Icariin Supplementation Alleviates Cognitive Impairment Induced by <scp>d</scp>-Galactose via Modulation of the Gut–Brain Axis

Aging-related cognitive impairment seriously diminishes individuals' life quality. Icariin (ICA), a natural flavonoid separated from the herb <i>Epimedium</i>, is applied in the food industry to bolster immunity and cognitive function in Chinese culture, demonstrating considerable potential in alleviating aging-related cognitive impairment. However, the mechanisms by which ICA mitigates aging-related cognitive impairment have yet to be elucidated. In the study, an 8 week ICA administration strongly improved spatial learning and memory ability, reduced neural damage, and restored hippocampal mitochondrial ultrastructure in mice subjected to d-galactose (d-gal) induction. Mechanically, ICA alleviated colonic pathology and upregulated the expression of tight junction proteins. Moreover, ICA reshaped microbial composition, enriched short-chain fatty acid (SCFA)-producing genera, and upregulated microbiota-derived SCFA contents. Additionally, ICA enhanced cognitively related anti-inflammatory properties and antioxidant capacity. Intriguingly, SCFAs regulated by ICA mitigated mitochondrial dysfunction <i>in vitro</i>, namely, reversing inflammatory cytokine levels and antioxidant capacity, elevating ATP contents, and mitochondrial membrane potential. Furthermore, SCFAs regulated by ICA alleviated mitochondrial dysfunction by enhancing the oxidative phosphorylation pathway and upregulating mRNA expression of genes related to mitochondrial respiratory chain, thus improving cognitive function. The findings suggest that ICA alleviates d-gal-induced cognitive impairment via modulation of the gut-brain axis and mitochondrial function. The investigation underscores the potential therapeutic benefits of incorporating an ICA-enriched diet for cognitive enhancement.