Polysaccharide from Flammulina velutipes residues protects mice from Pb poisoning by activating Akt/GSK313/Nrf-2/HO-1 signaling pathway and modulating gut microbiota

Lead (Pb) can cause damages to the brain, liver, kidney, endocrine and other systems. Flammulina velutipes residues polysaccharide (FVRP) has been reported to exhibit anti-heavy metal toxicity on yeast, but its regulating mechanism is unclear. Therefore, the protective effect and the underlying mechanism of FVRP on Pb-intoxicated mice were investigated. The results showed that FVRP could reduce liver and kidney function indexes, serum inflammatory factor levels, and increase antioxidant enzyme activity of Pb-poisoned mice. FVRP also exhibited a protective effect on histopathological damages in organs of Pb-intoxicated mice. Furthermore, FVRP attenuated Pb-induced kidney injury by inhibiting apoptosis via activating the Akt/GSK313/Nrf-2/HO-1 signaling pathway. In addition, based on 16 s rRNA and ITS-2 sequencing data, FVRP regulated the imbalance of gut microbiota to alleviate the damage of Pb-poisoned mice by increasing the abundance of beneficial microbiota (Lachnospiraceae, Lactobacillaceae, Saccharomyces and Mycosphaerella) and decreasing the abundance of harmful microbiota (Muribaculaceae and Pleosporaceae). In conclusion, FVRP inhibited kidney injury in Pb-poisoned mice by inhib-iting apoptosis via activating Akt/GSK313/Nrf-2/HO-1 signaling pathway, and regulating gut fungi and gut bacteria. This study not only revealed the role of gut fungi in Pb-toxicity, but also laid a theoretical foundation for FVRP as a natural drug against Pb-toxicity.