Ganoderma lucidum polysaccharides ameliorate cognitive decline and neuroinflammation in aging via the Blautia coccoides-butyrate-NLRP3 axis

Aging is frequently accompanied by cognitive decline and neuroinflammation, both of which are closely linked to dysbiosis of the intestinal microbiota. Ganoderma lucidum polysaccharides (GLPs), as natural bioactive compounds, exhibit anti-inflammatory, immunomodulatory, and neuroprotective properties. Recent studies suggest that GLPs may influence brain function via the gut-brain axis; however, the precise mechanisms underlying this effect remain unclear. This study demonstrates that GLPs alleviate cognitive impairment in aging mice through a gut-microbiota-dependent pathway. GLPs treatment enriched the butyrate-producing bacterium Blautia coccoides , elevated fecal acetyl-CoA and butyrate levels. Direct supplementation with Blautia coccoides or butyrate similarly improved cognition and suppressed neuroinflammation. GLPs notably ameliorated intestinal barrier damage and attenuated systemic inflammation. In the hippocampus, it inhibited microglial activation and NLRP3 inflammasome-mediated neuroinflammation. In NLRP3-knockout mice, these beneficial effects were not observed, thereby confirming that the pathway is NLRP3-dependent. Fecal microbiota transplantation from GLPs-treated donors replicated cognitive and anti-inflammatory effects in recipients, establishing microbial causality. Furthermore, butyrate and Blautia coccoides -derived metabolites directly suppressed NLRP3 activation in microglial cells in vitro. Our work defines a novel Blautia coccoides -butyrate-NLRP3 axis through which GLPs mitigates brain aging, supporting its potential as a prebiotic therapy for age-related cognitive disorders.