Background/Objectives: Long-term spaceflight in a microgravity environment frequently results in gastrointestinal dysfunction, presenting substantial challenges to astronauts’ health. Hericium erinaceus, a plant recognized for its dual use as food and medicine, contains a key functional component called Hericium erinaceus polysaccharide (HEP), which is purported to promote gastrointestinal health. This study aims to investigate the protective effects of HEP against gastrointestinal disturbances induced by simulated weightlessness and to elucidate its regulatory mechanisms. Methods: Sprague Dawley rats subjected to a tail suspension model were administered either a standard diet or a diet supplemented with 0.125% HEP over a period of 4 weeks (the intake of HEP is approximately 157.5 mg/kg bw/d, n = 8), metagenomics and targeted metabolomics to investigate the effects of HEP on gastrointestinal hormone secretion disorders, gut microbiota dysbiosis, and intestinal barrier damage induced by simulated weightlessness. Results: Dietary supplementation with HEP was observed to significantly alleviate weightlessness-induced gastrointestinal hormone disruptions, enhancing motility and intestinal barrier function while reducing inflammation. In addition, HEP improved gut microbiota by boosting beneficial bacteria as Oscillibacter sp.1-3, Firmicutes bacterium ASF500, and Lactobacillus reuteri, while reducing harmful bacteria like Escherichia coli and Mucispirillum schaedleri at the species level. Furthermore, HEP altered the serum metabolic profile of the rats, reducing inflammation by upregulating the tryptophan metabolism pathway and enhancing the production of short-chain fatty acids. Conclusions: HEP effectively protects against gastrointestinal dysfunction induced by simulated weightlessness by regulating hormone secretion and maintaining intestinal homeostasis.

Acrylamide (AA), a well-known neurotoxin, shows obvious damage to the nervous system. Cyanidin-3-O-glucoside (C3G), a representative anthocyanin, is identified as a promising neuroprotective agent as its excellent antioxidant capacity. This study evaluated the mitoprotective effects of C3G against AA-mediated neurotoxicity. The results showed that pretreatment with C3G (10 μmol/L) significantly lessened the reduction in AA-induced cell survival rate, increasing cell viability by 1.31 times compared to the AA-only group. C3G reduced intracellular ROS and MDA level accumulation by 84.0% and 61.9%, respectively. Furthermore, C3G suppressed the activation of NLRP3 inflammasome and Caspase-3-dependent apoptosis pathways induced by AA. Further mitochondrial analysis revealed that C3G pretreatment enhanced mitochondrial membrane potential recovery by 1.50 times and preserved the mitochondrial ultrastructure, while also restoring the aerobic respiratory capacity. PCR array demonstrated that C3G reversed the AA-induced downregulation of mitochondrial biogenesis genes PGC-1α and TFAM by 2.67-fold and 1.88-fold, respectively, and mitochondrial dynamics genes Mfn2 and Opa1 by 2.76-fold and 3.08-fold. Further in vivo studies confirmed that the blueberry anthocyanin extracts, which are mainly composed of C3G, showed neuroprotective function through maintaining mitochondrial function, alleviating inflammation, and apoptosis. This article provides new insights into the neuroprotective effects of C3G.