Corni Fructus polysaccharide alleviates chronic unpredictable mild stress-induced depressive-like behaviors associated with modulating gut microbiota, neuroinflammation and oxidative stress.

Depression is a global public health issue with unclear pathogenesis and limited conventional treatments. Polysaccharides derived from traditional Chinese medicines have garnered attention for their safety and multitarget effects. This study aimed to evaluate the antidepressant efficacy of Corni Fructus polysaccharide (CFP) and explored its underlying mechanisms associated with oxidative stress, inflammation, and gut microbiota using a chronic unpredictable mild stress (CUMS) mouse model. Behavioral tests (sucrose preference, tail suspension, and open field), hematoxylin-eosin (H&E) staining, GC-MS, 16S rRNA gene sequencing, reverse transcription-quantitative PCR (RT-qPCR) and western blotting (WB) were adopted. CFP treatment significantly alleviated CUMS-induced depressive-like behaviors. It lowered the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and stress hormones (CRH, ACTH, CORT), decreased the accumulation of lipid peroxidation product (MDA), enhanced the activities of antioxidant enzymes CAT and SOD, increased the synthesis of brain-derived neurotrophic factor (BDNF) and monoamine neurotransmitters (5-HT, NE, DA), and alleviated neuronal damage in the hippocampus. Such benefits were associated with CFP-mediated modulation of gut microbiota composition, specifically a reduction in the proportion of Bacillota, an enrichment of beneficial bacteria, and increased levels of colonic and serum short-chain fatty acids (SCFAs), particularly butyric acid. These SCFAs may enter the central nervous system via the bloodstream, suppress the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, regulate the NF-κB/Nrf2 pathway, promote BDNF and monoamine production, thereby alleviating CUMS-induced depressive-like behaviors. Collectively, these findings provide a solid theoretical basis for considering CFP as a potential multitarget antidepressant candidate.