Immunotherapy-Mediated Modulation of the Gut Microbiota in Multiple Sclerosis: The Effects of High-Efficacy (Cladribine) and Moderate-Efficacy (Interferon Beta-1a) Treatments.

Interactions between the gut microbiota, immune system, and brain seem to be involved in the pathogenesis and disease activity of multiple sclerosis (MS). Some MS disease-modifying therapies (DMTs) have been shown to alter the microbiota, but whether this is related to their specific mode of action or indirectly related to their immune-modulatory effect is unknown. In this longitudinal study, we characterized the effects of two DMTs on the microbiota under similar conditions and populations: the injectable, moderate-efficacy DMT interferon beta-1a (INFβ-1a) and the oral, high-efficacy DMT cladribine tablets (CladT). Taxonomic differences were identified following 6 months of therapy for each DMT, and both were associated with the elevation of short-chain fatty acid (SCFA) producers from the Lachnospiraceae, Lactobacillaceae, and Ruminococcaceae families (Firmicutes), while members of Bacteroidetes and Proteobacteria were reduced. Moreover, a higher abundance of Alphaproteobacteria and Betaproteobacteria at baseline was associated with disease activity within 1-2 years of follow-up, while a higher abundance of Lachnospiraceae, Ruminococcaceae, Bifidobacteriaceae, and Streptococcaceae microbes, among others, was associated with no evidence of disease activity (NEDA). Our results provide supporting evidence that alteration of the microbiota by DMTs is part of their beneficial effect, and while some modifications seem to be DMT-specific, MS-DMTs in general promote SCFA-producing microbes, which positively correlate with a favorable clinical outcome. Future therapeutic strategies for PwMS may benefit from microbiome modulation, contingent upon additional mechanistic and interventional studies.