Immunotherapy-mediated modulation of the gut microbiota in multiple sclerosis and associations with diet and clinical response-the effect of dimethyl fumarate therapy.

Background: Accumulating evidence supports a role of the microbiota in health and disease, including in multiple sclerosis (MS). How MS drugs affect the microbiota and whether this is part of their mode of action is yet unknown.

Objectives: To assess how dimethyl fumarate (DMF) affects the gut microbiota and whether the microbiota is associated with clinical response or adverse events (AEs) to DMF or diet.

Design: An observational cohort study, in which the microbiota from 45 patients with relapsing-remitting MS pre-DMF initiation and following 6 months of DMF therapy, and from 47 matched healthy controls, were compared, and associations with clinical and dietary data assessed.

Data sources and methods: Microbial DNA was sequenced and analyzed using MicrobiomeAnalyst. The clinical response was assessed after 1-year DMF therapy based upon evidence of disease activity (relapse, ΔEDSS increase >1, or MRI activity compared to pre-treatment). Dietary data were obtained by food questionnaires.

Results: Alterations in relative abundance of several microbes were identified post 6-month DMF therapy compared to pre-treatment, including an increase in Firmicutes, Lachnospiraceae, and Ruminococcaceae, while reduction in Bacteroidetes and Proteobacteria. Patients who showed disease activity within 1 year from DMF initiation had pre-treatment higher abundance of Proteobacteria, Flavonifractor, and Acidaminococcaceae, while lower abundance of Firmicutes, Ruminococcaceae, Butyricicoccus, and Massiliprevotella massiliensis, compared to patients without disease activity. Patients who discontinued DMF therapy due to AEs had pre-treatment higher abundance of Proteobacteria, Bacteroidetes, Eggerthella, and Lachnoclostridium and lower abundance of Ruminococcaceae, Megamonas, and Holdemanella, among others. Differentially abundant microbes correlated with intake of several nutrients.

Conclusion: DMF immunotherapy is associated with modifications of the microbiota. The microbiota may affect the severity of AEs and the clinical response to DMF, and is potentially modulated by diet. Microbiota-based, personalized treatment approach, integrating pharmacotherapy with dietary components, carries potential to improved clinical outcome.