Ocrelizumab transiently alters microbiota and modulates immune response depending on treatment outcome

Multiple sclerosis (MS) is an autoimmune disease characterized by central nervous system atrophy. Microbiota dysbiosis is implicated in MS pathogenesis and treatment outcomes. In our study, we observed microbiota changes already present in treatment-naïve individuals with clinically isolated syndrome, affecting both bacteria and viruses. Gut bacteria alterations were transient during the first 12 months of anti-CD20 therapy. After 12 months, responders showed increased gut microbiota alpha diversity approaching healthy control levels, while non-responders showed a significant decline. Key changes involved <i>Parabacteroides</i> spp., producers of short-chain fatty acids that support gut barrier function and have anti-inflammatory potential. We detected altered gut barrier biomarkers and antibodies against common commensals in MS patients, which were modulated by anti-CD20 treatment. Notably, lipopolysaccharide-binding protein and mannose-binding lectin decreased only in responders. These findings suggest that intestinal barrier damage contributes to immune responses linked to microbial translocation, MS pathogenesis, and treatment outcomes.