The causal role of skin microbiota in rheumatoid arthritis via gut microbiota and immune cell mediation: A Mendelian randomization study

Emerging evidence suggests that disturbances in skin microbiota homeostasis may contribute to rheumatoid arthritis (RA) development through systemic immunomodulatory pathways. However, the causal relationships and underlying intermediary mechanisms remain to be clarified. We utilized summary-level data from large-scale genome-wide association studies and the FinnGen database, including 150 skin microbiota taxa, 731 immune cell phenotypes, 473 gut microbiota taxa, and RA cases. Two-sample Mendelian randomization (TSMR) was applied to evaluate potential causal associations with RA. Mediation analysis was further performed to identify the intermediary roles of immune cells and gut microbiota. Multiple sensitivity analyses were conducted to ensure the robustness of the findings. We identified significant causal associations between 6 skin microbiota, 25 immune cell phenotypes, and 19 gut microbiotas with RA. Mediation analysis indicated that certain immune cell traits and gut microbes may act as intermediaries in these relationships. Specifically, 20.3% of the protective effect of phylum Proteobacteria_Dry on RA risk was mediated by species Eubacterium F sp000434115. In contrast, genus Photobacterium accounted for 21.1% of the risk effect mediated by family Micrococcaceae_Dry. Additionally, immune phenotypes such as CD3+ Tregs and CX3CR1+ monocytes partially offset microbial risks, underscoring a novel "skin-gut-immune" axis in RA etiology. This Mendelian randomization study provides robust genetic evidence supporting the causal role of skin microbiota in rheumatoid arthritis pathogenesis via dual mediation pathways involving gut microbiota and immune cells. Our results suggest that targeting the skin and gut microbiota could represent a novel preventive or adjunctive therapeutic strategy for RA. For instance, probiotics or prebiotics aimed at enriching protective taxa (e.g., Proteobacteria, Fournierella massiliensis) or suppressing risk-associated microbes (e.g., Photobacterium, Brachyspira) might help restore immune homeostasis. Additionally, immunomodulatory approaches focusing on Treg enhancement or CX3CR1+ monocyte regulation could be informed by the identified immune phenotypes. Future studies should validate these mechanisms in longitudinal cohorts and explore microbiome-based precision medicine for RA.