Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic
Implications

Xu       Wang; Zhen       Liang; Shengnan       Wang; Di       Ma; Mingqin       Zhu; Jiachun       Feng
Abstract

The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota have also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.
Keywords: Gut microbiota, multiple sclerosis, neuro-inflammatory diseases, gut-microbiota-brain axis, blood-brain barrier, fecal microbiota transplantation, antibiotic treatment, probiotic microbiota.
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Graphical Abstract

[1] 
Structure, function and diversity of the healthy human microbiome. Nature  2012; 486(7402): 207-14.
[http://dx.doi.org/10.1038/nature11234] [PMID: 22699609] 
[2] 
Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature  2007; 449(7164): 804-10.
[http://dx.doi.org/10.1038/nature06244] [PMID: 17943116] 
[3] 
Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell  2006; 124(4): 837-48.
[http://dx.doi.org/10.1016/j.cell.2006.02.017] [PMID: 16497592] 
[4] 
Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature  2010; 464(7285): 59-65.
[http://dx.doi.org/10.1038/nature08821] [PMID: 20203603] 
[5] 
Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe  2015; 17(5): 565-76.
[http://dx.doi.org/10.1016/j.chom.2015.04.011] [PMID: 25974299] 
[6] 
Bauer KC, Huus KE, Finlay BB. Microbes and the mind: emerging hallmarks of the gut microbiota-brain axis. Cell Microbiol  2016; 18(5): 632-44.
[http://dx.doi.org/10.1111/cmi.12585] [PMID: 26918908] 
[7] 
Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science  2001; 292(5519): 1115-8.
[http://dx.doi.org/10.1126/science.1058709] [PMID: 11352068] 
[8] 
Mosca A, Leclerc M, Hugot JP. Gut Microbiota Diversity and Human Diseases: Should We Reintroduce Key Predators in Our Ecosys-tem? Front Microbiol  2016; 7: 455.
[http://dx.doi.org/10.3389/fmicb.2016.00455] [PMID: 27065999] 
[9] 
Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans. Cell  2016; 164(3): 337-40.
[http://dx.doi.org/10.1016/j.cell.2016.01.013] [PMID: 26824647] 
[10] 
Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang RF. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation  2019; 16(1): 53.
[http://dx.doi.org/10.1186/s12974-019-1434-3] [PMID: 30823925] 
[11] 
Larroya-García A, Navas-Carrillo D, Orenes-Piñero E. Impact of gut microbiota on neurological diseases: Diet composition and novel treatments. Crit Rev Food Sci Nutr  2019; 59(19): 3102-16.
[http://dx.doi.org/10.1080/10408398.2018.1484340] [PMID: 29870270] 
[12] 
Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology  2014; 146(6): 1489-99.
[http://dx.doi.org/10.1053/j.gastro.2014.02.009] [PMID: 24560869] 
[13] 
Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature  2012; 490(7418): 55-60.
[http://dx.doi.org/10.1038/nature11450] [PMID: 23023125] 
[14] 
Arrieta MC, Stiemsma LT, Dimitriu PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med  2015; 7(307): 307ra152.
[http://dx.doi.org/10.1126/scitranslmed.aab2271] [PMID: 26424567] 
[15] 
Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature  2009; 457(7228): 480-4.
[http://dx.doi.org/10.1038/nature07540] [PMID: 19043404] 
[16] 
Dinan TG, Cryan JF. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. 2017; 595(2): 489-503.
[http://dx.doi.org/10.1113/JP273106] 
[17] 
Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol  2017; 133(2): 223-44.
[http://dx.doi.org/10.1007/s00401-016-1631-4] [PMID: 27766432] 
[18] 
Magyari M, Sorensen PS. The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis. Curr Opin Neurol  2019; 32(3): 320-6.
[http://dx.doi.org/10.1097/WCO.0000000000000695] [PMID: 30925518] 
[19] 
Orton SM, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol  2006; 5(11): 932-6.
[http://dx.doi.org/10.1016/S1474-4422(06)70581-6] [PMID: 17052660] 
[20] 
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology  2014; 83(3): 278-86.
[http://dx.doi.org/10.1212/WNL.0000000000000560] [PMID: 24871874] 
[21] 
Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav  2015; 5(9): e00362.
[http://dx.doi.org/10.1002/brb3.362] [PMID: 26445701] 
[22] 
Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain  2017; 140(3): 527-46.
