The gut microbiota and associated metabolites in multiple sclerosis
PDF

Keywords

Gut
Microbiota
Metabolites
Multiple sclerosis
Inflammation

DOI

10.36922/an.413

Abstract

Multiple sclerosis (MS) is a severe central nervous system autoimmune inflammatory disease featured by the presence of infiltrated immune cells, demyelination, and degeneration. Recent research has shown that gut microbiota, including some commensal bacteria, is capable of interacting with the host immune system and remarkably influencing the development and outcome of experimental autoimmune encephalomyelitis, a classic animal model of MS. In addition, gut dysbiosis, presented with a significantly altered composition of commensal bacteria, is linked to the immune response and inflammation, such as Th17 activation and B cell function. Moreover, it has been observed that microbiota impacts the immune system by regulating the metabolites in the gut. In this review, we summarize the new research on the relationship and mechanism between the gut microbiota and MS, as well as the implications for developing new strategies in MS by modulating the gut microbiota and metabolites.

References

Dendrou CA, Fugger L, Friese MA, 2015, Immunopathology of multiple sclerosis. Nat Rev Immunol, 15: 545–558. https://doi.org/10.1038/nri3871

Fox EJ, 2004, Immunopathology of multiple sclerosis. Neurology 63: S3–S7. https://doi.org/10.1212/wnl.63.12_suppl_6.s3

Harbo HF, Gold R, Tintore M, 2013, Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord, 6: 237–248. https://doi.org/10.1177/1756285613488434

Sospedra M, Martin R, 2005, Immunology of multiple sclerosis. Annu Rev Immunol, 23: 683–747. https://doi.org/10.1146/annurev.immunol.23.021704.115707

Bar-Or A, Li R, 2021, Cellular immunology of relapsing multiple sclerosis: Interactions, checks, and balances. Lancet Neurol, 20: 470–483. https://doi.org/10.1016/S1474-4422(21)00063-6

Fletcher JM, Lalor SJ, Sweeney CM, et al., 2010, T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol, 162: 1–11. https://doi.org/10.1111/j.1365-2249.2010.04143.x

Cekanaviciute E, Yoo BB, Runia TF, et al., 2017, Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A, 114: 10713–10718. https://doi.org/10.1073/pnas.1711235114

Cantarel BL, Waubant E, Chehoud C, et al., 2015, Gut microbiota in multiple sclerosis: Possible influence of immunomodulators. J Investig Med, 63: 729–734. https://doi.org/10.1097/JIM.0000000000000192

Tremlett H, Zhu F, Arnold D, et al., 2021, The gut microbiota in pediatric multiple sclerosis and demyelinating syndromes. Ann Clin Transl Neurol, 8: 2252–2269. https://doi.org/10.1002/acn3.51476

Cosorich I, Dalla-Costa G, Sorini C, et al., 2017, High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv, 3: e1700492. https://doi.org/10.1126/sciadv.1700492

Miyake S, Kim S, Suda W, et al., 2015, 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, 10: e0137429. https://doi.org/10.1371/journal.pone.0137429

Zeng Q, Gong J, Liu X, et al, 2019, Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis. Neurochem Int, 129: 104468. https://doi.org/10.1016/j.neuint.2019.104468

Tremlett H, Fadrosh DW, Faruqi AA, et al., 2016, Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls. BMC Neurol, 16: 182. https://doi.org/10.1186/s12883-016-0703-3

Kadowaki A, Saga R, Lin Y, et al., 2019, Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis. Brain, 142: 916–931. https://doi.org/10.1093/brain/awz012

Scher JU, Ubeda C, Artacho A, et al., 2015, Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol, 67: 128–139. https://doi.org/10.1002/art.38892

Steri M, Orrù V, Idda ML, et al., 2017, Overexpression of the cytokine BAFF and autoimmunity risk. N Engl J Med, 376: 1615–1626. https://doi.org/10.1056/NEJMoa1610528

Hauser SL, Waubant E, Arnold DL, et al., 2008, B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med, 358: 676–688. https://doi.org/10.1056/NEJMoa0706383

