Propionic acid promotes neurite recovery in damaged multiple sclerosis neurons

Neurodegeneration in the autoimmune disease multiple sclerosis 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 multiple sclerosis (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 CNS neurons. We analyzed neurite recovery in the presence of the SCFAs propionic acid (PA) and butyric acid (BA) in a reverse translational disease-in-a-dish model of human induced primary neurons (iPNs) differentiated from pwMS-derived induced pluripotent stem cells (iPSCs). We found that recovery of damaged neurites is induced by PA and BA, respectively. We could also show that administration of BA is able to enhance PA-associated neurite recovery. Whole cell proteome analysis of iPNs following recovery in the presence of PA revealed abundance changes of protein groups that are associated with the chromatin assembly, translational-, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylases (HDAC) class I/II following both PA and BA treatment, mediated by free fatty acid receptor (FFAR) signaling. While neurite recovery in the presence of PA is promoted by activation of the anti-oxidative response, administration of BA increases neuronal ATP synthesis in pwMS-specific iPNs.