Polygonatum sibiricum Polysaccharides Alleviate Simulated Weightlessness-Induced Cognitive Impairment by Gut Microbiota Modulation and Suppression of NLRP3/NF-κB Pathways

Background/Objectives: Polygonatum sibiricum (PS), possessing both medicinal and edible dual functions, boasts a long history of application in Chinese traditional practices. As a component of its effectiveness, Polygonatum sibiricum polysaccharides (PSPs) have been reported to exert neuroprotective effects. However, the protective effects of PS on the cognitive deficits induced by simulated weightlessness remain unclear. This study evaluated the therapeutic potential of PSPs to counteract the cognitive deficits induced by simulated weightlessness using the Hindlimb Unloading (HU) method. Methods: Mice were subjected to HU to establish cognitive impairment, and PSP was administered for four weeks. The Morris water maze test (MWMT) and passive avoidance test (PAT) were used to evaluate the cognitive abilities of mice, followed by an analysis of molecular mechanisms. Results: PSP treatment increased learning and memory in mice. PSP treatment partially restored gut microbial diversity and composition towards beneficial taxa, including Lactobacillus and Firmicutes, while inhibiting proinflammatory genera, including Alistipes and Proteus. At the same time, PSP upregulated Claudin-5 and Zonula Occludens-1 (ZO-1) levels in the colon, suggesting improved intestinal barrier integrity, and decreased neuroinflammatory response by inhibiting NLRP3 inflammasome activation and NF-κB phosphorylation in the hippocampus. It also modulated neurotransmitter homeostasis along the microbiota–gut–brain (MGB) axis by increasing the levels of gamma-aminobutyric acid (GABA) and serotonin (5-HT) while reducing the levels of excitotoxic metabolites, including Glutamate (Glu) and 3-hydroxykynurenine (3-HK). Conclusions: These results indicate that PSP may have beneficial effects on HU-induced cognitive impairment by regulating gut microbiota, enhancing barrier function, suppressing neuroimmune signaling, and restoring neurotransmitter balance.