[PMID: 27794524] 
[23] 
Dobson R, Giovannoni G. Multiple sclerosis - a review. Eur J Neurol  2019; 26(1): 27-40.
[http://dx.doi.org/10.1111/ene.13819] [PMID: 30300457] 
[24] 
Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med  2006; 354(9): 942-55.
[http://dx.doi.org/10.1056/NEJMra052130] [PMID: 16510748] 
[25] 
McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol  2007; 8(9): 913-9.
[http://dx.doi.org/10.1038/ni1507] [PMID: 17712344] 
[26] 
Prat A, Antel J. Pathogenesis of multiple sclerosis. Curr Opin Neurol  2005; 18(3): 225-30.
[http://dx.doi.org/10.1097/01.wco.0000169737.99040.31] [PMID: 15891404] 
[27] 
Sadovnick AD, Armstrong H, Rice GP, et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol  1993; 33(3): 281-5.
[http://dx.doi.org/10.1002/ana.410330309] [PMID: 8498811] 
[28] 
Mumford CJ, Wood NW, Kellar-Wood H, Thorpe JW, Miller DH, Compston DA. The British Isles survey of multiple sclerosis in twins. Neurology  1994; 44(1): 11-5.
[http://dx.doi.org/10.1212/WNL.44.1.11] [PMID: 8290043] 
[29] 
Alfredsson L, Olsson T. Lifestyle and Environmental Factors in Multiple Sclerosis. Cold Spring Harb Perspect Med  2019; 9(4): a028944.
[http://dx.doi.org/10.1101/cshperspect.a028944] [PMID: 29735578] 
[30] 
Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabo-lism in mice. Science  2013; 341(6150): 1241214.
[http://dx.doi.org/10.1126/science.1241214] [PMID: 24009397] 
[31] 
Cantarel BL, Waubant E, Chehoud C, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med  2015; 63(5): 729-34.
[http://dx.doi.org/10.1097/JIM.0000000000000192] [PMID: 25775034] 
[32] 
Miyake S, Kim S, Suda W, 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.
[http://dx.doi.org/10.1371/journal.pone.0137429] [PMID: 26367776] 
[33] 
Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota composition and re-lapse risk in pediatric MS: A pilot study. J Neurol Sci  2016; 363: 153-7.
[http://dx.doi.org/10.1016/j.jns.2016.02.042] [PMID: 27000242] 
[34] 
Jangi S, Gandhi R, Cox LM, Li N, von Glehn F. Alterations of the human gut microbiome in multiple sclerosis. 2016; 7: 12015.
[http://dx.doi.org/10.1038/ncomms12015] 
[35] 
Berer K, Mues M, Koutrolos M, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature  2011; 479(7374): 538-41.
[http://dx.doi.org/10.1038/nature10554] [PMID: 22031325] 
[36] 
Budhram A, Parvathy S, Kremenchutzky M, Silverman M. Breaking down the gut microbiome composition in multiple sclerosis. Mult Scler  2017; 23(5): 628-36.
[http://dx.doi.org/10.1177/1352458516682105] [PMID: 27956557] 
[37] 
Mirza A, Forbes JD, Zhu F, et al. The multiple sclerosis gut microbiota: A systematic review. Mult Scler Relat Disord  2020; 37: 101427.
[http://dx.doi.org/10.1016/j.msard.2019.101427] [PMID: 32172998] 
[38] 
Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The central nervous system and the gut microbiome. Cell  2016; 167(4): 915-32.
[http://dx.doi.org/10.1016/j.cell.2016.10.027] [PMID: 27814521] 
[39] 
Durgan DJ, Lee J, McCullough LD, Bryan RM Jr. Examining the role of the microbiota-gut-brain axis in stroke. Stroke  2019; 50(8): 2270-7.
[http://dx.doi.org/10.1161/STROKEAHA.119.025140] [PMID: 31272315] 
[40] 
Burokas A, Moloney RD, Dinan TG, Cryan JF. Microbiota regulation of the mammalian gut-brain axis. Adv Appl Microbiol  2015; 91: 1-62.
[http://dx.doi.org/10.1016/bs.aambs.2015.02.001] [PMID: 25911232] 
[41] 
Martin CR, Osadchiy V, Kalani A, Mayer EA. The brain-gut-microbiome axis. Cell Mol Gastroenterol Hepatol  2018; 6(2): 133-48.
[http://dx.doi.org/10.1016/j.jcmgh.2018.04.003] [PMID: 30023410] 
[42] 
Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci  2011; 12(8): 453-66.
