Modification effects of SanWei GanJiang Powder on liver and intestinal damage through reversing bile acid homeostasis

Abstract

Background: Sanwei Ganjiang Powder (SWGJ), derived from traditional Chinese medicine (TCM), has long demonstrated its effectiveness in long-term liver damage therapy. Recent studies indicated that it can also regulate the intestinal tract, although the underlying molecular mechanisms of this remain mysterious. The aim of the study is to investigate the mechanisms of SWGJ against dysbacteriosis and carbon tetrachloride (CCl₄)-induced gut-liver axis damage underlying bile acid enterohepatic circulation.

Methods: To observe the regulatory effects of SWGJ on Liver and Intestinal Damage, we explored two animal models. In model 1, sixty BALB/c mice were subjected to oral gavage with 12 g/kg of ceftriaxone sodium for 10d; during this time, SWGJ, bifendate and bifico were sequentially administered over 7d. In model 2, the model of chronic liver injury was induced by subcutaneous injection of 40% CCl₄ oil solution twice per week for 8 weeks. From the 3rd week, SWGJ, bifendate and bifico were sequentially administered for 6 weeks. Intestinal flora (16S rDNA analysis), histology (H&E staining), tight connections (Immunohistochemistry, IHC), ultrastructure (Transmission electron microscopy, TEM), inflammatory cytokines and LPS (Enzyme-linked immunosorbent assay, ELISA) of the intestines were assessed, and liver function was also evaluated by methods including ALT, AST and H&E staining. The levels of protein associated with bile acid metabolism were assessed by western blot.

Results: In model 1, SWGJ significantly decreased the activity of inflammatory cytokines and LPS compared with the ceftriaxone sodium group. In addition, SWGJ improved symptoms of intestinal flora imbalance; further, ZO-1 and occludin in the cytoplasm of intestinal villus epithelial cells was increased, and the histopathology of the ileum was improved. Notably, the expression of ALT and AST was significant increased, and disordered hepatic lobule structures were clearly observed in liver histopathology in model group; SWGJ can significantly improve these changes. Furthermore, the levels of proteins related to bile acid synthesis, such as CYP7A1, were significantly upregulated in the SWGJ group compared with the model, and proteins related to excretion and reabsorption, such as NTCP, Mrp2 and BESP, were also upregulated. Importantly, SWGJ increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). Similar results appeared in model 2.

Conclusion: This study suggests that SWGJ may elicit significant effects on the treatment of gut-liver axis damage, potential mechanisms at least partially involve bile acid enterohepatic, and increasing of the nuclear Nrf2 levels.

Keywords: Bile acid enterohepatic circulation; Gut microbiota; Gut-liver axis; Nuclear factor-E2-related factor-2; Sanwei Ganjiang Powder; Traditional Chinese medicine.