Protective Mechanism of Polysaccharide ORP‐1 Isolated from Oudemansiella raphanipes against Age‐Related Cognitive Decline through the Microbiota‐Gut‐Brain Axis

Age‐related cognitive decline is primarily attributed to the progressive weakening of synaptic function and loss of synapses, while age‐related gut microbial dysbiosis is known to impair synaptic plasticity and cognitive behavior by metabolic alterations. To improve the health of the elderly, the protective mechanisms of Oudemansiella raphanipes polysaccharide (ORP‐1) against age‐related cognitive decline are investigated. The results demonstrate that ORP‐1 and its gut microbiota‐derived metabolites SCFAs restore a healthy gut microbial population to handle age‐related gut microbiota dysbiosis mainly by increasing the abundance of beneficial bacteria Dubosiella, Clostridiales, and Prevotellaceae and reducing the abundance of harmful bacteria Desulfovibrio, strengthen intestinal barrier integrity by abolishing age‐related alterations of tight junction (TJ) and mucin 2 (MUC2) proteins expression, diminish age‐dependent increase in circulating inflammatory factors, ameliorate cognitive decline by reversing memory‐ and synaptic plasticity‐related proteins levels, and restrain hyperactivation of microglia‐mediated synapse engulfment and neuroinflammation. These findings expand the understanding of prebiotic–microbiota–host interactions. ORP‐1 and its fermentation product SCFAs restore a healthy gut microbial population, strengthen intestinal barrier integrity by abolishing age‐related alterations of TJ and MUC2 proteins expression, diminish age‐dependent increase in circulating inflammatory factors, maintain synaptic integrity by reversing memory‐ and synaptic plasticity‐related proteins levels, restrain hyperactivation of microglia‐mediated synapse engulfment and neuroinflammation, and finally prohibit the development of age‐related cognitive decline.