Effect of dimethyl fumarate and glatiramer acetate on the immunological profiles and gut microbiota in Multiple Sclerosis patients

Objective: To address whether two therapies used for Relapsing Remitting Multiple Sclerosis (RRMS) might differentially impact the gut microbiota composition and DNA methylation profiles of CD4 + T cells. Background: The importance of environmental factors in MS pathogenesis is well established, though much remains to be learned to discern the identity of the significant environmental components as well as the mechanisms by which environment impacts disease onset and course. The gut microbiome, the composition of which is highly regulated by various environmental factors, has recently been suggested to play an important role. In addition, current knowledge regarding the mechanism of action of MS therapies remains incomplete. One potential link is the modulation of biological processes by epigenetic regulation of gene expression. We hypothesize that the composition of the gut microbiota that differ among patients might exert reciprocal interactions with disease-modifying therapies, leading to differential modulation of immune responses. Design/Methods: We collected blood and stool samples from carefully phenotyped RRMS patients who were either untreated or treated with GA or DMF for at least 3 months. Blood samples were immunophenotyped by flow cytometry. DNA methylation of sorted CD4 + T cells was evaluated by the Infinium MethylationEpic 850K arrays. Fecal microbiome was assessed by 16S rRNA amplicon sequencing. Results: Treatment with DMF resulted in more extensive epigenome-wide methlylation changes in CD4 + T cells than treatment with GA. Both agents were associated with changes in fecal microbiota as compared to untreated MS patients. The effects of DMF were more pronounced. Some of these paralleled changes noted in other studies while others were different. Conclusions: We suggest that microbial changes induced by MS treatments may modulate T cell function and may therefore potentially contribute to therapeutic response. Study Supported by: The National Multiple Sclerosis Society, The United States Department of Defense Disclosure: Dr. Katz Sand has nothing to disclose. Dr. Zhu has nothing to disclose. Dr. Cekanaviciute has nothing to disclose. Dr. Cree has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Novartis and Shire as a consultant. Dr. Mazmanian has nothing to disclose. Dr. Disla has nothing to disclose. Dr. Debelius has nothing to disclose. Dr. Knight has nothing to disclose. Dr. Watson has nothing to disclose. Dr. Singh has nothing to disclose. Dr. Kanner has nothing to disclose. Dr. Baranzini has received personal compensation for activities with EMD Serono, and Novartis. Dr. Casaccia has nothing to disclose.