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

Alexander Duscha; Barbara Gisevius; Sarah Hirschberg; Nissan Yissachar; Gabriele I. Stangl; Eva Dawin; Verian Bader; Stefanie Haase; Johannes Kaisler; Christina David; Ruth Schneider; Riccardo Troisi; Daniel Zent; Tobias Hegelmaier; Nikolaos Dokalis; Sara Gerstein; Sara Del Mare-Roumani; Sivan Amidror; Ori Staszewski; Gereon Poschmann; Kai Stühler; Frank Hirche; Andras Balogh; Stefan Kempa; Pascal Träger; Mario M. Zaiss; Jacob Bak Holm; Megan G. Massa; Henrik Bjørn Nielsen; Andreas Faissner; Carsten Lukas; Sören G. Gatermann; Markus Scholz; Horst Przuntek; Marco Prinz; Sofia K. Forslund; Konstanze F. Winklhofer; Dominik N. Müller; Ralf A. Linker; Ralf Gold; Aiden Haghikia

doi:10.1016/j.cell.2020.02.035

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

Alexander Duscha
, Barbara Gisevius
, Sarah Hirschberg
, Nissan Yissachar
, Gabriele I. Stangl
, Eva Dawin
, Verian Bader
, Stefanie Haase
, Johannes Kaisler
, Christina David
, Ruth Schneider
, Riccardo Troisi
, Daniel Zent
, Tobias Hegelmaier
, Nikolaos Dokalis
, Sara Gerstein
, Sara Del Mare-Roumani
, Sivan Amidror
, Ori Staszewski
, Gereon Poschmann

Kai Stühler, Frank Hirche, Andras Balogh, Stefan Kempa, Pascal Träger, Mario M. Zaiss, Jacob Bak Holm, Megan G. Massa, Henrik Bjørn Nielsen, Andreas Faissner, Carsten Lukas, Sören G. Gatermann, Markus Scholz, Horst Przuntek, Marco Prinz, Sofia K. Forslund, Konstanze F. Winklhofer, Dominik N. Müller, Ralf A. Linker, Ralf Gold, Aiden Haghikia

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

517 Scopus citations

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.

Original language	English
Pages (from-to)	1067-1080.e16
Journal	Cell
Volume	180
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2020.02.035
State	Published - 19 Mar 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

