Neuroinflammation is a prevalent pathological characteristic of numerous neurodegenerative disorders. Inhibition of neuroinflammation can slow the progression of these diseases. Armillariella tabescens is a valuable medicinal fungus that is often used in traditional Chinese medicine to treat acute and chronic hepatitis, appendicitis, otitis media and cholecystitis. Its mycelium polysaccharide (ATMP) has excellent biological activities, including anti-inflammatory, antioxidation and anti-aging. However, the mechanism of ATMP against neuroinflammation has not been elucidated. This study aimed to investigate the intervention effects of ATMP on lipopolysaccharide (LPS)-induced neuroinflammation and to elucidate the underlying mechanisms. The neuroprotective effects of ATMP were evaluated by behavioral tests, histological analysis of brain and colon tissues, and quantification of relevant inflammatory biomarkers. Gut microbiota composition and metabolic changes were assessed by 16S rRNA gene sequencing and serum non-targeted metabolomics. Fecal microbiota transplantation (FMT) was used to confirm gut microbiota-dependent effects of ATMP. Additionally, real-time quantitative PCR was performed to determine the expression of genes in related metabolic pathways. The results demonstrated that ATMP significantly alleviated LPS-induced cognitive impairment, inhibited brain inflammation and neuronal damage, attenuated intestinal inflammation and repaired the intestinal barrier function. Its neuroprotective effect was mediated via the microbiota-gut-brain axis (MGBA) by regulating gut microbiota composition and modulating amino acid and fatty acid metabolites, particularly balancing linoleic acid (LA) and arachidonic acid (AA) metabolic pathways. This work provides new mechanistic insights into the protective effect of ATMP against neuroinflammation and highlights its potential as an MGBA-mediated intervention strategy.
