Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism

• Published in: Cell Vol. 180; no. 6; pp. 1067 - 1080.e16
• Main Authors: Duscha, Alexander, Gisevius, Barbara, Hirschberg, Sarah, Yissachar, Nissan, Stangl, Gabriele I., Dawin, Eva, Bader, Verian, Haase, Stefanie, Kaisler, Johannes, David, Christina, Schneider, Ruth, Troisi, Riccardo, Zent, Daniel, Hegelmaier, Tobias, Dokalis, Nikolaos, Gerstein, Sara, Del Mare-Roumani, Sara, Amidror, Sivan, Staszewski, Ori, Poschmann, Gereon, Stühler, Kai, Hirche, Frank, Balogh, Andras, Kempa, Stefan, Träger, Pascal, Zaiss, Mario M., Holm, Jacob Bak, Massa, Megan G., Nielsen, Henrik Bjørn, Faissner, Andreas, Lukas, Carsten, Gatermann, Sören G., Scholz, Markus, Przuntek, Horst, Prinz, Marco, Forslund, Sofia K., Winklhofer, Konstanze F., Müller, Dominik N., Linker, Ralf A., Gold, Ralf, Haghikia, Aiden
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.03.2020
• Subjects: Adult; Aged; autoimmune diseases; Disease Progression; Feces - chemistry; Feces - microbiology; Female; Humans; immune modulation; Immunomodulation - physiology; Male; microbiome; Middle Aged; multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - therapy; neuroregeneration; Propionates - immunology; Propionates - metabolism; Propionates - therapeutic use; propionic acid; regulatory T cells; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; autoimmune diseases; regulatory T cells; neuroregeneration; multiple sclerosis; immune modulation; microbiome; propionic acid
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.02.035

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. [Display omitted] •PA is reduced in MS patients, particularly early after disease manifestation•PA reduction is associated with an altered gut microbiome composition•After 14 days of PA supplementation, Treg cell/TH17 imbalance was restored•Longitudinal PA supplementation might have clinical implications Supplementation of the short-chain fatty acid propionic acid (PA) in multiple sclerosis (MS) patients reverses the Treg cell/Th17 cell imbalance via increased Treg cell induction and enhancement of Treg cell function and is associated with disease course improvement.