Updated project metadata. Neurodegeneration in the autoimmune disease multiple sclerosis (MS) still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with MS (pwMS), supplementation of the short-chain fatty acid (SCFA) propionic acid (PA), as microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine, whether the neuroprotective impact of PA is a direct mode of action of SCFAs on central nervous system (CNS) neurons.