Systematic druggable genome-wide Mendelian randomization to identify therapeutic targets and dominant flora for...

The relationship and mechanism among gut microbiota (GM), metabolites and active ulcerative colitis (UC) are unclear. This study aims to infer the causal relationship between druggable-genes and active UC using Mendelian randomization (MR) and bioinformatics methods. The "microbiota-target" and "microbiota- metabolite" network was constructed to screen the microorganisms and metabolites associated with active UC, and the mechanism of GM, metabolites and active-UC was analyzed. These findings were verified through molecular docking, molecular dynamics (MD) simulations and co-localization analysis. Subsequently, the effects of key GM and targets on mice with UC induced by dextran sulfate sodium (DSS) was investigated. Our findings indicated that four drug targets (IFN-γ, IL24, CXCR6, PRKCZ) are closely associated with the risk of active UC, with IL24 specifically found to be colocalized with UC. These four targets were significantly correlated with differences of immune cell infiltration in active-UC. Faecalibacterium prausnitzii (F. prausnitzii) was predicted to inhibit IFN-γ and promote the remission of active UC. Additionally, seven GM were identified to be associated with the risk of active UC. Molecular docking and MD further confirmed the stable interactions between IFN-γ and metabolites of F. prausnitzii. We also verified the alleviating effect of F. prausnitzii on DSS-induced UC mice. The result indicated that F. prausnitzii can reduce inflammatory cell infiltration and goblet cell death in the colon, lower myeloperoxidase activity, and downregulate IFN-γ expression levels. This study revealed that GM can modify the immune microenvironment of active UC, providing new ideas for the prevention and treatment of UC.