Elaeagnus angustifolia L. Polysaccharide Alleviates High-Fat High-Fructose Diet (HFFD)-Induced Cognitive Impairment by Modulating the Gut-Liver-Brain Axis

Cognitive impairment induced by a high-fat high-fructose diet (HFFD) is associated with gut–liver–brain axis dysfunction, yet whether polysaccharide intervention can modulate this axis to achieve cognitive rescue remains unexplored. This study investigated whether Elaeagnus angustifolia polysaccharide (EAP) is associated with protection against HFFD-induced cognitive decline by modulating this axis. Male C57BL/6J mice (n = 15/group) received Control, HFFD, HFFD + LEAP (300 mg/kg/day EAP), or HFFD + HEAP (800 mg/kg/day EAP) for 14 weeks. HEAP improved spatial memory, reducing escape latency by 31.2% on day 5 (p < 0.01). Multi-omics and histopathological analyses revealed that EAP was dose-dependently associated with restructuring of the gut microbiota, expanding Muribaculaceae and other SCFA-producers while suppressing pathobionts, thereby reversing the Firmicutes/Bacteroidota ratio from 1.71 to 0.94 (p < 0.01). Elevated cecal, hepatic, and cerebral acetate, propionate, and butyrate (p < 0.01) were associated with improved intestinal barrier integrity, attenuated systemic LPS translocation, and reduced hepatic inflammation and changes consistent with normalization toward control levels of PPARα/γ signaling. These peripheral improvements were accompanied by changes in the hippocampus, where EAP suppressed IBA-1 microglial activation (from 4.5-fold to 2.1-fold of control, p < 0.01) and IL-6/TNF-α signaling, changes in neurotransmitter balance (Glu, 5-HT, DA), and preserved postsynaptic density ultrastructure and PSD-95 expression (p < 0.01). These findings support a role for EAP in modulating the gut–liver–brain axis and may help prevent diet-related cognitive impairment, supporting its development as a microbiome-targeted functional food ingredient.