Short-chain fatty acids and intestinal inflammation in multiple sclerosis: modulation of female susceptibility by microbial products?

Springer Science and Business Media LLC - Tập 12 Số 1 - 2021
Anouck Becker1, Mosab Abuazab2, Andreas Schwiertz3, Silke Walter1, Klaus Faßbender1, Mathias Fousse1, Marcus M. Unger1
1Department of Neurology, Saarland University, Kirrberger Str. 100, 66421, Homburg, Germany
2Klinik für Neurologie, Gesundheitszentrum Glantal, Liebfrauenberg 32, 55590, Meisenheim, Germany
3Institute of Microecology, Herborn, Germany

Tóm tắt

AbstractBackgroundMultiple Sclerosis (MS) is an autoimmune-mediated disease of the central nervous system. Experimental data suggest a role of intestinal microbiota and microbial products such as short-chain fatty acids (SCFAs) in the pathogenesis of MS. A recent clinical study reported beneficial effects (mediated by immunomodulatory mechanisms) after oral administration of the SCFA propionate in MS patients. Based on available evidence, we investigated whether SCFAs and the fecal inflammation marker calprotectin are altered in MS.Methods76 subjects (41 patients with relapsing–remitting MS and 35 age-matched controls) were investigated in this case–control study. All subjects underwent clinical assessment with established clinical scales and provided fecal samples for a quantitative analysis of fecal SCFA and fecal calprotectin concentrations. Fecal markers were compared between MS patients and controls, and were analyzed for an association with demographic as well as clinical parameters.ResultsMedian fecal calprotectin concentrations were within normal range in both groups without any group-specific differences. Fecal SCFA concentrations showed a non-significant reduction in MS patients compared to healthy subjects. Female subjects showed significantly reduced SCFA concentrations compared to male subjects.ConclusionsIn our cohort of MS patients, we found no evidence of an active intestinal inflammation. Yet, the vast majority of the investigated MS patients was under immunotherapy which might have affected the outcome measures. The sex-associated difference in fecal SCFA concentrations might at least partially explain female predominance in MS. Large-scale longitudinal studies including drug-naïve MS patients are required to determine the role of SCFAs in MS and to distinguish between disease-immanent effects and those caused by the therapeutic regime.

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Tài liệu tham khảo

Dobson R, Giovannoni G. Multiple sclerosis—a review. Eur J Neurol. 2019;26(1):27–40.

Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune Neuroinflammation. Immunol Rev. 2014;259(1):231–44.

Melbye P, Olsson A, Hansen TH, Søndergaard HB, Bang OA. Short-chain fatty acids and gut microbiota in multiple sclerosis. Acta Neurol Scand. 2019;139(3):208–19.

Robinson AP, Harp CT, Noronha A, Miller SD. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 2014;122:173–89.

Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479(7374):538–41. https://www.nature.com/articles/nature10554.pdf.

Chen T, Noto D, Hoshino Y, Mizuno M, Miyake S. Butyrate suppresses demyelination and enhances remyelination. J Neuroinflammation. 2019;16(1):165.

Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun; 2019;10(1):1–12.

Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Eilers E, et al. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell. 2020;180(6):1067-1080.e16.

Park J, Goergen CJ, HogenEsch H, Kim CH. Chronically elevated levels of short-chain fatty acids induce T cell-mediated ureteritis and hydronephrosis. J Immunol. 2016;196(5):2388–400.

Luu M, Visekruna A. Short-chain fatty acids: bacterial messengers modulating the immunometabolism of T cells. Eur J Immunol. 2019;49(6):842–8. https://doi.org/10.1002/eji.201848009.

Koh A, de Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332–45.

Haase S, Haghikia A, Wilck N, Müller DN, Linker RA. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018;154(2):230–8.

Hirschberg S, Gisevius B, Duscha A, Haghikia A. Implications of diet and the gut microbiome in neuroinflammatory and neurodegenerative diseases. Int J Mol Sci 2019; 20(12).

Zeng Q, Junli G, Liu X, Chen C, Sun X, Li H, et al. Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis. Neurochem Int. 2019;129:104468.

Park J, Wang Q, Wu Q, Mao-Draayer Y, Kim CH. Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation. Sci Rep. 2019;9(1):1–13.

Ayling RM, Kok K. Fecal calprotectin. Adv Clin Chem. 2018;87:161–90.

Schwiertz A, Spiegel J, Dillmann U, Grundmann D, Bürmann J, Faßbender K, et al. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease. Parkinsonism Relat Disord. 2018;50:104–7.

Mulak A, Koszewicz M, Panek-Jeziorna M, Koziorowska-Gawron E, Budrewicz S. Fecal calprotectin as a marker of the gut immune system activation is elevated in parkinson’s disease. Front Neurosci. 2019;13:992.

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–86.

Díaz C, Zarco LA, Rivera DM. Highly active multiple sclerosis: an update. Mult Scler Relat Disord. 2019;30:215–24.

Deutsche Gesellschaft für Neurologie (DGN) e.V. Diagnose und Therapie der Multiplen Sklerose, Neuromyelitis Optica Spektrum und MOG-IgG-assoziierte Erkrankungen (cited 2021 Feb 5). https://dgn.org/wp-content/uploads/2020/09/200902_MS-LL_Hauptteil_Konsultationsfassung_KKNMS_202008_final.pdf.

Fenu G, Lorefice L, Frau F, Coghe GC, Marrosu MG, Cocco E. Induction and escalation therapies in multiple sclerosis. Antiinflamm Antiallergy Agents Med Chem. 2015;14(1):26–34.

Multiple Sklerose e.V. Qualitätshandbuch MS/NMOSD: Empfehlungen zur Therapie der Multiplen Sklerose / Neuromyelitis-optica-Spektrum-Erkrankungen für Ärzte. Kompetenznetz Multiple Sklerose (cited 2021 Feb 16); 2020. https://www.kompetenznetz-multiplesklerose.de/wp-content/uploads/2021/01/KKN_2004_WEB_medikamentenhandbuch.pdf.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.

Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” J Psychiatr Res. 1975;12(3):189–98.

Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46(10):1121–3.

Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J. An inventory for measuring depression. Arch General Psychiatry. 1961;4:561–71.

Unger MM, Spiegel J, Dillmann K-U, Grundmann D, Philippeit H, Bürmann J, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72.

Berg-Hansen P, Vandvik B, Fagerhol M, Holmøy T. Calprotectin levels in the cerebrospinal fluid reflect disease activity in multiple sclerosis. J Neuroimmunol. 2009;216(1–2):98–102.

Nelson SM, Nguyen TM, McDonald JW, MacDonald JK. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2018;8:CD006097.

Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Miyake S, Kim S, Suda W, Oshima K, Nakamura M, Matsuoka T, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to clostridia XIVa and IV clusters. PLoS ONE. 2015;10(9):e0137429.

Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Paz Soldan MM, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6:28484.

Rizzetto L, Fava F, Tuohy KM, Selmi C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: the role of sex. J Autoimmun. 2018;92:12–34.

Jakobsdottir G, Bjerregaard JH, Skovbjerg H, Nyman M. Fasting serum concentration of short-chain fatty acids in subjects with microscopic colitis and celiac disease: no difference compared with controls, but between genders. Scand J Gastroenterol. 2013;48(6):696–701.

Chen Z, Wu Y, Shrestha R, Gao Z, Zhao Y, Miura Y, et al. Determination of total, free and esterified short-chain fatty acid in human serum by liquid chromatography-mass spectrometry. Ann Clin Biochem. 2019;56(2):190–7.

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