The study was funded by SFB TR128 (Deutsche Forschungsgemeinschaft), the DMSG (Deutsche MS Gesellschaft in NRW), FoRUM (Ruhr-University Bochum), the Rose-Stiftung, ProDi (Proteindiagnostik RUB), the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin – inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung. Statistical analyses and gene expression data were supported by the German Network for Bioinformatics Infrastructure (Karin Schork) – de.NBI, Service Center BioInfra.Prot, a project of the German Federal Ministry of Education and Research (BMBF) (FKZ 031 A 534A). D.N.M. is supported by the DZHK and the DFG (SFB 1365). K.F.W. is supported by the German Research Foundation (DFG, Research Unit 2848). SR-SIM microscopy was funded by the German Research Foundation and the State Government of North Rhine-Westphalia (INST 213/840-1 FUGG). We thank Anna Lena Fisse, Miriam Fels, Christoph Schröder, Katrin Straßburger-Krogias, Laura Tomaske, Daniel Richter, and Janina Kneiphof for identifying subjects with MS of interest for this study. Conceptualization, A.D. B.G. S. Hirschberg, N.Y. R.A.L. R.G. and A.H.; Formal Analysis, A.D. S. Hirschberg, N.Y. M.S. S.K.F. and A.H.; Funding Acquisition, R.G. and A.H.; Investigation, A.D. B.G. S. Hirschberg, N.Y. E.E. V.B. S. Haase, J.K. C.D. R.S. R.T. D.Z. T.H. N.D. S.G. S.D.M.-R. O.S. S.A. K.S. F.H. A.B. S.K. P.T. M.M.Z. J.B.H. H.B.N. C.L. S.G.G. G.P. and A.H.;, Methodology, A.D. V.B. E.E. N.Y. and A.H.; Project Administration, N.Y. A.F. H.P. R.A.L. D.N.M. M.P. R.G. and A.H.; Supervision, N.Y. G.I.S. K.F.W. and A.H.; Visualization, A.D. S. Hirschberg, N.Y. V.B. and A.H.; Writing – Original Draft, A.D. B.G. S. Hirschberg, N.Y. R.S. S.K.F. and A.H.; Writing – Review & Editing, A.D. B.G. S. Hirschberg, N.Y. J.K. R.S. M.G.M. M.S. S.K.F. R.A.L. R.G. and A.H. R.G. and A.H. have filed a patent on the supportive immunomodulatory effect of C3-C8 aliphatic fatty acids. The study was funded by SFB TR128 ( Deutsche Forschungsgemeinschaft ), the DMSG (Deutsche MS Gesellschaft in NRW), FoRUM (Ruhr-University Bochum), the Rose-Stiftung, ProDi (Proteindiagnostik RUB), the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen , the Regierende Bürgermeister von Berlin – inkl. Wissenschaft und Forschung , and the Bundesministerium für Bildung und Forschung . Statistical analyses and gene expression data were supported by the German Network for Bioinformatics Infrastructure (Karin Schork) – de.NBI , Service Center BioInfra.Prot , a project of the German Federal Ministry of Education and Research (BMBF) ( FKZ 031 A 534A ). D.N.M. is supported by the DZHK and the DFG ( SFB 1365 ). K.F.W. is supported by the German Research Foundation (DFG, Research Unit 2848 ). SR-SIM microscopy was funded by the German Research Foundation and the State Government of North Rhine-Westphalia ( INST 213/840-1 FUGG ). We thank Anna Lena Fisse, Miriam Fels, Christoph Schröder, Katrin Straßburger-Krogias, Laura Tomaske, Daniel Richter, and Janina Kneiphof for identifying subjects with MS of interest for this study.

Funders	Funder number
Deutsche MS Gesellschaft
Rose-Stiftung
State Government of North Rhine-Westphalia	INST 213/840-1 FUGG
Wissenschaft und Forschung
Deutsches Zentrum für Herz-Kreislaufforschung
FORUM Pharmaceuticals
Deutsche Forschungsgemeinschaft	SFB 1365
Bundesministerium für Bildung und Forschung	FKZ 031 A 534A
Ruhr-Universität Bochum
Deutschen Multiple Sklerose Gesellschaft
Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
German Network for Bioinformatics Infrastructure

Keywords

autoimmune diseases
immune modulation
microbiome
multiple sclerosis
neuroregeneration
propionic acid
regulatory T cells

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10.1016/j.cell.2020.02.035

http://www.cell.com/article/S0092867420302129/pdf

Cite this

Duscha, A., Gisevius, B., Hirschberg, S., Yissachar, N., Stangl, G. I., Dawin, E., Bader, V., Haase, S., Kaisler, J., David, C., Schneider, R., Troisi, R., Zent, D., Hegelmaier, T., Dokalis, N., Gerstein, S., Del Mare-Roumani, S., Amidror, S., Staszewski, O., ... Haghikia, A. (2020). Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell, 180(6), 1067-1080.e16. https://doi.org/10.1016/j.cell.2020.02.035

@article{d6d1b53770424a52bce31d016b3ad95a,

title = "Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism",

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.",

keywords = "autoimmune diseases, immune modulation, microbiome, multiple sclerosis, neuroregeneration, propionic acid, regulatory T cells",