Rojas OL, Pröbstel AK, Porfilio EA, et al., 2019, Recirculating intestinal iga-producing cells regulate neuroinflammation via IL-10. Cell, 177: 492–493. https://doi.org/10.1016/j.cell.2019.03.037

Ivanov II, Atarashi K, Manel N, et al., 2009, Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 139: 485–498. https://doi.org/10.1016/j.cell.2009.09.033

Lee YK, Menezes JS, Umesaki Y, et al., 2011, Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A, 108 Suppl 1: 4615–4622. https://doi.org/10.1073/pnas.1000082107

Berer K, Mues M, Koutrolos M, et al., 2011, Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature, 479: 538–541. https://doi.org/10.1038/nature10554

Yang Y, Torchinsky MB, Gobert M, et al., 2014, Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature, 510: 152–156. https://doi.org/10.1038/nature13279

Sano T, Huang W, Hall JA, et al., 2015, An IL-23R/IL-22 Circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell, 163: 381–393. https://doi.org/10.1016/j.cell.2015.08.061

Lai NY, Musser MA, Pinho-Ribeiro FA, et al., 2020, Gut-innervating nociceptor neurons regulate peyer’s patch microfold cells and SFB levels to mediate Salmonella host defense. Cell, 180: 33–49, e22. https://doi.org/10.1016/j.cell.2019.11.014

Omura S, Sato F, Park AM, et al., 2020, Bioinformatics analysis of gut microbiota and CNS transcriptome in virus-Induced acute myelitis and chronic Inflammatory demyelination; potential association of distinct bacteria with CNS IgA upregulation. Front Immunol, 11: 1138. https://doi.org/10.3389/fimmu.2020.01138

Stanisavljević S, Lukić J, Soković S, et al., 2016, Correlation of gut microbiota composition with resistance to experimental autoimmune encephalomyelitis in rats. Front Microbiol, 7: 2005. https://doi.org/10.3389/fmicb.2016.02005

Lin X, Liu Y, Ma L, et al., 2021, Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice. J Transl Med, 19: 317. https://doi.org/10.1186/s12967-021-02995-z

Derrien M, Vaughan EE, Plugge CM, et al., 2004, Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol, 54: 1469–1476. https://doi.org/10.1099/ijs.0.02873-0

Derrien M, Van Baarlen P, Hooiveld G, et al., 2011, Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader Akkermansia muciniphila. Front Microbiol, 2: 166. https://doi.org/10.3389/fmicb.2011.00166

Ganesh BP, Klopfleisch R, Loh G, et al., 2013, Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella Typhimurium-infected gnotobiotic mice. PLoS One, 8: e74963. https://doi.org/10.1371/journal.pone.0074963

Berer K, Gerdes LA, Cekanaviciute E, et al., 2017, Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A, 14: 10719–10724. https://doi.org/10.1073/pnas.1711233114

Nunes PR, Romao-Veiga M, Matias ML, et al., 2022, Vitamin D decreases expression of NLRP1 and NLRP3 inflammasomes in placental explants from women with preeclampsia cultured with hydrogen peroxide. Hum Immunol, 83: 74–80. https://doi.org/10.1016/j.humimm.2021.10.002

Jiang S, Zhang H, Li X, et al., 2021, Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. J Steroid Biochem Mol Biol, 206: 105789. https://doi.org/10.1016/j.jsbmb.2020.105789

Donovan C, Liu G, Shen S, et al., 2020, The role of the microbiome and the NLRP3 inflammasome in the gut and lung. J Leukoc Biol, 108: 925–935. https://doi.org/10.1002/JLB.3MR0720-472RR

Jangi S, Gandhi R, Cox LM, et al., 2016, Alterations of the human gut microbiome in multiple sclerosis. Nat Commun, 7: 12015. https://doi.org/10.1038/ncomms12015

