Ting Linghu, Ting Hu, Zhenning Wu, Qi Wang, Yunhao Zhao, Yujing Wang, Kaiwen Li, Xuemei Qin, Junsheng Tian, Ruiping Zhang
MXYS alleviates social avoidance in CSDS-induced depressed mice is associated with the restoration of intestinal barrier function via gut microbiota-mediated pathways. Specifically, it may reduces colon Desulfovibrio abundance to modulate β-alanine/aspartate metabolism and enhance claudin-1 expression, while increasing jejunal Clostridium sp. mbf VZ-132 to regulate glycerophospholipid metabolism and upregulate occludin expression. These findings suggested that MXYS may improves depression-like behavior through segment-specific microbial and metabolic modulation of intestinal permeability.
BACKGROUND: Increased intestinal permeability is implicated in the pathogenesis of depression. Modified Xiaoyaosan (MXYS) has demonstrated antidepressant-like effects in chronic social defeat stress (CSDS) mice, particularly in improving social avoidance behavior. However, direct evidence that MXYS improves depressive behavior by regulating intestinal permeability remains lacking.
METHODS: Using a CSDS-induced depression mouse model, we investigated the effects of MXYS through an integrated multi-omics approach, combining intestinal histopathology, microbiome, metabolomics, and molecular biology techniques. This strategy allowed systematic assessment of pathological changes, gut microbial composition, metabolite profiles, and protein expression.
RESULTS: MXYS treatment significantly alleviated social avoidance behavior in CSDS mice. It upregulated the expression of tight junction proteins in the colon, jejunum, and hippocampus. MXYS also reduced serum permeability markers of lipopolysaccharide (LPS), D-lactate (D-Lac), and diamine oxidase (DAO), as well as concentrations of pro-inflammatory cytokines TNF-α and IL-1β in both intestinal tissues and the hippocampus. Gut microbiota analysis revealed that MXYS notably decreased the relative abundance of Desulfovibrio in the colon, which was associated with modulation of β-alanine metabolism. In the jejunum, MXYS increased the relative abundance of Clostridium sp. mbf VZ-132 and influenced glycerophospholipid metabolism.
CONCLUSION: MXYS alleviates social avoidance in CSDS-induced depressed mice is associated with the restoration of intestinal barrier function via gut microbiota-mediated pathways. Specifically, it may reduces colon Desulfovibrio abundance to modulate β-alanine/aspartate metabolism and enhance claudin-1 expression, while increasing jejunal Clostridium sp. mbf VZ-132 to regulate glycerophospholipid metabolism and upregulate occludin expression. These findings suggested that MXYS may improves depression-like behavior through segment-specific microbial and metabolic modulation of intestinal permeability.