Dietary kaempferol attenuates aging-related cognitive decline through gut microbiota modulation and intestinal barrier strengthening with suppression of neuroinflammation in mice

Kaempferol, a natural dietary flavonoid, has shown neuroprotective potential. However, its mechanisms of protection against age-related cognitive decline, especially those mediated <i>via</i> the gut-brain axis, are not fully understood. This study investigated the role of kaempferol in alleviating D-galactose-induced brain aging and elucidated its functional mechanisms related to gut microbiota composition, microbial metabolite production, and intestinal barrier integrity. An aging mouse model was induced by D-galactose and subsequently treated with kaempferol. Results revealed that kaempferol significantly ameliorated anxiety-like behaviors and spatial working memory deficits in D-galactose-treated mice. In the hippocampus, it reduced neuronal loss, upregulated synaptic plasticity-related genes (Bdnf and Snap25), and suppressed neuroinflammation through inhibition of microglial activation and the TLR4/Myd88 signaling pathway. Importantly, kaempferol restored intestinal barrier integrity, as indicated by increased expression of colonic MUC2 and tight junction proteins (Zo-1 and Occludin). It also markedly reshaped gut microbiota composition by enriching beneficial genera such as <i>Faecalibaculum</i> and <i>Akkermansia</i>, which correlated with elevated fecal propionate and butyrate levels, and a reduction in serum LPS. Our findings demonstrate that kaempferol mitigates D-galactose-induced cognitive impairment by modulating gut microbiota, increasing beneficial SCFA production, enhancing gut barrier function, and subsequently inhibiting systemic and neuroinflammation. This study provides mechanistic support for kaempferol as a dietary intervention strategy to promote brain health <i>via</i> the gut-brain axis.