Abstract
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have
immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis
(MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS
exhibited significantly reduced PA amounts compared with controls, particularly after the first
relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as
an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained
increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells
decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore,
PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA
can serve as a potent immunomodulatory supplement to MS drugs.