Daidzein alleviates chronic restraint stress-induced depression-like behavior by regulating neuroinflammation and synaptic plasticity via microbiota-gut-brain axis

BACKGROUND: Depression is one of the most serious psychological disorders worldwide. Growing evidence suggests that the gut-brain axis plays a pivotal role in its pathophysiology. Daidzein, a naturally occurring isoflavone compound, exhibits neuroprotective properties and can be metabolized by gut microbiota into highly bioactive secondary metabolites. PURPOSE: This study aims to evaluate the antidepressant effects of daidzein and to investigate its underlying mechanisms, particularly mediated by the gut microbiome. STUDY DESIGN AND METHODS: We employed the chronic restraint stress (CRS) mice models and classic behavioral tests to investigate the therapeutic effect of daidzein. Furthermore, we used 16S rRNA sequencing and metabolomics methods to explore the regulatory effects of daidzein on key functional bacteria and metabolites after CRS exposure. Intestinal barrier function was evaluated by histopathology and FITC-dextran detection. Neuroinflammatory responses, neuronal morphology, and plasticity were also evaluated using immunofluorescence staining, western blotting, and Nissl staining. Finally, we employed an antibiotic intervention experiment to validate the pivotal role of gut microbiota in the antidepressant effect of daidzein. RESULTS: Our data demonstrate that daidzein administration mitigated the depression-like behaviors in CRS mice, with gut microbiota composition playing a potentially critical mediating role. Specifically, daidzein induced significant modulations in gut microbial communities (Rikenella, Enterococcus, Akkermansia, and Ruminococcus) and associated metabolic profiles, particularly affecting short-chain fatty acid biosynthesis (valeric acid and acetic acid) and bile acid metabolism (cholic acid/allocholic acid, taurine-deoxycholic acid, and 3-dehydrocholic acid). Mechanistic investigations revealed that daidzein exerted protective effects on intestinal barrier integrity while concurrently reducing pro-inflammatory cytokine levels in both serum and hippocampus. At the neurobiological level, daidzein exhibited multifaceted regulatory effects, including attenuation of glial cell activation (microglia and astrocytes), normalization of FXR/NF-κB/NLRP3 inflammasome signaling, and enhancement of BDNF/TrkB neurotrophic pathways. These molecular changes were further associated with improved neuronal morphological complexity and upregulated expression of synaptic plasticity markers (SYP and PSD95) in the hippocampus. CONCLUSION: These data propose a gut-brain axis-mediated mode of action for daidzein's antidepressant-like effects, highlighting its promise as a potential candidate for depression, while further investigations are required to elucidate the specific microbial and metabolic drivers of these effects.