Polygonum multiflorum-derived tetrahydroxy stilbene glucoside alleviates APP/PS1 mice by regulating gut microbiota and feces metabolomics

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline. Tetrahydroxy stilbene glucoside (TSG) has been demonstrated to improve learning and memory in aged mice; however, its underlying mechanisms remain incompletely understood. This study aimed to elucidate the effects of TSG on cognitive impairment in APP/PS1 mice through analysis of gut microbiota and associated metabolites. Behavioral tests, immunohistochemistry, and 16S rDNA sequencing revealed that TSG treatment improved cognitive function and alleviated neuroinflammation. Furthermore, TSG restored gut microbiota homeostasis and normalized aberrant metabolite profiles, accompanied by elevated levels of short-chain fatty acids (SCFAs). Correlation analysis indicated associations between alterations in gut microbiota, metabolites, and SCFAs. Notably, TSG promoted the production and content of SCFAs, especially acetic acid, propionic acid, and hexanoic acid. These findings suggest that TSG mitigates AD-related pathology possibly via modulation of specific gut microbial communities and their metabolic outputs, providing a basis for further therapeutic exploration.