Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). While the cause of MS is not known, environmental factors and genetic disposition are considered to increase the risk of acquiring the disease. Previous studies have shown that a ‘western diet’, rich in salt and saturated long chain fatty acids (LCFA) enhances the pro-inflammatory immune responses in experimental autoimmune encephalomyelitis (EAE). The LCFA lauric acid (LA) leads to an enhanced differentiation and proliferation of TH1/TH17 cells and worsened clinical course of EAE. In contrast, the short chain fatty acid propionate (PA) ameliorated EAE, via an increased Treg differentiation in the gut. This study investigated the harmful effects of LA and the potential therapeutic effects of PA on the course of EAE during feeding a LA rich diet. Methods: MOG-EAE was induced in C57BL/6 mice fed a normal diet (ND) or LA-rich diet starting four weeks before immunization. In another experiment LA-fed mice received additionally PA or water as a control via oral gavage starting at the day of immunization. Mice were clinically evaluated; spinal cord cross sections were stereologically analyzed after staining for demyelination (Luxol Fast Blue), infiltrating immune cells (CD3, Mac3), glial cells (GFAP, Olig2, NogoA), neurons (Kresyl-Violett) and axons (Bielschowsky silver staining) at the maximum and the long-term course of disease. Results: Mice fed a LA-diet showed a more severe EAE course compared to ND-fed mice. The deleterious clinical effect of LA diet was reversed by oral gavage of PA after immunization. The clinical effect was paralleled by a significantly reduced T cell infiltration and reduced number of macrophages in the spinal cord at the maximum of EAE. In addition, PA treated mice showed less pronounced demyelination, reduced axonal loss, and diminished astrogliosis. Conclusion: In conclusion propionate treatment reverts the deleterious effect of a LA diet. Therefore, a propionate therapy may serve as a safe and effective immune- regulatory add-on therapy in multiple sclerosis.