Huaganjian decoction ameliorates metabolic dysfunction-associated steatotic liver disease through liver-gut crosstalk

Huaganjian decoction (HGJD), a traditional Chinese medicine formula, has been widely acknowledged for its remarkable effects in soothing the liver, relieving depression, and alleviating hepatic inflammation. Clinically, it has been extensively applied in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, the underlying mechanisms of its therapeutic actions remain incompletely understood, thus necessitating further in-depth investigations.

This study aimed to comprehensively investigate the mechanisms through which HGJD modulates MASLD via liver-gut crosstalk.

In this research, a MASLD rat model was successfully established using a high-fat diet, and the therapeutic efficacy of HGJD was assessed through various indices. Subsequently, non-targeted liver metabolomics was employed to identify the relevant metabolic pathways in the liver. Concurrently, 16S rRNA sequencing and short-chain fatty acids (SCFAs) quantification analysis were used to explore differential gut microbiota. Finally, bile acid (BA) target metabolomics, immunohistochemical staining, Western blotting, qPCR, and ELISA were performed on liver and gut tissues to further validate the potential mechanisms of HGJD by which HGJD exerts its effects against MASLD.

This study demonstrated that HGJD effectively mitigated the liver fat accumulation and improved liver function in MASLD models. Hepatic metabolomics analysis indicated that HGJD ameliorated MASLD primarily by modulating the biosynthesis of unsaturated fatty acids and primary BA. Results from 16S rRNA sequencing, SCFAs analysis and BA-targeted metabolomics revealed that HGJD regulated gut microbiota, increased intestinal SCFAs, and regulated BA homeostasis in both the gut and liver. Further investigations using immunohistochemical staining, Western blotting, qPCR, and ELISA elucidated that FXR/FGF15/SHP2/CYP7A1 pathway is implicated in the mechanism by which HGJD modulates liver-gut crosstalk. Additionally, HGJD inhibited the expression of lipogenic proteins (AMPK, SREBP-1c, FAS and P-ACC), activated lipid oxidation proteins (PPARα, CTP1B), strengthened the intestinal barrier, and alleviated liver inflammation.

HGJD could ameliorate MASLD by regulating liver-gut crosstalk, primarily through modulating gut microbiota-dependent BA biosynthesis, FXR/FGF15/SHP2/CYP7A1 pathway, fatty acid biosynthesis and intestinal barrier protection.