Lycium barbarum polysaccharide improves the cognitive deficits in APP/PS1 mice of Alzheimer’s disease via modulating the microbiota-gut-brain axis

Abstract Background Alzheimer’s disease (AD) is increasingly recognized as a systemic disorder in which gut dysbiosis and intestinal barrier dysfunction contribute to neurodegeneration through the microbiota-gut-brain axis. Recent evidence suggests that modulation of gut microbiota by dietary bioactives may represent a promising strategy for AD prevention and treatment. Purpose This study aimed to investigate whether Lycium barbarum polysaccharides (LBP), a major bioactive component of Lycium barbarum with known antioxidant and anti-inflammatory properties, could alleviate cognitive impairment and neuropathological alterations in APP/PS1 transgenic mice by regulating the microbiota-gut-brain axis. Methods APP/PS1 mice were orally administered LBP, and their cognitive performance was evaluated using the Morris water maze (MWM) test. The effects of LBP on neuropathology, inflammation, and gut function were assessed through immunofluorescence, western blotting, enzyme-linked immunosorbent assay, and histological analyses. In addition, 16S rRNA sequencing and non-targeted fecal metabolomics were performed to characterize gut microbiota composition and metabolic alterations associated with LBP treatment. Results LBP markedly improved spatial learning and memory and reduced beta-amyloid (Aβ) deposition in the cortex and hippocampus. It modulated APP processing by downregulating phosphorylated APP (p-APP) and BACE1 while upregulating ADAM10 expression. LBP also suppressed neuroinflammation by reducing microglial (IBA-1) and astrocytic (GFAP) activation and by rebalancing pro- and anti-inflammatory cytokines in both brain and serum. 16S rRNA sequencing and metabolomics analyses revealed that LBP restored microbial diversity, enriched beneficial taxa (e.g., Alistipes, Turicibacter), and normalized metabolic disturbances in bile acid, lipid, and amino acid pathways. Furthermore, histological and immunohistochemical analyses demonstrated that LBP repaired intestinal barrier injury, enhanced tight junction protein expression (Claudin-1, Occludin, ZO-1), and alleviated jejunal inflammation. Conclusion Collectively, these findings indicate that LBP ameliorates cognitive decline and neuropathological changes in APP/PS1 mice by modulating gut microbiota composition, remodeling microbial metabolism, reinforcing intestinal barrier integrity, and suppressing systemic and central inflammation. This study highlights LBP as a promising functional polysaccharide with potential therapeutic value for preventing or mitigating AD through microbiota-gut-brain axis regulation.