Yinchen Wuling San ameliorates high-fat diet-induced metabolic-associated fatty liver disease in rats by remodeling the gut microbiota

Abstract

BACKGROUND

Metabolic-associated fatty liver disease (MAFLD) is a common metabolic disorder characterized by hepatic steatosis, obesity, abnormal liver function, and dyslipidemia, with limited effective drug options available. Increasing evidence links MAFLD to dysbiosis of the gut microbiota and microbial metabolites, including short-chain fatty acids (SCFAs). We hypothesized that Yinchen Wuling San (YCWLS) mitigates MAFLD by remodeling gut microbiota and associated SCFAs profiles.

AIM

To determine whether YCWLS alleviates MAFLD by inducing gut microbiota remodeling in rats.

METHODS

A high-fat diet was used to induce MAFLD in rats. The animals were assigned to control, model, positive drug (Bifidobacterium quadruple live bacteria tablets, 2.1 g/kg), and YCWLS (6.38 g/kg) groups and treated for 4 weeks. Liver and adipose histopathology was evaluated using hematoxylin-eosin staining. Serum lipids and liver enzymes were measured, gut microbiota was profiled by 16S rRNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry.

RESULTS

Compared to the model group, YCWLS reduced the liver index and improved liver injury markers, specifically alanine aminotransferase and aspartate aminotransferase (alanine aminotransferase model 50.05 ± 8.98 vs YCWLS 22.97 ± 2.40 P < 0.01; aspartate aminotransferase model 217.32 ± 13.70 vs YCWLS 122.65 ± 6.49 P < 0.01), alleviating hepatic steatosis and tissue injury. YCWLS also decreased serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol (triglycerides model 1.26 ± 0.18 vs YCWLS 0.61 ± 0.09 P < 0.01; total cholesterol model 2.83 ± 0.30 vs YCWLS 1.79 ± 0.09 P < 0.01; low-density lipoprotein cholesterol model 0.49 ± 0.16 vs YCWLS 0.17 ± 0.02 P < 0.01; high-density lipoprotein cholesterol model 0.50 ± 0.11 vs YCWLS 1.01 ± 0.09 P < 0.01). Microbiota analysis revealed a reduction in Firmicutes-related taxa (including Ruminococcaceae and Clostridiales) and an increase in Verrucomicrobia, Lachnospiraceae, Peptostreptococcaceae, and Akkermansia. Most fecal SCFAs exhibited modest, non-significant increases; however, butyrate displayed a near-significant upward trend (P = 0.052).

CONCLUSION

Yinchen Wuling San improves liver injury and dyslipidemia in MAFLD rats and is associated with the enrichment of Akkermansia and Lachnospiraceae, supporting a gut microbiota-linked mechanism.

Keywords: Metabolic-associated fatty liver disease; Yinchen Wuling San; Gut microbiota; Short-chain fatty acids; Gut-liver axis

Core Tip: Yinchen Wuling San (YCWLS), a classical traditional Chinese medicine formula, alleviated the phenotypes of metabolic-associated fatty liver disease in rats fed a high-fat diet. This improvement was evidenced by enhanced liver histopathology, reduced levels of alanine aminotransferase and aspartate aminotransferase, and corrected dyslipidemia. Profiling of the 16S rRNA revealed that YCWLS reshaped the gut microbiota by significantly enriching Akkermansia and Lachnospiraceae while decreasing Firmicutes-associated taxa. Although there were only modest and non-significant increases in fecal short-chain fatty acids, the observed shift in microbiota was associated with metabolic improvements, suggesting a microbiota-linked mechanism through which YCWLS exerts its effects on metabolic-associated fatty liver disease.