Cox LM, Maghzi AH, Liu S, et al., 2021, Gut microbiome in progressive multiple sclerosis. Ann Neurol, 89: 1195–1211. https://doi.org/10.1002/ana.26084

Chen J, Chia N, Kalari KR, et al., 2016, Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep, 6: 28484. https://doi.org/10.1038/srep28484

Korkina L, Kostyuk V, De Luca C, et al., 2011, Plant phenylpropanoids as emerging anti-inflammatory agents. Mini Rev Med Chem, 11: 823–835. https://doi.org/10.2174/138955711796575489

Schogor AL, Huws SA, Santos GT, et al., 2014, Ruminal Prevotella spp. may play an important role in the conversion of plant lignans into human health beneficial antioxidants. PLoS One, 9: e87949. https://doi.org/10.1371/journal.pone.0087949

Toh H, Oshima K, Suzuki T, et al., 2013, Complete genome sequence of the equol-producing bacterium

Adlercreutzia equolifaciens DSM 19450T. Genome Announc, 1. https://doi.org/10.1128/genomeA.00742-13

Saresella M, Marventano I, Barone M, et al., 2020, Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis. Front Immunol, 11: 1390. https://doi.org/10.3389/fimmu.2020.01390

Barone M, Mendozzi L, D’Amico F, et al., 2021, Influence of a high-impact multidimensional rehabilitation program on the gut microbiota of patients with multiple sclerosis. Int J Mol Sci, 22: 7173. https://doi.org/10.3390/ijms22137173

Mangalam A, Shahi SK, Luckey D, et al., 2017, Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep, 20: 1269–1277. https://doi.org/10.1016/j.celrep.2017.07.031

Horton MK, McCauley K, Fadrosh D, et al., 2021, Gut microbiome is associated with multiple sclerosis activity in children. Ann Clin Transl Neurol, 8: 1867–1883. https://doi.org/10.1002/acn3.51441

Peng L, Li ZR, Green RS, et al., 2009, Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr, 139: 1619–1625. https://doi.org/10.3945/jn.109.104638

Dalile B, Van Oudenhove L, Vervliet B, et al., 2019, The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol, 16: 461–478. https://doi.org/10.1038/s41575-019-0157-3

Bachem A, Makhlouf C, Binger KJ, et al., 2019, Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T Cells. Immunity, 51: 285–297.e5. https://doi.org/10.1016/j.immuni.2019.06.002

Mitchell RW, On NH, Del Bigio MR, et al., 2011, Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J Neurochem, 117: 735–746. https://doi.org/10.1111/j.1471-4159.2011.07245.x

Bonini JA, Anderson SM, Steiner DF, 1997, Molecular cloning and tissue expression of a novel orphan G protein-coupled receptor from rat lung. Biochem Biophys Res Commun, 234: 190–193. https://doi.org/10.1006/bbrc.1997.6591

Kim CH, 2018, Immune regulation by microbiome metabolites. Immunology, 154: 220–229. https://doi.org/10.1111/imm.12930

Deleu S, Machiels K, Raes J, et al., 2021, Short chain fatty acids and its producing organisms: An overlooked therapy for IBD? EBioMedicine, 66: 103293. https://doi.org/10.1016/j.ebiom.2021.103293

Park J, Wang Q, Wu Q, et al., 2019, Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation. Sci Rep, 9: 8837. https://doi.org/10.1038/s41598-019-45311-y

Duscha A, Gisevius B, Hirschberg S, et al., 2020, Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell, 180: 1067–1080.e16. https://doi.org/10.1016/j.cell.2020.02.035

Takewaki D, Suda W, Sato W, et al., 2020, Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis. Proc Natl Acad Sci U S A, 117: 22402–22412. https://doi.org/10.1073/pnas.2011703117

Ling Z, Cheng Y, Yan X, et al., 2020, Alterations of the fecal microbiota in Chinese patients with multiple sclerosis. Front Immunol, 11: 590783. https://doi.org/10.3389/fimmu.2020.590783

Luu M, Pautz S, Kohl V, et al., 2019, The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun, 10: 760. https://doi.org/10.1038/s41467-019-08711-2

