Multiomics Approach to Explore the Different Amelioration Mechanisms of Chaihu Shugan San and Hypericum perforatum L. on the Metabolic Disorder of CUMS-induced Depressive Rats

In traditional herbal medicine, the roles of Chaihu Shugan San (CSGS) and Hypericum perforatum L. (SJW) in depression are highly valued. However, the two drugs’ mechanisms of action remain unclear. Our work studies potential antidepressant mechanisms of CSGS and SJW by analyzing ultra-performance liquid chromatography mass spectrometry metabolomics, data independent acquisition-based quantitative proteomics, and 16S rDNA sequencing experiments in chronic unpredictable mild stress (CUMS) rats. Under the CUMS-induced depressive model, we assessed the antidepressant effects of CSGS and SJW by behavioral tests. Serum differential metabolites analysis was conducted through hierarchical clustering, Venn analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Bioinformatics analysis of liver differential proteins was conducted through hierarchical clustering, Gene Ontology (GO) annotation enrichment, Reactome pathway enrichment, and KEGG pathway enrichment. We also performed 16S rDNA sequencing analysis via hierarchical clustering and KEGG pathway enrichment. Behavioral results demonstrate that CSGS and SJW could effectively improve depression symptoms. After treatment with CSGS, 49 differential metabolites and 204 differential proteins were identified. KEGG enrichment analysis and Pearson's correlation analysis indicated that differential metabolites and proteins were abundant in arachidonic acid metabolism and lipid metabolism related processes including biosynthesis of unsaturated fatty acids, pantothenate and coenzyme A (CoA) biosynthesis, peroxisome proliferator-activated receptors (PPAR) signaling pathway, and Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. After treatment with SJW, a total of 69 differential metabolites and 473 differential proteins were identified and the intestinal flora composition changed significantly. KEGG and Spearman correlation analysis showed that histidine metabolism, lipid metabolism, and intestinal bacterial regulation might be the principal pathways through which SJW acts on depression. Our experimental results indicate that CSGS and SJW play important roles in antidepressant actions by restoring differential metabolites and proteins, resulting in the recovery of the metabolic disorders in depression. Moreover, these results provide novel perspectives on the potential targets of traditional herbal medicine in depression.