Qing-Kai-Ling oral liquid alleviates non-alcoholic fatty liver disease via remodeling gut microbiota and activating AMPK/ACC1 axis

BACKGROUND: Qing-Kai-Ling (QKL) oral liquid, evolving from a classical Chinese formula known as An-Gong-Niu-Huang pills, has demonstrated hepatoprotective, lung-protective, and gut microbiota-modulating properties. However, its efficacy in preventing high fat diet (HFD) -induced non-alcoholic fatty liver disease (NAFLD) and its relationship with gut microbiota and hepatic inflammation remain unclear. PURPOSE: The study aims to investigate whether QKL can prevent HFD-induced NAFLD, focusing on the mechanistic role of gut microbiota, microbial metabolites, and hepatic inflammation. METHODS: QKL was subjected to extraction and chemical profiling to identify its active compounds. In vivo studies were conducted in HFD-fed mice to assess the effects of QKL on hepatic lipid accumulation, inflammation, gut microbiota composition, SCFAs production, intestinal permeability, body weight, and fat mass. RESULTS: Chemical analysis revealed that the major components of QKL are gallic acid, corilagin, and chebulagic acid. QKL administration (12. 33 and 24. 66 mL/kg) for 8 weeks significantly reduced hepatic steatosis, serum lipid profiles (TG, LDL-C), and body weight in high-fat diet-induced NAFLD mice, while improving glucose tolerance and intestinal barrier integrity. Gut microbiota analysis revealed QKL enriched beneficial taxa (e. g. , Akkermansia, Bacteroides) and suppressed pathobionts (e. g. , Lachnospiraceae NK4A136group), effects replicated through faecal microbiota transplantation from QKL-treated donors. QKL upregulated intestinal gene GPR41/43 and hepatic protein GPR135 expression, enhanced SCFAs production (acetic, propionic, and butyric acids), and activated AMPK/ACC1 signaling to suppress lipogenesis and promote lipid oxidation. Untargeted metabolomics demonstrated QKL restored hepatic fatty acid metabolism by reducing palmitic acid and arachidonic acid accumulation. CONCLUSION: These findings established QKL as a microbiota-modulating therapeutic agent for NAFLD through SCFA-AMPK/ACC1 axis activation, providing a foundation for developing QKL-based treatments.