Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by neuroinflammation, for which gut dysbiosis may be implicated. Our previous study showed that treatment with Pseudostellaria heterophylla aqueous extract and one of its cyclopeptides, heterophyllin B, attenuate memory deficits via immunomodulation and neurite regeneration. However, whether Pseudostellaria heterophylla polysaccharide (PH-PS) exerts neuroprotective effects against AD and its underlying mechanisms remain unclear. The infrared spectrum, molecular weight, and carbohydrate composition of the PH-PS were determined. The results showed that PH-PS (Mw 8.771 kDa) was composed of glucose (57.78 %), galactose (41.52 %), and arabinose (0.70 %). PH-PS treatment ameliorated learning and spatial memory deficits, reduced amyloid β build-up, and suppressed reactive glia and astrocytes in 5 × FAD mice. 16S rRNA sequencing further showed that PH-PS remodelled the intestinal flora composition by promoting probiotic microbiota, such as Lactobacillus, Muribaculum, Monoglobus, and [Eubacterium]_siraeum_group, and suppressing inflammation-related UCG-009 and Blautia. Additionally, PH-PS restored intestinal barrier function; ameliorated peripheral inflammation by reducing the secretion of inflammatory cytokines, thereby converting M1 microglia and A1 astrocyte toward beneficial M2 and A2 phenotypes; and contributed to Aβ plaques clearance by upregulation of insulin degradation enzyme and neprilysin. Collectively, our findings demonstrate that PH-PS may prevent the progression of AD via modulation of the gut microbiota and regulation of glial polarisation, which could provide evidence to design a potential diet therapy for preventing or curing AD.
