Modified Xiaoyaosan rescues depression-like behavior via remodeling gut microbiota and leucine metabolism

Social avoidance is a hallmark symptom of depression. Although Modified Xiaoyaosan (MXYS) has been reported to attenuate this behavior, the underlying mechanisms remain poorly understood.

This study aimed to investigate the mechanisms by which MXYS alleviates social avoidance, with particular emphasis on gut microbiota composition and leucine metabolism.

A chronic social defeat stress (CSDS) mouse model was established to evaluate the antidepressant effects of MXYS. Fecal samples were subjected to LC-MS-based untargeted metabolomics and 16S rRNA sequencing to characterize alterations in gut microbiota and metabolites. Fecal microbiota transplantation (FMT) was conducted to verify the contribution of gut microbes to MXYS's antidepressant effects. Furthermore, targeted GC-MS, LC-MS/MS, and Western blotting analyses were employed to elucidate the mechanisms underlying leucine reduction. Finally, exogenous leucine supplementation was administered to determine its potential antidepressant efficacy.

MXYS treatment significantly ameliorated CSDS-induced social avoidance and other depression-like behaviors. Integrated metabolomic and 16S rRNA analyses identified leucine metabolism as a potential therapeutic target. MXYS modulated gut microbial composition and functional pathways, particularly those involved in leucine metabolism. FMT experiments confirmed the essential role of gut microbiota in mediating the antidepressant effects of MXYS. Targeted metabolic profiling and protein expression analyses revealed that enhanced microbial degradation of leucine contributed to its systemic reduction. Moreover, leucine supplementation robustly reversed depressive-like behaviors and attenuated hippocampal oxidative stress.

MXYS alleviates social avoidance in CSDS mice by modulating gut microbiota-mediated leucine degradation, thereby restoring systemic leucine levels and improving hippocampal oxidative stress.