Haase S, Mäurer J, Duscha A, et al., 2021, Propionic acid rescues high-fat diet enhanced immunopathology in autoimmunity via effects on Th17 responses. Front Immunol, 12: 701626. https://doi.org/10.3389/fimmu.2021.701626

Perez-Perez S, Domínguez-Mozo MI, Alonso-Gómez A, et al., 2020, Acetate correlates with disability and immune response in multiple sclerosis. PeerJ, 8: e10220. https://doi.org/10.7717/peerj.10220

Olsson A, Gustavsen S, Nguyen TD, et al., 2021, Serum short-chain fatty acids and associations with inflammation in newly diagnosed patients with multiple sclerosis and healthy controls. Front Immunol, 12: 661493. https://doi.org/10.3389/fimmu.2021.661493

Lim CK, Bilgin A, Lovejoy DB, et al., 2017, Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Sci Rep, 7: 41473. https://doi.org/4147310.1038/srep41473

Rothhammer V, Mascanfroni ID, Bunse L, et al., 2016, Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med, 22: 586–597. https://doi.org/10.1038/nm.4106

Nourbakhsh B, Bhargava P, Tremlett H, et al., 2018, Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course. Ann Clin Transl Neurol, 5: 1211–1221. https://doi.org/10.1002/acn3.637

Rothhammer V, Borucki DM, Sanchez MI, et al., 2017, Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS. Neurol Neuroimmunol Neuroinflamm, 4: e359. https://doi.org/10.1212/NXI.0000000000000359

Kaye J, Piryatinsky V, Birnberg T, et al., 2016, Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A, 113: E6145–E6152. https://doi.org/10.1073/pnas.1607843113

Rothhammer V, Kenison JE, Li Z, et al., 2021, Aryl hydrocarbon receptor activation in astrocytes by laquinimod ameliorates autoimmune inflammation in the CNS. Neurol Neuroimmunol Neuroinflamm, 8: e946. https://doi.org/10.1212/NXI.0000000000000946

Vollmer TL, Sorensen PS, Selmaj K, et al., 2014, A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol, 261: 773–783. https://doi.org/10.1007/s00415-014-7264-4

Wilck N, Matus MG, Kearney SM, et al., 2017, Salt-responsive gut commensal modulates TH17 axis and disease. Nature, 551: 585–589. https://doi.org/10.1038/nature24628

Rothhammer V, Borucki DM, Tjon EC, et al., 2018, Microglial control of astrocytes in response to microbial metabolites. Nature, 557: 724–728. https://doi.org/10.1038/s41586-018-0119-x

Rietjens IMC, Louisse J, Beekmann K, 2017, The potential health effects of dietary phytoestrogens. Br J Pharmacol, 174: 1263–1280. https://doi.org/10.1111/bph.13622

Masilamani M, Wei J, Sampson HA, 2012, Regulation of the immune response by soybean isoflavones. Immunol Res, 54: 95–110. https://doi.org/10.1007/s12026-012-8331-5

Rafii F, 2015, The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol. Metabolites, 5: 56–73. https://doi.org/10.3390/metabo5010056

Clavel T, Borrmann D, Braune A, et al., 2006, Occurrence and activity of human intestinal bacteria involved in the conversion of dietary lignans. Anaerobe, 12: 140–147. https://doi.org/10.1016/j.anaerobe.2005.11.002

Freedman SN, Shahi SK, Mangalam AK, 2018, The “gut feeling”: Breaking down the role of gut microbiome in multiple sclerosis. Neurotherapeutics, 15: 109–125. https://doi.org/10.1007/s13311-017-0588-x

Jensen SN, Cady NM, Shahi SK, et al., 2021, Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis. Sci Adv, 7: eabd4595. https://doi.org/10.1126/sciadv.abd4595

Suez J, Zmora N, Segal E, et al., 2019, The pros, cons, and many unknowns of probiotics. Nat Med, 25: 716–729. https://doi.org/10.1038/s41591-019-0439-x