[http://dx.doi.org/10.1038/nrn3071] [PMID: 21750565] 
[43] 
Strader AD, Woods SC. Gastrointestinal hormones and food intake. Gastroenterology  2005; 128(1): 175-91.
[http://dx.doi.org/10.1053/j.gastro.2004.10.043] [PMID: 15633135] 
[44] 
Wang FB, Powley TL. Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation. Cell Tissue Res  2007; 329(2): 221-30.
[http://dx.doi.org/10.1007/s00441-007-0413-7] [PMID: 17453246] 
[45] 
Asano Y, Hiramoto T, Nishino R, et al. Critical role of gut microbiota in the pro-duction of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol Gastrointest Liver Physiol  2012; 303(11): G1288-95.
[http://dx.doi.org/10.1152/ajpgi.00341.2012] [PMID: 23064760] 
[46] 
Barrett E. Ross, R.P.; O’Toole, P.W.; Fitzgerald, G.F.; Stanton, C. γ-aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol  2012; 113(2): 411-7.
[http://dx.doi.org/10.1111/j.1365-2672.2012.05344.x] [PMID: 22612585] 
[47] 
Erny D. Hrabě de Angelis, A.L.; Jaitin, D.; Wieghofer, P.; Staszewski, O.; David, E.; Keren-Shaul, H.; Mahlakoiv, T.; Jakobshagen, K.; Buch, T.; Schwierzeck, V.; Utermöhlen, O.; Chun, E.; Garrett, W.S.; McCoy, K.D.; Diefenbach, A.; Staeheli, P.; Stecher, B.; Amit, I.; Prinz, M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci  2015; 18(7): 965-77.
[http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851] 
[48] 
Sun J, Ling Z, Wang F, et al. Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. Neurosci Lett  2016; 613: 30-5.
[http://dx.doi.org/10.1016/j.neulet.2015.12.047] [PMID: 26733300] 
[49] 
Sun J, Wang F, Ling Z, et al. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Res  2016; 1642: 180-8.
[http://dx.doi.org/10.1016/j.brainres.2016.03.042] [PMID: 27037183] 
[50] 
Singh V, Roth S, Llovera G, et al. Microbiota dysbiosis controls the neuroin-flammatory response after stroke. J Neurosci  2016; 36(28): 7428-40.
[http://dx.doi.org/10.1523/JNEUROSCI.1114-16.2016] [PMID: 27413153] 
[51] 
Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med  2016; 22(5): 516-23.
[http://dx.doi.org/10.1038/nm.4068] [PMID: 27019327] 
[52] 
Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol  2009; 183(10): 6041-50.
[http://dx.doi.org/10.4049/jimmunol.0900747] [PMID: 19841183] 
[53] 
Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe  2014; 15(3): 382-92.
[http://dx.doi.org/10.1016/j.chom.2014.02.005] [PMID: 24629344] 
[54] 
Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease pa-tients. Proc Natl Acad Sci USA  2008; 105(43): 16731-6.
[http://dx.doi.org/10.1073/pnas.0804812105] [PMID: 18936492] 
[55] 
Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife  2013; 2: e01202.
[http://dx.doi.org/10.7554/eLife.01202] [PMID: 24192039] 
[56] 
Nusrat S, Gulick E, Levinthal D, Bielefeldt K. Anorectal dysfunction in multiple sclerosis: a systematic review. ISRN Neurol  2012; 2012: 376023.
[http://dx.doi.org/10.5402/2012/376023] [PMID: 22900202] 
[57] 
Minuk GY, Lewkonia RM. Possible familial association of multiple sclerosis and inflammatory bowel disease. N Engl J Med  1986; 314(9): 586.
[http://dx.doi.org/10.1056/NEJM198602273140921] [PMID: 3945303] 
[58] 
Sadovnick AD, Paty DW, Yannakoulias G. Concurrence of multiple sclerosis and inflammatory bowel disease. N Engl J Med  1989; 321(11): 762-3.
[http://dx.doi.org/10.1056/NEJM198909143211115] [PMID: 2770807] 
[59] 
Yacyshyn B, Meddings J, Sadowski D, Bowen-Yacyshyn MB. Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig Dis Sci  1996; 41(12): 2493-8.
[http://dx.doi.org/10.1007/BF02100148] [PMID: 9011463] 
[60] 
Kimura K, Hunter SF, Thollander MS, et al. Concurrence of inflammatory bowel disease and multiple sclerosis. Mayo Clin Proc  2000; 75(8): 802-6.
