Background: The gut microbiota and plasma metabolites have been shown to contribute to the etiology of post-traumatic stress disorder (PTSD). The relationship between the gut microbiome and plasma metabolome in PTSD is poorly understood. This study aims to integrate the gut microbiome data and plasma metabolome data to elucidate microbial–metabolite associations specific for PTSD in a mouse model. Methods: A PTSD mouse model was induced by single prolonged stress and electric foot shock (SPS&S). We sequenced the gut microbiota composition by 16S rRNA gene sequencing and used ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) for the plasma metabolomic profiling to explore the association between the gut microbiota and the plasma metabolites in mice with PTSD. Results: The PTSD mice exhibited robust anxiety-like behaviors, significantly elevated plasma IL-1β and TNF-α, and profound gut dysbiosis characterized by a marked depletion of Muribaculaceae and Akkermansia and expansion of the Lachnospiraceae_NK4A136_group. The plasma metabolomics identified 24 significantly dysregulated metabolites, including upregulated L-arginine, palmitic acid, and oleic acid, and downregulated uridine. The pathway enrichment analysis revealed coordinated perturbations in arginine biosynthesis, pyrimidine metabolism, unsaturated fatty acid biosynthesis, and glycerophospholipid metabolism. Critically, genus-level correlation analysis uncovered biologically coherent associations. The Muribaculaceae abundance showed strong negative correlations with L-arginine and palmitic acid and positive correlations with L-glutamine and thymidine. Conclusions: This study provides an exploratory investigation into the association network between the gut microbiota and the plasma metabolites in a PTSD mouse model, offering preliminary insights into potential microbe–metabolite interactions in PTSD.

Background: The gut microbiota and plasma metabolites have been shown to contribute to the etiology of Post-Traumatic Stress Disorder (PTSD). The relationship between the gut microbiome and plasma metabolome in PTSD is poorly understood. This study aims To integrate the gut microbiome data and plasma metabolome data to elucidate microbial–metabolite associations specific for PTSD in a mouse model. Methods: A PTSD mouse model was induced by Single Prolonged Stress and Electric Foot Shock (SPS&S). We sequenced gut microbiota composition by 16S rRNA gene sequencing and used Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) for plasma metabolomic profiling, to explore the association Between gut microbiota and plasma metabolites in mice with PTSD. Results: UHPLC-MS/MS analysis showed significant differences in the abundance of multiple plasma metabolites, including L-arginine, palmitic acid, oleic acid, uridine, in mice with PTSD versus control mice. Pathway enrichment analysis further revealed that these differentially abundant metabolites were all enriched in pathways such as arginine biosynthesis, unsaturated fatty acid biosynthesis, pyrimidine metabolism and glycerophospholipid metabolism. Meanwhile, 16S rRNA sequencing revealed differences in the composition and diversity of the gut microbes in PTSD mice and control mice. For example, the relative abundance of the Muribaculaceae and Akkermansia genera decreased significantly in the PTSD group, while relative abundance of Lachnospiraceae NK4A136_group increased significantly in the PTSD group. Further correlation analysis showed strong correlation between the plasma metabolome and gut microbiome. Conclusions: These findings confirm the association between the gut microbiome and the plasma metabolome in PTSD and point to these specific taxa and their connected metabolites as potential biomarkers and treatment targets in PTSD.