Effects of in vitro fermentation of Astragalus polysaccharide on gut microbiota and neurotransmitter metabolites in patients with major depressive disorder

Background Major depressive disorder (MDD) is a common and heterogeneous mental illness with an unclear pathogenesis and often suboptimal treatment outcomes. Astragalus polysaccharide (APS) has shown potential antidepressant effects and may serve as a functional food; however, its impact on the gut microbiota and metabolome in MDD remains unexplored. Methods Using an in vitro fermentation model coupled with 16S rRNA sequencing and targeted metabolomics, we characterized the gut microbial composition and neurotransmitter metabolites in fecal samples from 15 MDD patients and 15 healthy subjects. Results MDD samples exhibited elevated Fusobacteriaecae and Eggerthellaceae , reduced levels of Eubacterium hallii , Faecalibacterium , and Ruminococcus , and higher concentrations of glutamine (Gln) and glutamate (Glu). APS fermentation significantly increased Bifidobacterium and Lactobacillus while decreasing Eubacterium hallii and Bilophila , without increasing the total gas volume, CO 2 , and H 2 S production. Additionally, beneficial metabolites were elevated in MDD samples after APS addition, including glutamine (Gln), γ-aminobutyric acid (GABA), dopamine (DA), and 5-hydroxytryptophan (5-HTP). The increase in GABA among healthy subjects was more significant. Conclusions These findings indicate that MDD is associated with disruptions in gut microbiota and Glu/GABA metabolism. When APS are applied directly to the colon, they may mitigate these disruptions by modulating microbial composition and key neuroactive metabolites, thereby influencing the central nervous system via the gut-brain axis. This effect appears to be more pronounced in healthy individuals. Clinical Trial Registration https://www.medicalresearch.org.cn , identifier MR-33-25-010733.