Chlorogenic acid (CGA) displays cognition-improving properties, but the underlying mechanisms remain unclear. Herein, CGA supplementation (150 mg/kg body weight) for 14 weeks significantly prevented obesity and insulin resistance, cognitive-behavioral disturbances, and synaptic dysfunction induced by a high-fat and high-fructose diet (HFFD). Moreover, CGA supplementation enhanced the expression of genes enriched in the neuroactive ligand-receptor interaction pathway and reduced inflammatory factor expressions. Furthermore, CGA treatment increased gut microbiota diversity and the level of bacterial genera producing SCFAs. CGA also decreased the concentration of energy metabolism substrates, while it increased phosphorylcholine. Finally, we observed a significant correlation among synaptic transmission genes, gut microbiota, and neurotransmission in the CGA supplementation group by targeted multiomics analysis. Together, our results supported that the alteration of gut microbiota and metabolite composition is the underlying mechanism of CGA improving cognitive function. CGA is also a promising intervention strategy to prevent HFFD-induced cognitive impairment.
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