Inulin Combined with Rosmarinic Acid Alleviates D-Galactose-Induced Cognitive Impairment by Regulating Indoxyl Sulfate and the AhR/NF-κB/NLRP3 Inflammatory Pathway

Age-related cognitive impairment is associated with oxidative stress, intestinal barrier dysfunction, and gut–brain axis disruption. This study evaluated how rosmarinic acid (RA), alone or combined with the prebiotic inulin, ameliorates D-galactose-induced cognitive impairment in mice. Male ICR mice received D-galactose for 6 weeks with RA, or RA plus inulin, followed by behavioral testing, histology, biochemical assays, 16S rRNA sequencing, serum metabolomics, molecular dynamics and inflammatory signaling analyses. RA ameliorated exploratory behavior and recognition and spatial memory, restored antioxidant enzyme (SOD/CAT/GSH-Px) activities, reduced lipid peroxidation (MDA), and attenuated hippocampal neuronal injury and glial activation. The RA-inulin combination exhibited additional protection, improving colonic barrier markers, increasing Lactobacillus and Lachnospiraceae, lowering indoxyl sulfate, and modulating AhR/NF-κB/NLRP3 activation. Meanwhile, the level of IL-1β/IL-18 (in the hippocampus) decreased by 15.96% and 24.41%, respectively. These findings suggest that the combined dietary intervention of RA and inulin mitigates aging-related cognitive impairment through the gut–brain axis.