Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.
Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany. Electronic address: aiden.haghikia@rub.de.
Aiden
A
Haghikia
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Stefanie
S
Jörg
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany.
Alexander
A
Duscha
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany.
Johannes
J
Berg
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Arndt
A
Manzel
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Anne
A
Waschbisch
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Anna
A
Hammer
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
De-Hyung
DH
Lee
Medical Proteom-Center, Ruhr-University Bochum, 44801 Bochum, Germany.
Caroline
C
May
Experimental and Clinical Research Center & Max-Delbrück Center Berlin, 13125 Berlin, Germany.
Nicola
N
Wilck
Experimental and Clinical Research Center & Max-Delbrück Center Berlin, 13125 Berlin, Germany.
Andras
A
Balogh
Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
Annika I
AI
Ostermann
Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Department of Food Chemistry, University of Wuppertal, 42097 Wuppertal, Germany.
Nils Helge
NH
Schebb
Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany.
Denis A
DA
Akkad
Translational Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
Diana A
DA
Grohme
Translational Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
Markus
M
Kleinewietfeld
Integrative Metabolomics and Proteomics, Berlin Institute of Medical Systems Biology/Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Stefan
S
Kempa
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany.
Jan
J
Thöne
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany.
Seray
S
Demir
Experimental and Clinical Research Center & Max-Delbrück Center Berlin, 13125 Berlin, Germany.
Dominik N
DN
Müller
Department of Neurology, Ruhr-University Bochum, 44801 Bochum, Germany.
Ralf
R
Gold
Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany. Electronic address: ralf.linker@uk-erlangen.de.
Ralf A
RA
Linker
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D002490:Central Nervous System / Q000276:immunology*; D004041:Dietary Fats / Q000494:pharmacology* / Q000633:toxicity; D004386:Duodenum / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000069467:Fecal Microbiota Transplantation; D000069196:Gastrointestinal Microbiome / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D007850:Lauric Acids / Q000633:toxicity; D000071518:Liver X Receptors; D038041:Lymphopoiesis / Q000187:drug effects*; D020935:MAP Kinase Signaling System; D051379:Mice; D008970:Molecular Weight; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D059467:Transcriptome
D004041:Dietary Fats; D005227:Fatty Acids; D007850:Lauric Acids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D043562:Receptors, G-Protein-Coupled; C030358:lauric acid