Morshedi M, Hashemi R, Moazzen S, et al., 2019, Immunomodulatory and anti-inflammatory effects of probiotics in multiple sclerosis: A systematic review. J Neuroinflammation, 16: 231. https://doi.org/10.1186/s12974-019-1611-4

Mestre L, Carrillo-Salinas FJ, Feliú A, et al., 2020, How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process. Gut Microbes, 12: 1813532. https://doi.org/10.1080/19490976.2020.1813532

Calvo-Barreiro L, Eixarch H, Ponce-Alonso M, et al., 2020, A commercial probiotic induces tolerogenic and reduces pathogenic responses in experimental autoimmune encephalomyelitis. Cells, 9: 906. https://doi.org/10.3390/cells9040906

Colpitts SL, Kasper EJ, Keever A, et al., 2017, A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis. Gut Microbes, 8: 561–573. https://doi.org/10.1080/19490976.2017.1353843

Tankou SK, Regev K, Healy BC, et al., 2018. A probiotic modulates the microbiome and immunity in multiple sclerosis. Ann Neurol, 83: 1147–1161. https://doi.org/10.1002/ana.25244

Abdurasulova IN, Matsulevich AV, Tarasova EA, et al., 2016, Enterococcus faecium strain L-3 and glatiramer acetate ameliorate experimental allergic encephalomyelitis in rats by affecting different populations of immune cells. Benef Microbes, 7: 719–729. https://doi.org/10.3920/BM2016.0018

Secher T, Kassem S, Benamar M, et al., 2017, Oral administration of the probiotic strain Escherichia coli Nissle 1917 reduces susceptibility to neuroinflammation and repairs experimental autoimmune encephalomyelitis-induced intestinal barrier dysfunction. Front Immunol, 8: 1096. https://doi.org/10.3389/fimmu.2017.01096

He B, Hoang TK, Tian X, et al., 2019, Lactobacillus reuteri reduces the severity of experimental autoimmune encephalomyelitis in mice by modulating gut microbiota. Front Immunol, 10: 385. https://doi.org/10.3389/fimmu.2019.00385

Kouchaki E, Tamtaji OR, Salami M, et al., 2017, Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr, 36: 1245–1249. https://doi.org/10.1016/j.clnu.2016.08.015

Tamtaji OR, Kouchaki E, Salami M, et al., 2017, The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. J Am Coll Nutr, 36: 660–665. https://doi.org/10.1080/07315724.2017.1347074

Miyauchi E, Kim SW, Suda W, et al., 2020, Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature, 585: 102–106. https://doi.org/10.1038/s41586-020-2634-9

Montgomery TL, Künstner A, Kennedy JJ, et al., 2020, Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity. Proc Natl Acad Sci U S A, 117: 27516–27527. https://doi.org/10.1073/pnas.2002817117

Mestre L, Carrillo-Salinas FJ, Mecha M, et al., 2019, Manipulation of gut microbiota influences immune responses, axon preservation, and motor disability in a model of progressive multiple sclerosis. Front Immunol, 10: 1374. https://doi.org/10.3389/fimmu.2019.01374

Gödel C, Kunkel B, Kashani A, et al., 2020, Perturbation of gut microbiota decreases susceptibility but does not modulate ongoing autoimmune neurological disease. J Neuroinflammation, 17: 79. https://doi.org/10.1186/s12974-020-01766-9

Chen H, Ma X, Liu Y, et al., 2019, Gut microbiota interventions with Clostridium butyricum and norfloxacin modulate immune response in experimental autoimmune encephalomyelitis mice. Front Immunol, 10: 1662. https://doi.org/10.3389/fimmu.2019.01662

Minagar A, Alexander JS, Schwendimann RN, et al., 2008, Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: An open-label trial. Arch Neurol, 65: 199–204. https://doi.org/10.1001/archneurol.2007.41

Mazdeh M, Mobaien AR, 2012, Efficacy of doxycycline as add-on to interferon beta-1a in treatment of multiple sclerosis. Iran J Neurol, 11: 70–73.

