Alpha-glycosyl isoquercitrin alleviates subchronic social defeat stress-induced depressive symptoms via the modulating the microbiota-gut-brain axis in mice

There is increasing evidence of the association between gut microbial dysbiosis and the pathogenesis of depression. Alpha-glycosyl isoquercitrin (AGIQ) consists of isoquercitrin and its glycosylated derivatives and has potential effects on brain functions. However, the effect of AGIQ on depression and its underlying mechanism remains unclear. Here, we investigated the potential antidepressant effect of four-week administration of AGIQ (0.05% and 0.5% in drinking water) and underlying mechanisms using a mouse model of depression induced by subchronic social defeat stress before behavioral testing. Behavior tests showed 0.5% AGIQ treatment significantly mitigated depression-like behaviors, accompanied by increased hippocampal 5-hydroxytryptamine (5-HT) level. 16s rRNA sequencing indicated that AGIQ mitigated gut microbial abnormalities induced by stress. Meanwhile, AGIQ reduced the levels of lipopolysaccharide (LPS) in serum, which was shown to affect the relative gene level of 5-HT biosynthesis-related enzymes in vitro. Furthermore, AGIQ reversed the reduced level of butyrate in cecal contents and improved the impaired intestinal barrier by increasing the expression of zonula occluden-1 (ZO-1) and occludin in the colon, contributing to the decreased LPS leakage. Oral administration of butyrate could increase the gene level of ZO-1 and occludin. In summary, AGIQ could regulate gut microbial dysbiosis and metabolite butyrate level and restore intestinal permeability, thereby decreasing serum LPS concentration, the gene expression of pro-inflammatory cytokine in the hippocampus, and ultimately increasing hippocampal 5-HT level and mitigating depression-like behaviors.