Multi-omics integration reveals the ameliorative effects and underlying mechanisms of Astragalus membranaceus (Huangqi)-Fuzhuan brick tea on nonalcoholic fatty liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Nonalcoholic fatty liver disease (NAFLD) is a major clinical challenge and a growing global public health burden, yet no pharmacological therapy specific to this disease has been approved to date. Notably, Astragalus membranaceus (Huangqi, HQ) is incorporated into approximately 80% of multi-herb formulations employed for treating liver diseases. Fuzhuan brick tea, a distinctive Chinese fermented tea, is widely recognized for its unique fermentation process and hypolipidemic properties. However, whether co-fermentation with HQ enhances its lipid-lowering efficacy against NAFLD remains unexplored and unreported.

AIM OF THE STUDY: This study aimed to evaluate the therapeutic effects of HQ co-fermented Fuzhuan brick tea (HQT) on NAFLD and to elucidate the underlying molecular and systemic mechanisms.

MATERIALS AND METHODS: First, we characterized the chemical profile of HQT using UHPLC-QE-MS. Its anti-steatotic effects were evaluated in a mouse model of NAFLD, and transcriptomic analysis was employed to explore the molecular pathways involved in its hepatoprotective action. Subsequently, we integrated metabolomics, lipidomics, 16S rDNA sequencing of the gut microbiota, and qRT-PCR validation to systematically assess multi-level alterations associated with NAFLD. To further link pivotal genes with differential metabolites, multi-omics association analyses were conducted to prioritize putative targets for downstream interpretation.

RESULTS: HQT contained bioactive compounds with potential anti-NAFLD activity (e.g., Kaempferol, Quercetin, and Caffeic acid), and its therapeutic effects in NAFLD mice were comparable to those of polyene phosphatidylcholine capsules (PPC). HQT alleviated NAFLD by inhibiting cholesterol biosynthesis and lipogenesis, enhancing fatty acid oxidation, modulating triglyceride synthesis, suppressing de novo fatty acid synthesis, and reducing fatty acid uptake. These effects may be mediated by inhibiting the GPR146/PKA/ERK1/2/SREBP2 signaling pathway. Molecular docking analysis revealed that multiple HQT constituents exhibited high binding affinity for GPR146. Integrated transcriptomic and metabolomic analyses identified additional targets regulated by HQT, including Acat1, CYP2e1, and Plcg2. Furthermore, HQT significantly altered metabolomic and lipidomic profiles in NAFLD mice, reduced the abundance of Firmicutes, Erysipelotrichaceae, and Ileibacterium-valens, and restored Lactobacillus-murinus levels.

CONCLUSIONS: HQT ameliorates NAFLD, at least in part, by modulating the GPR146/PKA/ERK1/2/SREBP2 axis to suppress cholesterol biosynthesis, enhance fatty acid oxidation, regulate TG synthesis, and limit fatty acid uptake. Additionally, it reshapes the host's metabolic landscape and gut microbial composition. The integration of multi-omics approaches enabled the identification of putative bioactive constituents and key microbial taxa associated with HQT's beneficial effects, providing a preliminary mechanistic framework for its protective role in NAFLD. Collectively, these findings support the development of HQT as an innovative functional tea beverage for the prevention and management of NAFLD.