The Chinese Herbal TiaoGanXiaoZhi Formula Alleviates the Progression of Metabolic‐Associated Fatty Liver Disease by Regulating the Gut Microbiota

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Abstract
Aims: The TiaoGanXiaoZhi formula (TGXZ), a traditional Chinese medicine, has been shown to alleviate the progression of metabolic‐associated fatty liver disease (MAFLD) clinically. However, its underlying mechanism remains unclear. This study aimed to investigate the effects and mechanisms of TGXZ in treating MAFLD in mouse models. Methods: The MAFLD mouse model was established using a high‐fat diet and 5% fructose water over 16 weeks. At Week 8, mice exhibited significant steatosis, inflammation, and insulin resistance. A total of 42 mice were divided into the normal feed diet (NFD) group ( n = 18) and the high‐fat feed diet (HFD) group ( n = 24). Six mice from each group were killed at Week 8 for serological and histopathological assessments. The remaining mice were allocated into NFD ( n = 6), HFD ( n = 6), HFD + TGXZ ( n = 6), NFD + TGXZ ( n = 6), and HFD + Placebo ( n = 6) groups. TGXZ (or placebo) was administered at a clinical equivalent dose of 7.699 g/(kg·d) to the respective groups, while NFD and HFD groups received distilled water. Daily gavage started in Week 9. At Week 16, after fasting, body weight and liver condition were recorded, and mice were euthanized with pentobarbital sodium. Liver tissue was collected for further analysis, and the remaining tissue and feces were stored at −80°C. Data were graphed using GraphPad Prism 8.0.0 and analyzed with SPSS Statistics 25.0. Results are expressed as mean ± standard deviation. Statistical comparisons were made using Student's t ‐test for two groups and one‐way ANOVA for more than two groups, with significance set at p < 0.05. Results: Compared to the MAFLD mouse model group, TGXZ treatment significantly downregulated the weight of white adipose tissue (1.61 ± 0.66 vs. 3.06 ± 0.34 g, p < 0.0010), liver weight (1.22 ± 0.16 vs. 1.98 ± 0.39 g, p = 0.0031), and the levels of alanine aminotransferase (20.6 ± 3.4 vs. 46.1 ± 12.3 U/L, p < 0.0010), aspartate aminotransferase (99.9 ± 19.1 vs. 168.4 ± 34.3 U/L, p = 0.0014), cholesterol (2.95 ± 0.56 vs. 4.38 ± 0.34 mmol/L, p = 0.0053), triglycerides (2.25 ± 0.41 vs. 4.18 ± 0.67 mmol/L, p < 0.0010), low‐density lipoprotein (0.66 ± 0.11 vs. 1.41 ± 0.52 mmol/L, p = 0.0073), and total bile acid (0.71 ± 0.41 vs. 2.18 ± 0.61 mmol/L, p = 0.0017), except for high‐density lipoprotein (2.41 ± 0.81 vs. 2.55 ± 0.31 mmol/L, p = 0.5655). The liver transcriptome, fecal microbiota sequencing, and fecal lipidomics analysis demonstrated that TGXZ treatment improved the expression of genes related to lipid metabolism, alleviated intestinal microbiota disorders, and mitigated lipid disturbances caused by MAFLD. Conclusions: Our study demonstrated that TGXZ treatment effectively alleviated the progression of MAFLD. The inhibitory effects of TGXZ on MAFLD may be attributed to its regulation of gut microbiota, lipid metabolism, and hepatic inflammation.

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