Effect of diroximel fumarate on gut dysbiosis and autoimmunity in the central nervous system

Diroximel fumarate (DRF) is an approved treatment for relapsing-remitting multiple sclerosis (RRMS). It has demonstrated better gastrointestinal tolerability compared to dimethyl fumarate (DMF). Recent studies indicate that gut dysbiosis may contribute to the development of multiple sclerosis (MS) and that reducing gut dysbiosis may be beneficial for disease progression. This study investigated the effects of DRF on gut dysbiosis and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We examined the effect of DRF on the expression of α4β1 and α4β7 integrins on CD4 + T cells, which are essential for guiding their migration into the central nervous system (CNS) and the gut, respectively. The expression of α4β1 increased in lymph nodes when EAE was induced, but DRF treatment reduced its expression and the production of IL-17. The expression of α4β7 on T cells was also upregulated in the lymph nodes, and the infiltration of α4β7 + CD4+ T cells into the gut increased following EAE induction. DRF treatment reduced the development of α4β7 + CD4+ T cells in the lymph nodes and their infiltration into the small intestine. This led to a decrease in the gut dysbiosis biomarker, lipocalin 2 (Lcn2), and a reduction in pathogenic bacteria from the Desulfovibrionaceae family in EAE mice. In patients with relapsing-remitting multiple sclerosis (RRMS), treatment with DRF showed a trend toward decreased levels of α4β1 + CD4+ T cells and endotoxin, which is a blood marker of intestinal permeability. Furthermore, DRF reduced the production of CCL22, a chemokine derived from macrophages. Overall, our findings suggest that DRF can reduce neuroinflammation by lowering the production of IL-17, inhibiting the development of α4β1 + CD4+ T cells and α4β7 + CD4+ T cells in the lymph nodes, and alleviating dysfunction associated with gut dysbiosis and intestinal permeability.