Mechanism of Nobiletin in Ameliorating High-Salt-Diet-Induced Cognitive Impairment via the miR-132–3p-Mediated Gut–Brain Axis

This study investigated whether nobiletin (NOB) alleviates high-salt diet (HSD)-induced cognitive impairment via the microRNA miR-132-3p and gut microbiota. Using behavioral tests, molecular analyses, and 16S rRNA sequencing in mice, we found that the NOB ameliorated HSD-induced deficits in spatial learning and memory. Mechanistically, NOB restored gut microbiota homeostasis, reduced serum LPS, and suppressed hippocampal neuroinflammation via the TLR4/NF-κB pathway. These benefits were mediated by the upregulation of miR-132-3p, which crucially linked gut microbiota changes to neuroprotection, as its deficiency abolished NOB's effects. Our findings reveal a gut microbiota-miR-132-3p axis through which NOB confers neuroprotection, offering a novel strategy for flavonoid-based therapy targeting the gut-brain axis.