Xiaoyaosan Modulates Gut-Brain Metabolic Pathways and Brain Microstructure in Depression: A Multi-Omics Insight

Background Depression is closely associated with metabolic disorders in the gut-brain axis. Our previous studies using antibiotics (ABX)-treated mice and germ-free mice models demonstrated that Xiaoyaosan (XYS) alleviates depression by modulating metabolic pathways involved in gut-brain interactions. However, the key metabolic pathways remain to be fully characterized. Study design We enriched relevant metabolic pathways and analyzed the correlation between depressive-like behaviors and these pathways. We investigated the effects of XYS on metabolic pathways associated with chronic restraint stress (CRS)-induced depression. We further investigated the impact of these metabolic differences on brain microstructure in depression and the recovery situation after the intervention with XYS. Methods To comprehensively assess the role of XYS in gut-brain metabolic reprogramming, we employed an integrated multi-omics approach, including the 16S rRNA sequencing, metabolomic analyses, AFADESI-MSI analysis, and brain diffusion tensor properties analysis. Results We observed that XYS could decrease the relative abundances of Desulfovibrio , Erysipelatoclostridium , Parasutterella and significantly increase the relative abundances of Dubosiella , Akkermansia , and regulate the glycerophospholipid metabolism and tryptophan metabolism. Spatial and quantitative differences in lipid metabolism, tryptophan metabolism, glutamate/glutamine metabolism, acetylcholine and adenosine metabolism in the brain were observed after XYS treatment. Diffusion tensor analysis further demonstrated that treatment with XYS effectively suppressed the loss of neural integrity in the medial prefrontal cortex and hippocampus caused by chronic restraint stress. Conclusion These findings suggest that the antidepressant efficacy of XYS may involve the regulation of gut microbiota and microbial metabolites, improve synaptic loss, influencing the spatial distribution and concentration of brain-specific functional metabolites and reprogramming gut-brain axis metabolism.