Metz LM, Eliasziw M, 2017, Trial of minocycline in clinically isolated syndrome of multiple sclerosis. N Engl J Med, 377: 789. https://doi.org/10.1056/NEJMc1708486

Ross CL, Spinler JK, Savidge TC, 2016, Structural and functional changes within the gut microbiota and susceptibility to Clostridium difficile infection. Anaerobe, 41: 37–43. https://doi.org/10.1016/j.anaerobe.2016.05.006

Zmora N, Suez J, Elinav E, 2019, You are what you eat: Diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol, 16: 35–56. https://doi.org/10.1038/s41575-018-0061-2

Sonnenburg ED, Smits SA, Tikhonov M, et al., 2016, Diet-induced extinctions in the gut microbiota compound over generations. Nature, 529: 212–215. https://doi.org/10.1038/nature16504

Sonnenburg JL, Backhed F, 2016, Diet-microbiota interactions as moderators of human metabolism. Nature, 535: 56–64. https://doi.org/10.1038/nature18846

Kap YS, Bus-Spoor C, van Driel N, et al., 2018, Targeted diet modification reduces multiple sclerosis-like disease in adult marmoset monkeys from an outbred colony. J Immunol, 201: 3229–3243. https://doi.org/10.4049/jimmunol.1800822

Cignarella F, Cantoni C, Ghezzi L, et al., 2018, Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab, 27: 1222–1235.e6. https://doi.org/10.1016/j.cmet.2018.05.006

Saresella M, Mendozzi L, Rossi V, et al., 2017, Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study. Front Immunol, 8: 1391. https://doi.org/10.3389/fimmu.2017.01391

Esposito S, Sparaco M, Maniscalco GT, et al., 2021, Lifestyle and Mediterranean diet adherence in a cohort of Southern Italian patients with Multiple Sclerosis. Mult Scler Relat Disord, 47: 102636, https://doi.org/10.1016/j.msard.2020.102636

Kao D, Roach B, Silva M, et al., 2017, Effect of oral capsule-vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: A randomized clinical trial. JAMA, 318: 1985–1993. https://doi.org/10.1001/jama.2017.17077

Cammarota G, Ianiro G, 2019, FMT for ulcerative colitis: Closer to the turning point. Nat Rev Gastroenterol Hepatol, 16: 266–268. https://doi.org/10.1038/s41575-019-0131-0

El-Salhy M, Hatlebakk JG, Gilja OH, et al., 2020, Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut, 69: 859–867. https://doi.org/10.1136/gutjnl-2019-319630

Stanisavljević S, Dinić M, Jevtić B, et al., 2018, Gut microbiota confers resistance of albino Oxford rats to the induction of experimental autoimmune encephalomyelitis. Front Immunol, 9: 942. https://doi.org/10.3389/fimmu.2018.00942

Chitrala KN, Guan H, Singh NP, et al., 2017, CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice. Eur J Immunol, 47: 1188–1199. https://doi.org/10.1002/eji.201646792

Chen H, Shen L, Liu Y, et al., 2021, Strength exercise confers protection in central nervous system autoimmunity by altering the gut microbiota. Front Immunol, 12: 628629. https://doi.org/10.3389/fimmu.2021.628629

Al-Ghezi ZZ, Busbee PB, Alghetaa H, et al., 2019, Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain Behav Immun, 82: 25–35. https://doi.org/10.1016/j.bbi.2019.07.028

Lu XY, Han B, Deng X, et al., 2020, Pomegranate peel extract ameliorates the severity of experimental autoimmune encephalomyelitis via modulation of gut microbiota. Gut Microbes, 12: 1857515. https://doi.org/10.1080/19490976.2020.1857515

Engen PA, Zaferiou A, Rasmussen H, et al., 2020, Single-arm, non-randomized, time series, single-subject study of fecal microbiota transplantation in multiple sclerosis. Front Neurol, 11: 978. https://doi.org/10.3389/fneur.2020.00978

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