[http://dx.doi.org/10.4065/75.8.802] [PMID: 10943233] 
[61] 
Gupta G, Gelfand JM, Lewis JD. Increased risk for demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology  2005; 129(3): 819-26.
[http://dx.doi.org/10.1053/j.gastro.2005.06.022] [PMID: 16143121] 
[62] 
Ott SJ, Musfeldt M, Wenderoth DF, et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut  2004; 53(5): 685-93.
[http://dx.doi.org/10.1136/gut.2003.025403] [PMID: 15082587] 
[63] 
Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut  2006; 55(2): 205-11.
[http://dx.doi.org/10.1136/gut.2005.073817] [PMID: 16188921] 
[64] 
Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut mi-crobiota compared to healthy controls. Sci Rep  2016; 6: 28484.
[http://dx.doi.org/10.1038/srep28484] [PMID: 27346372] 
[65] 
Castillo-Álvarez F, Pérez-Matute P, Oteo JA, Marzo-Sola ME. The influence of interferon β-1b on gut microbiota composition in patients with multiple sclerosis. Neurologia (Engl Ed)  2018; S0213-4853(18)30158-0.
[PMID: 29895466] 
[66] 
Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediat-ric multiple sclerosis: a case-control study. Eur J Neurol  2016; 23(8): 1308-21.
[http://dx.doi.org/10.1111/ene.13026] [PMID: 27176462] 
[67] 
Cosorich I, Dalla-Costa G, Sorini C, et al. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv  2017; 3(7): e1700492-.
[http://dx.doi.org/10.1126/sciadv.1700492] [PMID: 28706993] 
[68] 
Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell  1993; 72(4): 551-60.
[http://dx.doi.org/10.1016/0092-8674(93)90074-Z] [PMID: 7679952] 
[69] 
Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental auto-immune encephalomyelitis. Proc Natl Acad Sci USA  2011; 108(Suppl. 1): 4615-22.
[http://dx.doi.org/10.1073/pnas.1000082107] [PMID: 20660719] 
[70] 
Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol  2010; 185(7): 4101-8.
[http://dx.doi.org/10.4049/jimmunol.1001443] [PMID: 20817872] 
[71] 
Mangalam A, Shahi SK, Luckey D, et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep  2017; 20(6): 1269-77.
[http://dx.doi.org/10.1016/j.celrep.2017.07.031] [PMID: 28793252] 
[72] 
Lavasani S, Dzhambazov B, Nouri M, et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One  2010; 5(2): e9009.
[http://dx.doi.org/10.1371/journal.pone.0009009] [PMID: 20126401] 
[73] 
Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci USA  2017; 114(40): 10719-24.
[http://dx.doi.org/10.1073/pnas.1711233114] [PMID: 28893994] 
[74] 
Cekanaviciute E, Yoo BB, Runia TF. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. 2017; 114(40): 10713-10718.
[http://dx.doi.org/10.1073/pnas.1711235114] 
[75] 
Buscarinu MC, Cerasoli B, Annibali V, et al. Altered intestinal permeability in patients with re-lapsing-remitting multiple sclerosis: A pilot study. Mult Scler  2017; 23(3): 442-6.
[http://dx.doi.org/10.1177/1352458516652498] [PMID: 27270497] 
[76] 
Buscarinu MC, Romano S, Mechelli R, et al. Intestinal permeability in relapsing-remitting multiple sclerosis. Neurotherapeutics  2018; 15(1): 68-74.
[http://dx.doi.org/10.1007/s13311-017-0582-3] [PMID: 29119385] 
[77] 
Nouri M, Bredberg A, Weström B, Lavasani S. Intestinal barrier dysfunction develops at the onset of experimental autoimmune en-cephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One  2014; 9(9): e106335.
[http://dx.doi.org/10.1371/journal.pone.0106335] [PMID: 25184418] 
[78] 
Welcome MO. Gut microbiota disorder, gut epithelial and blood-brain barrier dysfunctions in etiopathogenesis of dementia: molecular mechanisms and signaling pathways. Neuromolecular Med  2019; 21(3): 205-26.
[http://dx.doi.org/10.1007/s12017-019-08547-5] [PMID: 31115795] 
[79] 
Obermeier B, Mentele R, Malotka J, et al. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat Med  2008; 14(6): 688-93.
[http://dx.doi.org/10.1038/nm1714] [PMID: 18488038] 
[80] 
Tintoré M, Rovira A, Brieva L, et al. Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS. Mult Scler  2001; 7(6): 359-63.
