Qushi Huayu decoction alleviates NAFLD in mice by regulating gut microbiota homeostasis in the gut-liver axis via the pregnane X receptor.

BACKGROUND

Qushi Huayu decoction (QHD) is a traditional Chinese medicine formula with clinical experience in the treatment of non-alcoholic fatty liver disease (NAFLD). The gut-liver axis is directly connected via the portal vein, making gut microbiota dysbiosis and endotoxin circulation key drivers in the development and progression of NAFLD. However, the regulation of the gut-liver axis by QHD in NAFLD remains unreported, and its target mechanisms have yet to be elucidated.

MATERIALS AND

METHODS

NAFLD was induced in male C57BL/6J mice via high-fat diet feeding, followed by 4 weeks of QHD administration. Comprehensive evaluation included serum biochemical analysis, liver histopathology examination, and quantification of proinflammatory enzyme activity. Mechanism studies were conducted via 16S rRNA sequencing, transcriptomics analysis, SCFAs analysis, RT-qPCR, Western blotting and ELISA techniques.

RESULTS

QHD therapy effectively ameliorates hepatic steatosis and lipid accumulation in a mouse model of NAFLD. In addition, QHD significantly increases intestinal tight junction proteins, thereby restoring intestinal barrier integrity and alleviating inflammatory responses. Transcriptomics revealed that QHD regulates multiple biological functions through multiple genes, in which inflammatory responses may play a key role. Simultaneously, QHD exerts beneficial modulation of the gut microbiota, increasing beneficial bacteria, particularly Akkermansia, while decreasing the prevalence of harmful microorganisms, such as Desulfovibrio. Fecal microbiota transplantation experiments demonstrates that gut microbiota remodeling partially mediates pharmacological efficacy of QHD against NAFLD. Notably, subsequent investigations identified that QHD altered the composition of the gut microbiota and the levels of acetic acid, propionic acid, and valeric acid in SCFAs in a PXR-dependent manner.

CONCLUSIONS

QHD exerts therapeutic effects on NAFLD by regulating the gut-liver axis. The mechanism by which QHD intervention ameliorates gut microbiota dysbiosis in NAFLD mice is associated with its regulation of PXR. This provides further scientific evidence and support for QHD's efficacy in improving NAFLD.