The Molecular Mechanisms of Guizhi Fuling Pills in Alzheimer's Disease Treatment: Insights from Transcriptomics, Metabolomics, and Gut Microbiota

Abstract: Objective Guizhi Fuling Pills (GFP), a classic Chinese herbal formula documented in ancient medical texts, is composed of five medicinal components: Cinnamomi Ramulus, Poria, Persicae Semen, Paeoniae Radix, and Moutan Cortex. Clinical evidence has confirmed its efficacy in treating dementia. This study aims to explore the therapeutic effects and mechanisms of GFP on Alzheimer's disease (AD) through transcriptomics, metabolomics, and gut microbiota analysis.Methods: The active components of GFP were determined using HR-LC-MS. Cognitive function in AD model mice was assessed via the Morris water maze test, while pathological changes in hippocampal tissue were evaluated using H&E staining. Transcriptomics was employed to detect differential gene expression in mouse hippocampal tissues, 16S rRNA sequencing was utilized to analyze changes in gut microbiota, and network pharmacology was applied to predict the molecular mechanisms of GFP in AD treatment.Results: GFP intervention significantly improved cognitive dysfunction and alleviated AD-related pathology in mice. Transcriptomic analysis revealed that Kpna2 may serve as a key gene target in GFP's therapeutic effect on AD, with signaling pathways related to inflammatory response, apoptosis, and the blood-brain barrier playing important roles. Gut microbiota analysis indicated that GFP ameliorated gut dysbiosis in AD by increasing the abundance of Actinobacteria, Lactobacillus, and Verrucomicrobia, while reducing the abundance of Desulfovibrio, Parabacteroides, and Tannerella. Metabolomic analysis demonstrated that GFP reversed metabolic disturbances in AD by regulating the synthesis of lipids and lipid-like molecules. Network pharmacology results suggest that the treatment of AD with GFP is associated with the alleviation of endothelial cell injury and the improvement of inflammatory responses.Conclusion: GFP represent a potential therapeutic approach for AD, likely mediated through the regulation of metabolic disorders and gut microbiota dysbiosis, as well as the mitigation of endothelial injury and inflammatory responses.