[http://dx.doi.org/10.1177/135245850100700603] [PMID: 11795456] 
[81] 
Cameron EM, Spencer S, Lazarini J, et al. Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J Neuroimmunol  2009; 213(1-2): 123-30.
[http://dx.doi.org/10.1016/j.jneuroim.2009.05.014] [PMID: 19631394] 
[82] 
O’Connor KC, Appel H, Bregoli L, et al. Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein. J Immunol  2005; 175(3): 1974-82.
[http://dx.doi.org/10.4049/jimmunol.175.3.1974] [PMID: 16034142] 
[83] 
Yan W, Nguyen T, Yuki N, et al. Antibodies to neurofascin exacerbate adoptive transfer experimental autoimmune neuritis. J Neuroimmunol  2014; 277(1-2): 13-7.
[http://dx.doi.org/10.1016/j.jneuroim.2014.09.012] [PMID: 25262157] 
[84] 
Derfuss T, Parikh K, Velhin S, et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci USA  2009; 106(20): 8302-7.
[http://dx.doi.org/10.1073/pnas.0901496106] [PMID: 19416878] 
[85] 
Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med  2012; 367(2): 115-23.
[http://dx.doi.org/10.1056/NEJMoa1110740] [PMID: 22784115] 
[86] 
Kinzel S, Lehmann-Horn K, Torke S, et al. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. Acta Neuropathol  2016; 132(1): 43-58.
[http://dx.doi.org/10.1007/s00401-016-1559-8] [PMID: 27022743] 
[87] 
Wekerle H. Brain autoimmunity and intestinal microbiota: 100 trillion game changers. Trends Immunol  2017; 38(7): 483-97.
[http://dx.doi.org/10.1016/j.it.2017.03.008] [PMID: 28601415] 
[88] 
Lebeer S, Vanderleyden J, De Keersmaecker SC. Host interactions of probiotic bacterial surface molecules: comparison with commen-sals and pathogens. Nat Rev Microbiol  2010; 8(3): 171-84.
[http://dx.doi.org/10.1038/nrmicro2297] [PMID: 20157338] 
[89] 
Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol  2012; 42(1): 102-11.
[http://dx.doi.org/10.1007/s12016-011-8294-7] [PMID: 22095454] 
[90] 
Rojas M, Restrepo-Jiménez P, Monsalve DM, et al. Molecular mimicry and autoimmunity. J Autoimmun  2018; 95: 100-23.
[http://dx.doi.org/10.1016/j.jaut.2018.10.012] [PMID: 30509385] 
[91] 
Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut  2016; 65(2): 330-9.
[http://dx.doi.org/10.1136/gutjnl-2015-309990] [PMID: 26338727] 
[92] 
Hebbandi Nanjundappa R, Ronchi F, Wang J, et al. Bas-solas-Molina, H.; Salas, A.; Khan, H.; Slattery, R.M.; Wyss, M.; Mooser, C.; Macpherson, A.J.; Sycuro, L.K.; Serra, P.; McKay, D.M.; McCoy, K.D.; Santamaria, P. A gut microbial mimic that hijacks diabetogenic autoreactivity to suppress colitis. Cell  2017; 171(3): 655-667.e17.
[http://dx.doi.org/10.1016/j.cell.2017.09.022] [PMID: 29053971] 
[93] 
Anderson B, Park BJ, Verdaguer J, Amrani A, Santamaria P. Prevalent CD8(+) T cell response against one peptide/MHC complex in autoimmune diabetes. Proc Natl Acad Sci USA  1999; 96(16): 9311-6.
[http://dx.doi.org/10.1073/pnas.96.16.9311] [PMID: 10430939] 
[94] 
Lieberman SM, Evans AM, Han B, et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA  2003; 100(14): 8384-8.
[http://dx.doi.org/10.1073/pnas.0932778100] [PMID: 12815107] 
[95] 
Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol  2012; 72(1): 53-64.
[http://dx.doi.org/10.1002/ana.23651] [PMID: 22807325] 
[96] 
Martin R, Gran B, Zhao Y, et al. Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease. J Autoimmun  2001; 16(3): 187-92.
[http://dx.doi.org/10.1006/jaut.2000.0501] [PMID: 11334482] 
[97] 
Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell  1995; 80(5): 695-705.
