Aging-related cognitive impairment has emerged as a major health-threatening factor among the elderly, and cyanidin-3-glucoside (C3G) is a prominent anthocyanin with biological activities, including antioxidant, anti-inflammatory, and alleviation of neurodegeneration. However, the role of C3G in alleviating natural aging-induced cognitive impairment and the underlying mechanisms thereof remain unclear. In this study, experimental methods mainly included biochemical analysis, pathological analysis, immunofluorescence staining, transmission electron microscopy analysis, western blot, as well as the determination of the gut microbiota composition and detection of metabolites. We found that C3G may exert neuroprotective effects and promote brain health by alleviating brain atrophy and neuroinflammation, enhancing brain antioxidant capacity, regulating neurotransmitter expression and hypothalamic-pituitary-adrenal axis activity, and attenuating blood-brain barrier and hippocampal synaptic damage. Furthermore, C3G also promotes gut health by decreasing inflammatory responses and intestinal tissue crypt damage, upregulating the expression of tight junction proteins, and attenuating intestinal damage. Notably, C3G regulated the microbiota composition in different intestinal segments and intestinal mucosa, as well as the metabolic homeostasis of gut microbiota metabolites, such as short-chain fatty acids (SCFAs), amino acids, and bile acids. Substantially increased levels of SCFAs could activate the extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway by acting on the G protein-coupled receptors. Correlation analysis indicated that increased gut microbiota, such as Faecalibaculum and Bifidobacterium, and elevated SCFAs were positively correlated with behavioral improvement and brain health. In conclusion, our findings reveal that C3G has the potential to improve natural aging-induced cognitive impairment by modulating the gut microbiota and its metabolite SCFAs, thereby activating the ERK/CREB/BDNF pathway.
