ,  Danfeng Guo  4
Affiliations
  • 1. Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 2. Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, China.
  • 3. School of Pharmacy, Qilu Medical University, Zibo 255300, Shandong, China. Electronic address: [email protected].
  • 4. Henan Key Laboratory for Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. Electronic address: [email protected].
PMID: 42335639 DOI: 10.1016/j.phymed.2026.158426
Abstract

Background: Cholestatic liver injury (CLI) is mainly driven by intrahepatic cholestasis, a pathological condition characterized by systemic and intrahepatic accumulation of bile acids. Ciwujianoside B (CWB), the active constituent of Eleutherococcus senticosus, has demonstrated protective effects in various hepatic pathologies, but its functional role in CLI has not yet been investigated.

Purpose: This study aims to evaluate the therapeutic potential of CWB against CLI and investigate its mechanism.

Methods: CLI was induced via bile duct ligation, and the protective effects of CWB were assessed through H&E, Sirius red, and immunohistochemical staining. Inflammatory cytokines in serum were measured by ELISA. Integrated analysis of 16S rDNA Sequencing, serum metabolomics, and fecal microbiota transplantation was performed to investigate the interactions between gut microbiota and host metabolism. Trimethylamine oxide (TMAO) was supplemented to evaluate its impact on the hepatoprotective effects of CWB. In AML-12 cells, flavin-containing monooxygenase 3 (FMO3) was knockdown or overexpressed to assess TMAO levels, Apoptosis, Reactive Oxygen Species (ROS) content, and endoplasmic reticulum (ER) stress. The interaction between CWB and FMO3 was evaluated with molecular docking and molecular dynamics simulations.

Results: CWB alleviated hepatocellular damage and Apoptosis, which was accompanied by reduced serum levels of ALT, AST, ALP, and inflammatory cytokines. Mechanistic analyses revealed that CWB remodeled the gut microbiota, suppressed Cut C and Cut D levels in feces, thereby reducing systemic TMAO accumulation. Exogenous TMAO supplementation reversed the protective effect of CWB. Antibiotic treatment partially abrogated the hepatic protective effects of CWB. CWB significantly suppressed FMO3 expression. Knockdown of FMO3 in AML-12 cells led to a reduction in intracellular TMAO levels, Apoptosis rate, ROS content and ER stress activation. Molecular docking revealed a stable binding interaction between CWB and FMO3.

Conclusions: Our results suggest that CWB alleviates CLI by suppressing TMAO biosynthesis, primarily through reducing trimethylamine-producing bacteria and directly inhibiting hepatic FMO3 expression.

Keywords
Cholestatic liver injury; Ciwujianoside B; FMO3; Gut microbiota; TMAO.
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