[http://dx.doi.org/10.1016/0092-8674(95)90348-8] [PMID: 7534214] 
[98] 
Markovic-Plese S, Hemmer B, Zhao Y, Simon R, Pinilla C, Martin R. High level of cross-reactivity in influenza virus hemaggluti-nin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis. J Neuroimmunol  2005; 169(1-2): 31-8.
[http://dx.doi.org/10.1016/j.jneuroim.2005.07.014] [PMID: 16150497] 
[99] 
Schrijver IA, van Meurs M, Melief MJ, et al. Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis. Brain  2001; 124(Pt 8): 1544-54.
[http://dx.doi.org/10.1093/brain/124.8.1544] [PMID: 11459746] 
[100] 
Hughes LE, Smith PA, Bonell S, et al. Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendro-cyte glycoprotein in multiple sclerosis. J Neuroimmunol  2003; 144(1-2): 105-15.
[http://dx.doi.org/10.1016/S0165-5728(03)00274-1] [PMID: 14597104] 
[101] 
Planas R, Santos R, Tomas-Ojer P. GDP-l-fucose synthase is a CD4(+) T cell-specific autoantigen in DRB3*02:02 patients with multi-ple sclerosis. Sci Transl Med  2018; 10(462): eaat4301.
[http://dx.doi.org/10.1126/scitranslmed.aat4301] [PMID: 30305453] 
[102] 
Gloor SM, Wachtel M, Bolliger MF, Ishihara H, Landmann R, Frei K. Molecular and cellular permeability control at the blood-brain barrier. Brain Res Brain Res Rev  2001; 36(2-3): 258-64.
[http://dx.doi.org/10.1016/S0165-0173(01)00102-3] [PMID: 11690623] 
[103] 
Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta  2011; 1812(2): 252-64.
[http://dx.doi.org/10.1016/j.bbadis.2010.06.017] [PMID: 20619340] 
[104] 
Erdő F.; Denes, L.; de Lange, E. Age-associated physiological and pathological changes at the blood-brain barrier: A review. J Cereb Blood Flow Metab  2017; 37(1): 4-24.
[http://dx.doi.org/10.1177/0271678X16679420] [PMID: 27837191] 
[105] 
Wang X, Jiao W, Lin M, et al. Resolution of inflammation in neuromyelitis optica spectrum disorders. Mult Scler Relat Disord  2019; 27: 34-41.
[http://dx.doi.org/10.1016/j.msard.2018.09.040] [PMID: 30300851] 
[106] 
Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron  2008; 57(2): 178-201.
[http://dx.doi.org/10.1016/j.neuron.2008.01.003] [PMID: 18215617] 
[107] 
Agrawal SM, Yong VW. Immunopathogenesis of multiple sclerosis. Int Rev Neurobiol  2007; 79: 99-126.
[http://dx.doi.org/10.1016/S0074-7742(07)79005-0] [PMID: 17531839] 
[108] 
Michel L, Prat A. One more role for the gut: microbiota and blood brain barrier. Ann Transl Med  2016; 4(1): 15.
[PMID: 26855951] 
[109] 
Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med  2014; 6(263): 263ra158.
[http://dx.doi.org/10.1126/scitranslmed.3009759] [PMID: 25411471] 
[110] 
Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev  2001; 81(3): 1031-64.
[http://dx.doi.org/10.1152/physrev.2001.81.3.1031] [PMID: 11427691] 
[111] 
Braniste V, Al-Asmakh M, Kowal C. The gut microbiota influences blood-brain barrier permeability in mice  Sci Transl Med  2014; 6(263): 263ra158-263ra158.
[http://dx.doi.org/10.1126/scitranslmed.3009759] 
[112] 
Boveri M, Kinsner A, Berezowski V, et al. Highly purified lipoteichoic acid from gram-positive bacteria induces in vitro blood-brain barrier disruption through glia activation: role of pro-inflammatory cytokines and nitric oxide. Neuroscience  2006; 137(4): 1193-209.
[http://dx.doi.org/10.1016/j.neuroscience.2005.10.011] [PMID: 16343789] 
[113] 
Banks WA, Gray AM, Erickson MA, et al. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroin-flammation, and elements of the neurovascular unit. J Neuroinflammation  2015; 12: 223-3.
[http://dx.doi.org/10.1186/s12974-015-0434-1] [PMID: 26608623] 
[114] 
Nicol B, Salou M, Laplaud D-A, Wekerle H. The autoimmune concept of multiple sclerosis. Presse Med  2015; 44(4 Pt 2): e103-12.
