Ershiwuwei Shanhu Pill ameliorates cognitive impairment in Alzheimer's disease mice by remodeling gut microbiota and host serum metabolites.

Alzheimer's disease (AD), with the most prominent pathological feature of the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau proteins (P-tau), is the foremost cause of dementia. Ershiwuwei Shanhu Pill (ESP) is commonly used in clinical practice in Tibetan areas to treat AD, and has been shown to alleviate cognitive impairment. However, whether ESP exerts its therapeutic effects by modulating the gut microbiota and serum metabolites remains unclear. In this study, APPswe/PSEN1dE9 transgenic (APP/PS1) mice (n = 11 per group) were treated with ESP (200 mg/kg, oral gavage) daily for 2 months and evaluated using the Morris Water Maze (MWM), brain histopathology, immunofluorescence, 16S rRNA sequencing, and untargeted serum metabolomics. ESP improved cognitive performance, reduced Aβ deposition and P-tau levels, and attenuated neuroinflammation. Concurrently, ESP significantly reshaped the gut microbiota (e.g., increasing Dubosiella and decreasing Bacteroides) and altered serum metabolites involved in tryptophan metabolism and glycolysis pathways (e.g., elevating Fructose 1,6-bisphosphate and reducing N-Acetylserotonin). In conclusion, these neuroprotective effects of ESP are associated with a remodeling of the gut microbiota and metabolic profile, providing a pharmacological basis for its clinical application and novel insights into AD intervention via the gut microbiota-metabolite-brain axis.