Cyanidin 3-O-β-galactoside from black chokeberry ameliorates brain glucose hypometabolism and cognitive impairment in mice through gut microbiota-derived short-chain fatty acids and amino acids

Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are associated with cognitive impairment and impaired brain glucose metabolism, posing significant challenges for the public health. We previously demonstrated that cyanidin 3-O-β-galactoside (Cy3Gal) from black chokeberry alleviated cognitive impairment in aging mice through regulating brain energy metabolism in a direct way. However, the indirect mechanisms in mitigating brain glucose hypometabolism remain underexplored. Here, we utilized a bilaterally intracerebroventricular injection of streptozotocin (ICV/STZ, 3 mg/kg bw)-induced brain glucose hypometabolism model to investigate the effects of Cy3Gal on cognitive impairment alleviation. Our findings revealed that Cy3Gal administration significantly improved memory deficit and cognitive impairment in ICV/STZ-administrated mice. Subsequently, Cy3Gal showed excellent abilities in inhibiting astrocyte overactivation, regulating neurotransmitters metabolism, and promoting synaptic plasticity. Furthermore, Cy3Gal enhanced brain glucose metabolism by improving glycolysis and the TCA cycle. Additionally, Cy3Gal modulated levels of gut microbiota-derived metabolites, including acetate, butyrate, histidine, glutamine, serine, valine and isoleucine, which were closely linked to brain glucose metabolism. The in vitro results further demonstrated that these metabolites played an important role in the neuron-astrocyte energy metabolism, which accounted for the alleviation of glucose hypometabolism. Overall, our findings suggest that Cy3Gal mitigates ICV/STZ-induced cognitive impairment by modulating gut microbiota-derived short-chain fatty acids and amino acids, which in turn improves brain glucose metabolism.