Polygonatum kingianum polysaccharides ameliorate cognitive impairments in alcohol-exposed obese mice in a sex-specific manner by regulating the gut microbiome and metabolome.

High-fat diet and alcohol are often co-exposed in real life, contributing to cognitive deficits and posing a significant yet modifiable public health challenge. We extensively evaluated the efficacy of polysaccharides extracted from Polygonatum kingianum (PP) in mitigating cognitive deficits in high-fat-diet-induced obese mice exposed to alcohol in females and males. PP alleviated cognitive deficits assessed via open-field and Y-maze tests, with a more pronounced efficacy in females, accompanied by restored hippocampal histopathology and improved synaptic integrity markers. PP also ameliorated metabolic dysregulation (i.e., hyperglycemia, dyslipidemia, oxidative stress), improved colon morphology and tight junction proteins (ZO-1, Claudin-1). Sex-specific alterations were significantly prominent in remodeling gut microbiome and fecal metabolome induced by PP. For instance, Parabacteroides goldsteinii, Bacteroides caecimuris, and the families Staphylococcaceae and Prevotellaceae were elevated in females while Lactobacillus spp. and Clostridium spp. exclusively elevated in males. Mendelian randomization using large-scale human GWAS data demonstrated causal relationships between certain gut bacteria and cognitive function. Metabolomics identified largely non-overlapping sets of PP-regulated metabolites and pathways in females and males. Correlation analysis linked microbiota to microbiota-derived metabolites and network pharmacology identified core targets (e.g., BCL2, CASP3, TNF, STAT3, PTGS2, PPARG) involved in PP's cognition protection benefits. Molecular docking validated the binding ability of core targets to 8 pharmacokinetically favorable metabolites regulated by PP in each sex, reinforcing the sex-specific mechanism. Collectively, our findings provide novel insights into the benefits of PP in alleviating diet-induced cognitive deficits and underscore the necessity of considering sex as a critical biological variable in developing microbiome-targeted nutritional therapies.