<i>Cistanche deserticola</i> Polysaccharides Mitigate Alzheimer’s Disease Progression by Dynamic Regulation of Gut Microbiota Composition and Metabolites

<i>Cistanche deserticola</i> polysaccharides (CDPS) exhibit a range of pharmacological activities, most notably in immune modulation, anti-oxidation, and gut microbiota regulation. Emerging evidence suggests that restoring gut microbial and metabolic homeostasis may decelerate the progression of Alzheimer's disease (AD). However, the specific <i>in vivo</i> effects and underlying mechanisms of CDPS in the context of AD remain incompletely understood. In this study, we employed behavioral tests, 16S rRNA high-throughput sequencing, and time-resolved metabolomic analyses to comprehensively evaluate the therapeutic efficacy of CDPS. CDPS administration significantly ameliorated cognitive impairment, suppressed pro-inflammatory cytokine expression, and reduced A[Formula: see text] deposition and Tau hyperphosphorylation in the brains of APP/PS1 Tg mice. These effects were associated with CDPS-induced modulation of gut microbial composition - especially the <i>Firmicutes</i>/<i>Bacteroidetes</i> ratio - and regulation of <i>D</i>-Proline and Histidine metabolism. Further <i>in vitro</i> and <i>in vivo</i> validation confirmed that <i>D</i>-Proline and Histidine, key CDPS-associated metabolites, protected against A[Formula: see text]-induced apoptosis and oxidative stress. Notably, the cognitive benefits of CDPS were markedly weakened under conditions of gut microbiota disruption or immune suppression, which highlights the importance of microbial and immune system integrity in mediating its therapeutic effects. Collectively, these findings highlight gut microbial and metabolic disturbances as critical contributors to AD pathogenesis, and support CDPS as a promising multi-target therapeutic strategy. The integration of longitudinal microbiota and metabolomic profiling offers novel mechanistic insights into the neuroprotective actions of CDPS in AD.