Investigating the Gut Microbiota-Inflammatory Cytokine-Skin Axis in Inflammatory Skin Diseases: Evidence from Mendelian Randomization

Background: Previous studies have reported causal associations between gut microbiota and inflammatory skin diseases; however, the underlying mechanisms remain unclear. Inflammatory cytokines may mediate the gut-skin axis. This study aimed to investigate the mediating roles of inflammatory cytokines in the associations between gut microbiota and inflammatory skin diseases. Methods: Genome-wide association study (GWAS) summary data for 473 gut microbiota taxa, 91 inflammatory cytokines, and 11 inflammatory skin diseases were analyzed. Mendelian randomization (MR) analyses were performed using the inverse variance weighted method as the primary approach. Two-step MR analysis was further conducted to evaluate the mediating effects of inflammatory cytokines. Results: Ten inflammatory cytokines were identified as potential mediators linking gut microbiota and inflammatory skin diseases. Interleukin (IL)-10 and IL-18 mediated associations with eczema, while IL-18R1 mediated associations with eczema and atopic dermatitis. Fibroblast growth factor (FGF)-19 and IL-6 mediated associations with allergic contact dermatitis. In addition, C-C motif chemokine ligand 23 (CCL23), vascular endothelial growth factor A (VEGF-A), artemin (ARTN), IL-8, and Delta and Notch-like epidermal growth factor-related receptor (DNER) mediated associations involving alopecia areata, vitiligo, seborrheic dermatitis, and rosacea. All identified inflammatory cytokines showed mediation proportions greater than 5%. Conclusion: Our findings suggest that specific inflammatory cytokines may mediate the associations between gut microbiota and inflammatory skin diseases. These results provide new insights into the gut microbiota-cytokine-skin disease axis and may contribute to the identification of potential therapeutic targets for inflammatory skin diseases. Keywords: inflammatory skin diseases, Mendelian randomization, gut microbiota, inflammatory cytokines