ZeXie decoction alleviates non-alcoholic fatty liver disease in rats: the study of genes, lipids, and gut microbiotas

Recently, with increasing awareness of health issues, non-alcoholic fatty liver disease (NAFLD) has become an epidemic attracting global attention. As a serious chronic disease, NAFLD is clinically managed with pharmacological interventions that are usually associated with poor long-term efficacy and adverse effects. In this scenario, traditional Chinese medicine (TCM) characterized by "multiple ingredients-multiple targets-multiple pathways" shows promise as a potential option to treat NAFLD. Zexie decoction (ZXD) is a classical TCM formula that possesses favorable lipid-lowering and anti-inflammatory activities. Accumulating evidence indicates that ZXD displays robust efficacy in treating NAFLD. The effectiveness of ZXD against NAFLD has been evaluated in our previous studies. This study further examines its probable mechanism of action in an in-depth manner using multi-omic analysis based on the gut-liver axis and sheds light on the potential relationship among genes, hepatic lipid metabolites, and gut microbiotas. Totally, 71 differentially expressed genes (34 upregulated and 37 downregulated genes), 31 differential lipid molecules (8 upregulated and 23 downregulated), and 56 differential gut microbiotas (37 upregulated and 19 downregulated) were identified in the ZXD-treated group rats compared with the negative control group rats. Of these, owing to their key role in the association analysis, g_Blautia, g_Romboutsia, and g_Lactobacillus were hypothesized to be crucial gut microbiotas in the ZXD-mediated treatment of NAFLD. These microbiotas were found to synergize with key genes, such as AKR1B8, CCN1, and TNKS2, and hepatic lipid metabolites, such as glycerophospholipid and sphingomyelin, which might play a therapeutic role by regulating fatty acid synthesis, correcting lipid metabolism disorder, or reducing the inflammatory response. Overall, the present study provides fresh insights into the ZXD-mediated treatment of NAFLD, which, in turn, is expected to give a push to the modernization of TCM.