Integrating multi-omics to reveal the causal effect of gut microbiota on post-traumatic stress disorder and potential drug target analysis

<b>Background:</b> Observational evidence indicates genetic factors influence both gut microbiota composition and post-traumatic stress disorder (PTSD) susceptibility. But robust common variants have not been identified. This study aimed to investigate the common genetic variant loci and potential drug targets between the gut microbiota and PTSD. <b>Methods:</b> Based on public databases, we conducted a genome-wide association analysis (GWAS) of 207 microbial taxa and 205 pathways. Causal relationships were established through bidirectional Mendelian randomization (MR) and Bayesian weighted mendelian randomization (BWMR), with sensitivity analyses confirming robustness. Genetic risk loci were identified by single-nucleotide polymorphism (SNP) functional annotation, polygenic priority score (PoPs) and differentially expressed genes (DEGs). Summary-data-based Mendelian randomization (SMR) revealed the hypothesized druggable targets. Subsequently, a hypothetical verification was conducted through network pharmacology and molecular docking. Finally, we performed immune infiltration analysis for hypothesized gene targets. <b>Results:</b> Based on the results of the hypothetical analysis, we found that four taxa and one pathway demonstrated robust associations across analytical methods, validated by sensitivity analyses. On the basis of GWAS results and whole-blood expression quantitative trait locus (eQTL) data, ACOX3 was identified as a hypothesized locus with a causal role in PTSD treatment via SMR analysis. Moreover, further cross-validated in brain eQTL data. Network pharmacology and molecular docking analyses were used to predict hypothesized drug target interactions, further supporting their therapeutic potential. Immune infiltration analysis revealed a synergistic relationship between ACOX3 and T-cell gamma delta. <b>Conclusion:</b> Multi-omics analyses may suggest ACOX3 as a hypothesized drug target for PTSD, and future drug development has provided initial drug candidates and insights. Four taxa and one pathway showed robust associations with PTSD in different analysis methods.The multi-omics integrative analysis identified ACOX3 as a key risk locus for the treatment of PTSD.Network pharmacology and molecular docking revealed mechanism based drug-ACOX3 interactions. Four taxa and one pathway showed robust associations with PTSD in different analysis methods. The multi-omics integrative analysis identified ACOX3 as a key risk locus for the treatment of PTSD. Network pharmacology and molecular docking revealed mechanism based drug-ACOX3 interactions.