author = "Alexander Duscha and Barbara Gisevius and Sarah Hirschberg and Nissan Yissachar and Stangl, \{Gabriele I.\} and Eva Dawin and Verian Bader and Stefanie Haase and Johannes Kaisler and Christina David and Ruth Schneider and Riccardo Troisi and Daniel Zent and Tobias Hegelmaier and Nikolaos Dokalis and Sara Gerstein and \{Del Mare-Roumani\}, Sara and Sivan Amidror and Ori Staszewski and Gereon Poschmann and Kai St{\"u}hler and Frank Hirche and Andras Balogh and Stefan Kempa and Pascal Tr{\"a}ger and Zaiss, \{Mario M.\} and Holm, \{Jacob Bak\} and Massa, \{Megan G.\} and Nielsen, \{Henrik Bj{\o}rn\} and Andreas Faissner and Carsten Lukas and Gatermann, \{S{\"o}ren G.\} and Markus Scholz and Horst Przuntek and Marco Prinz and Forslund, \{Sofia K.\} and Winklhofer, \{Konstanze F.\} and M{\"u}ller, \{Dominik N.\} and Linker, \{Ralf A.\} and Ralf Gold and Aiden Haghikia",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = mar,

day = "19",

doi = "10.1016/j.cell.2020.02.035",

language = "אנגלית",

volume = "180",

pages = "1067--1080.e16",

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Duscha, A, Gisevius, B, Hirschberg, S, Yissachar, N, Stangl, GI, Dawin, E, Bader, V, Haase, S, Kaisler, J, David, C, Schneider, R, Troisi, R, Zent, D, Hegelmaier, T, Dokalis, N, Gerstein, S, Del Mare-Roumani, S, Amidror, S, Staszewski, O, Poschmann, G, Stühler, K, Hirche, F, Balogh, A, Kempa, S, Träger, P, Zaiss, MM, Holm, JB, Massa, MG, Nielsen, HB, Faissner, A, Lukas, C, Gatermann, SG, Scholz, M, Przuntek, H, Prinz, M, Forslund, SK, Winklhofer, KF, Müller, DN, Linker, RA, Gold, R & Haghikia, A 2020, 'Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism', Cell, vol. 180, no. 6, pp. 1067-1080.e16. https://doi.org/10.1016/j.cell.2020.02.035

TY - JOUR

T1 - Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism

AU - Duscha, Alexander

AU - Gisevius, Barbara

AU - Hirschberg, Sarah

AU - Yissachar, Nissan

AU - Stangl, Gabriele I.

AU - Dawin, Eva

AU - Bader, Verian

AU - Haase, Stefanie

AU - Kaisler, Johannes

AU - David, Christina

AU - Schneider, Ruth

AU - Troisi, Riccardo

AU - Zent, Daniel

AU - Hegelmaier, Tobias

AU - Dokalis, Nikolaos

AU - Gerstein, Sara

AU - Del Mare-Roumani, Sara

AU - Amidror, Sivan

AU - Staszewski, Ori

AU - Poschmann, Gereon

AU - Stühler, Kai

AU - Hirche, Frank

AU - Balogh, Andras

AU - Kempa, Stefan

AU - Träger, Pascal

AU - Zaiss, Mario M.

AU - Holm, Jacob Bak

AU - Massa, Megan G.

AU - Nielsen, Henrik Bjørn

AU - Faissner, Andreas

AU - Lukas, Carsten

AU - Gatermann, Sören G.

AU - Scholz, Markus

AU - Przuntek, Horst

AU - Prinz, Marco

AU - Forslund, Sofia K.

AU - Winklhofer, Konstanze F.

AU - Müller, Dominik N.

AU - Linker, Ralf A.

AU - Gold, Ralf

AU - Haghikia, Aiden

PY - 2020/3/19

Y1 - 2020/3/19

N2 - 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.

AB - 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.

KW - autoimmune diseases

KW - immune modulation

KW - microbiome

KW - multiple sclerosis

KW - neuroregeneration

KW - propionic acid

KW - regulatory T cells

UR - https://www.scopus.com/pages/publications/85081698624

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DO - 10.1016/j.cell.2020.02.035

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C2 - 32160527

SN - 0092-8674

VL - 180

SP - 1067-1080.e16

JO - Cell

JF - Cell

IS - 6

ER -

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

Abstract

Bibliographical note

Funding

Keywords

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