[http://dx.doi.org/10.1016/j.lpm.2015.02.009] [PMID: 25813101] 
[115] 
Lassmann H. Multiple sclerosis pathology: evolution of pathogenetic concepts. Brain Pathol  2005; 15(3): 217-22.
[http://dx.doi.org/10.1111/j.1750-3639.2005.tb00523.x] [PMID: 16196388] 
[116] 
Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implica-tions for the pathogenesis of demyelination. Ann Neurol  2000; 47(6): 707-17.
[http://dx.doi.org/10.1002/1531-8249(200006)47:6<707:AID-ANA3>3.0.CO;2-Q] [PMID: 10852536] 
[117] 
Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology  2007; 68(22)(Suppl. 3): S22-31.
[http://dx.doi.org/10.1212/01.wnl.0000275229.13012.32] [PMID: 17548565] 
[118] 
Lassmann H, Brück W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med  2001; 7(3): 115-21.
[http://dx.doi.org/10.1016/S1471-4914(00)01909-2] [PMID: 11286782] 
[119] 
Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain  2009; 132(Pt 12): 3329-41.
[http://dx.doi.org/10.1093/brain/awp289] [PMID: 19933767] 
[120] 
Matusevicius D, Kivisäkk P, He B, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler  1999; 5(2): 101-4.
[http://dx.doi.org/10.1177/135245859900500206] [PMID: 10335518] 
[121] 
Durelli L, Conti L, Clerico M, et al. T-helper 17 cells expand in mul-tiple sclerosis and are inhibited by interferon-beta. Ann Neurol  2009; 65(5): 499-509.
[http://dx.doi.org/10.1002/ana.21652] [PMID: 19475668] 
[122] 
Tzartos JS, Friese MA, Craner MJ, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol  2008; 172(1): 146-55.
[http://dx.doi.org/10.2353/ajpath.2008.070690] [PMID: 18156204] 
[123] 
Stockinger B, Veldhoen M, Martin B. Th17 T cells: linking innate and adaptive immunity. Semin Immunol  2007; 19(6): 353-61.
[http://dx.doi.org/10.1016/j.smim.2007.10.008] [PMID: 18023589] 
[124] 
Atarashi K, Tanoue T, Oshima K, et al. Treg in-duction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature  2013; 500(7461): 232-6.
[http://dx.doi.org/10.1038/nature12331] [PMID: 23842501] 
[125] 
Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature  2016; 535(7610): 75-84.
[http://dx.doi.org/10.1038/nature18848] [PMID: 27383982] 
[126] 
Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA  2010; 107(27): 12204-9.
[http://dx.doi.org/10.1073/pnas.0909122107] [PMID: 20566854] 
[127] 
Ochoa-Repáraz J, Mielcarz DW, Wang Y, et al. A polysaccharide from the hu-man commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol  2010; 3(5): 487-95.
[http://dx.doi.org/10.1038/mi.2010.29] [PMID: 20531465] 
[128] 
Ooijevaar RE, Terveer EM, Verspaget HW, Kuijper EJ, Keller JJ. Clinical application and potential of fecal microbiota transplanta-tion. Annu Rev Med  2019; 70: 335-51.
[http://dx.doi.org/10.1146/annurev-med-111717-122956] [PMID: 30403550] 
[129] 
Borody T, Leis S, Campbell J, Torres M, Nowak A. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS): 942. Am J Gastroenterol  2011; 106: S352.
[http://dx.doi.org/10.14309/00000434-201110002-00942] 
[130] 
Makkawi S, Camara-Lemarroy C, Metz L. Fecal microbiota transplantation associated with 10 years of stability in a patient with SPMS. Neurol Neuroimmunol Neuroinflam  2018; 5(4): e459.
[http://dx.doi.org/10.1212/NXI.0000000000000459] 
[131] 
Schepici G, Silvestro S, Bramanti P, Mazzon E. The Gut Microbiota in Multiple Sclerosis: An Overview of Clinical Trials. Cell Transplant  2019; 28(12): 1507-27.
[http://dx.doi.org/10.1177/0963689719873890] [PMID: 31512505] 
[132] 
Shahi SK, Freedman SN, Mangalam AK. Gut microbiome in multiple sclerosis: The players involved and the roles they play. Gut Microbes  2017; 8(6): 607-15.
[http://dx.doi.org/10.1080/19490976.2017.1349041] [PMID: 28696139] 
[133] 
Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome. Cell  2014; 159(4): 789-99.
