Ginsenoside Rg2 attenuates Alzheimer-like phenotypes in 3xTg-AD mice: Associations with gut microbiota and brain metabolomic profiles

Background and Purpose Alzheimer's disease (AD) is the most common form of dementia. The microbiota-gut-brain axis represents a critical pathway bridging peripheral metabolic signals and central AD pathology. This study aimed to evaluate the effects of ginsenoside Rg2 on AD-like phenotypes in 3xTg-AD mice and to examine its associations with gut microbiota and brain metabolomic profiles. Study Design and Methods A 3xTg-AD mouse model was used to assess the effects of Rg2 intervention in vivo. Behavioral performance was assessed using open field and water maze tests, Aβ and inflammatory factors were detected by ELISA, gut microbial changes were analyzed by 16S rRNA sequencing, and brain metabolic alterations were investigated using untargeted metabolomics. Results The results showed that Rg2 improved behavioral performance in mice, reduced Aβ deposition in the brain, and decreased serum and brain tissue inflammatory factors. Rg2 treatment was associated with alterations in gut microbial community characteristics. Metabolomics indicated that Rg2 was associated with alterations in the brain metabolic profile, with differential metabolites mainly involved in energy and lipid metabolism as well as inflammation-related pathways. The correlation network further revealed a close relationship between microbiota, SCFAs and brain metabolites, inflammation and behavioral indicators. Conclusion Rg2 attenuated AD-related pathology and functional impairment in 3xTg-AD mice. These protective effects were accompanied by changes in gut microbiota composition, brain metabolic profiles, and the inflammatory microenvironment. This study provides multi-omics evidence supporting the potential of Rg2 as a natural product for AD intervention and highlights its associations with gut microbiota and brain metabolism.