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INTRODUCTION: Patients with multiple sclerosis may have a distinct gut microbiota profile. Delayed-release dimethyl fumarate is an orally administered drug for relapsing-remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients. OBJECTIVES: The purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal side-effects. METHODS: Thirty-six patients with relapsing-remitting multiple sclerosis received either dimethyl fumarate (n = 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n = 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls. RESULTS: At baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients (n = 21) we observed a trend of reduced Actinobacteria (p = 0.03, QFDR = 0.24) at two weeks, mainly driven by Bifidobacterium (p = 0.06, QFDR = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p = 0.02, QFDR = 0.09), mostly driven by Faecalibacterium (p = 0.01, QFDR = 0.48). CONCLUSIONS: This pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrate-producing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms.
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We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge. Combining intracellular cytokine staining with DQ2-α-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-γ (IFN-γ) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines. Similarly, in DQ2-α-II-specific T cells in peripheral blood of gluten-challenged patients, very few stained for intracellular IL-17, whereas many cells stained for IFN-γ. We conclude that gluten-reactive T cells produce IL-21 and IFN-γ, but not IL-17. Their production of IL-21 suggests a role for this cytokine in the pathogenesis of celiac disease.