Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.
