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Accumulating evidence links the microbial communities inhabiting the gut to the pathophysiological processes underlying multiple sclerosis (MS). However, most studies on the microbiome in MS are correlative in nature, thus being at risk of confounding and reverse causality. Mendelian randomization (MR) analyses allow the estimation of the causal relationship between a risk factor and an outcome of interest using genetic variants as proxies for environmental exposures. Here, we performed a two-sample MR to assess the causality between the gut microbiome and MS. We extracted genetic instruments from summary statistics from three large genome-wide association studies (GWASs) on the gut microbiome (18,340, 8959, and 7738 subjects). The exposure data were derived from the latest GWAS on MS susceptibility (47,429 patients and 68,374 controls). We pinpointed several microbial strains whose abundance is linked with enhanced MS risk (<i>Actinobacteria</i> class, <i>Bifidobacteriaceae</i> family, <i>Lactobacillus</i> genus) or protection (<i>Prevotella</i> spp., <i>Lachnospiranaceae</i> genus, <i>Negativibacillus</i> genus). The largest risk effect was seen for <i>Ruminococcus Torques</i> (OR, 2.89, 95% C.I. 1.67–5, <i>p</i> = 1.51 × 10⁻⁴), while <i>Akkermansia municiphila</i> emerged as strongly protective (OR, 0.43, 95% C.I. 0.32–0.57, <i>p</i> = 1.37 × 10⁻⁸). Our findings support a causal relationship between the gut microbiome and MS susceptibility, reinforcing the relevance of the microbiome–gut–brain axis in disease etiology, opening wider perspectives on host–environmental interactions for MS prevention.