[http://dx.doi.org/10.1016/j.cell.2014.09.053] [PMID: 25417156] 
[134] 
Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science  2013; 339(6123): 1084-8.
[http://dx.doi.org/10.1126/science.1233521] [PMID: 23328391] 
[135] 
Hollister EB, Riehle K, Luna RA, et al. Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome  2015; 3: 36.
[http://dx.doi.org/10.1186/s40168-015-0101-x] [PMID: 26306392] 
[136] 
Biedermann L, Zeitz J, Mwinyi J, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One  2013; 8(3): e59260.
[http://dx.doi.org/10.1371/journal.pone.0059260] [PMID: 23516617] 
[137] 
Norman JM, Handley SA, Baldridge MT, et al. Dis-ease-specific alterations in the enteric virome in inflammatory bowel disease. Cell  2015; 160(3): 447-60.
[http://dx.doi.org/10.1016/j.cell.2015.01.002] [PMID: 25619688] 
[138] 
Kernbauer E, Ding Y, Cadwell K. An enteric virus can replace the beneficial function of commensal bacteria. Nature  2014; 516(7529): 94-8.
[http://dx.doi.org/10.1038/nature13960] [PMID: 25409145] 
[139] 
Davenport ER, Mizrahi-Man O, Michelini K, Barreiro LB, Ober C, Gilad Y. Seasonal variation in human gut microbiome compo-sition. PLoS One  2014; 9(3): e90731.
[http://dx.doi.org/10.1371/journal.pone.0090731] [PMID: 24618913] 
[140] 
David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature  2014; 505(7484): 559-63.
[http://dx.doi.org/10.1038/nature12820] [PMID: 24336217] 
[141] 
Le Chatelier E, Nielsen T, Qin J, et al. Richness of hu-man gut microbiome correlates with metabolic markers. Nature  2013; 500(7464): 541-6.
[http://dx.doi.org/10.1038/nature12506] [PMID: 23985870] 
[142] 
Piccio L, Stark JL, Cross AH. Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukoc Biol  2008; 84(4): 940-8.
[http://dx.doi.org/10.1189/jlb.0208133] [PMID: 18678605] 
[143] 
Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoim-mune disease by the induction of pathogenic TH17 cells. Nature  2013; 496(7446): 518-22.
[http://dx.doi.org/10.1038/nature11868] [PMID: 23467095] 
[144] 
Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler  2013; 19(10): 1323-9.
[http://dx.doi.org/10.1177/1352458513483889] [PMID: 23549432] 
[145] 
Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolat-ed syndrome. Neurology  2013; 80(6): 548-52.
[http://dx.doi.org/10.1212/WNL.0b013e31828154f3] [PMID: 23365063] 
[146] 
Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G. The role of diet in multiple sclerosis: A review. Nutr Neurosci  2018; 21(6): 377-90.
[http://dx.doi.org/10.1080/1028415X.2017.1303016] [PMID: 28338444] 
[147] 
Schirmer M, Smeekens SP, Vlamakis H, et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell  2016; 167(4): 1125-1136.e8.
[http://dx.doi.org/10.1016/j.cell.2016.10.020] [PMID: 27814509] 
[148] 
Crost EH, Tailford LE, Le Gall G, Fons M, Henrissat B, Juge N. Utilisation of mucin glycans by the human gut symbiont Rumino-coccus gnavus is strain-dependent. PLoS One  2013; 8(10): e76341.
[http://dx.doi.org/10.1371/journal.pone.0076341] [PMID: 24204617] 
[149] 
Shahi SK, Jensen SN, Murra AC, et al. Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encepha-lomyelitis. Front Immunol  2020; 11: 578648.
[http://dx.doi.org/10.3389/fimmu.2020.578648] [PMID: 33362764] 
[150] 
Shahi SK, Freedman SN, Murra AC, et al. Prevotella histicola, a human gut commensal, is as potent as COPAXONE® in an animal model of multiple sclerosis. Front Immunol  2019; 10: 462.
[http://dx.doi.org/10.3389/fimmu.2019.00462] [PMID: 30984162] 
[151] 
Sivieri K, Morales ML, Adorno MA, Sakamoto IK, Saad SM, Rossi EA. Lactobacillus acidophilus CRL 1014 improved “gut health” in the SHIME reactor. BMC Gastroenterol  2013; 13: 100.
[http://dx.doi.org/10.1186/1471-230X-13-100] [PMID: 23758634] 
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DOI https://dx.doi.org/10.2174/1570159X19666210629145351	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

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