Hovenia dulcis peduncle polysaccharide against alcohol-induced neural injury via gut-brain tight junctions restoration and microbiota-glutamate crosstalk.

Excessive alcohol consumption induces neurotoxicity through oxidative stress and disruption of the gut-brain axis. Hovenia dulcis peduncle polysaccharide (HDP) exhibits antioxidant properties, yet its mechanisms of neuroprotection against alcohol-induced injury remain unclear. This study investigated the neuroprotective effects and mechanisms of a purified Hovenia dulcis peduncle polysaccharide (HDP-2w) in an alcohol-exposed mouse model. C57BL/6 mice were administered alcohol (4.26 g/kg/day) with or without HDP-2w (100 mg/kg/day) for 14 days. Assessments included behavioral tests, oxidative stress markers, 16S rRNA sequencing of gut microbiota, brain metabolomics, and analysis of tight junction proteins. HDP-2w intervention significantly ameliorated alcohol-induced spatial memory deficits and locomotor impairment, reduced blood alcohol levels, and attenuated hippocampal oxidative stress and DNA damage (γ-H2AX foci). Importantly, qPCR and immunohistochemistry revealed that HDP-2w reversed the alcohol-induced downregulation of critical tight junction proteins, upregulating the mRNA and protein expression of Claudin-1 and ZO-1 in both the ileum and hippocampal CA1 region, thereby restoring gut-brain barrier integrity. Furthermore, HDP-2w mitigated gut dysbiosis by preserving microbial α-diversity, suppressing Proteobacteria, and enriching beneficial Lactobacillus. Brain metabolomics indicated that HDP-2w modulated cerebral glutamate metabolism, elevating levels of glutathione, glycine, and α-ketoglutarate. Significant correlations (r > 0.7) were established between these metabolic shifts and specific microbial alterations. Collectively, HDP-2w alleviates alcohol-induced neural injury via a multi-targeted mechanism involving the restoration of gut-brain tight junctions, rebalancing of gut microbiota, and normalization of glutamate metabolic homeostasis, highlighting its potential as a dietary polysaccharide targeting the gut-brain axis for intervention in alcohol-related neurological disorders.