Polysaccharide from Ganoderma sinense improves cognitive capacity in a mouse model of Alzheimer’s disease via reshaping the gut microbiota and short-chain fatty acid metabolism

Abstract Two types of polysaccharides from Ganoderma sinense termed GSP1 (Mw: 58.92 kDa, consisting of fourteen monosaccharides) and GSP2 (Mw: 3.27 kDa, consisting of fourteen monosaccharides) were purified, and their protective effects against Alzheimer's disease (AD) in a mouse model were investigated. An in vitro study suggested that GSPs protect SH-SY5Y cells from neurotoxicity and oxidative stress in response to glutamate. The effect of GSP1 on the cognitive and memory capacity of the AD mouse model was confirmed using the Morris Water Maze, Object Recognition, and Nestlet Shredding tests. Additionally, treatment with GSP1 could reduce the amyloid β plaques in the brains of AD mice. Multi-omics analysis of the gut microbiome, short-chain fatty acid (SCFAs) metabolomics, and behavioral tests were conducted to elucidate the therapeutic mechanisms of GSPs. The results revealed that GSP1 improved the diversity of the microbiome, restored the structure of the gut microflora, and regulated SCFA metabolism. Four genera (Turicibacter, Jeotgalicoccus, Staphylococcusa, and Odoribacter) were significantly associated with both behavioral tests and SCFAs metabolism in the GSP1-treated group. These findings provide a basis for the development of polysaccharide drugs against AD and for further development of GSP1.