Influence of oral and skin microbiota on multiple sclerosis risk and severity: A mendelian randomization analysis

Recent research on the impact of gut microbiota on multiple sclerosis (MS) has been extensive; however, the role of microbial composition in other body interfaces, such as the mouth and the skin, has received much less attention. In a first step towards addressing this gap, we used Mendelian Randomization (MR), an analytical approach using genetic variants as proxies for environmental exposures to estimate the causal relationship between a risk factor and an outcome. Here, we performed a two-sample MR analysis to assess the link between oral and skin microbiome composition and both MS risk and severity. Exposure data were extracted from summary statistics of two large genomewide association studies (GWAS) assessing the influence of host genetics on the microbiome composition of the oral cavity and skin. Outcome data derived from the largest GWAS on MS susceptibility and the recent GWAS on MS severity. After stringent instrumental variant selection, we applied inverse-variance-weighted (IVW) and Wald's ratio as primary MR methods, MR EGGER to control for horizontal pleiotropy, and checked directionality through Steiger's test. We found that the relative abundance of Veillonella genus in the skin may enhance MS risk, while no significant association between oral composition and MS susceptibility emerged. Furthermore, we found the Gammaproteobacteria class in the skin is associated with MS severity. We also identified suggestive, protective signals from different oral microbial strains (Bacilli class, Porphyromonas genus, Proteobacteria phylum and Veillonella dispar species). Overall, our findings provide preliminary evidence supporting the hypothesis that skin microbiota might contribute to MS risk, and both oral and skin microbial composition could affect disease severity, broadening the relevance of dysbiosis beyond the gut in MS etiopathogenesis.