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Review

Targeting gut microbiota: new therapeutic opportunities in multiple sclerosis

, , , & ORCID Icon
Article: 2274126 | Received 02 May 2023, Accepted 18 Oct 2023, Published online: 18 Nov 2023

References

  • Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):1–37. doi:10.1038/s41572-018-0041-4.
  • Waubant E, Lucas R, Mowry E, Graves J, Olsson T, Alfredsson L, Langer‐Gould A. Environmental and genetic risk factors for MS: an integrated review. Ann Clin Transl Neurol. 2019;6(9):1905–1922. doi:10.1002/acn3.50862.
  • Marrodan M, Alessandro L, Farez MF, Correale J. The role of infections in multiple sclerosis. Mult Scler. 2019;25(7):891–901. doi:10.1177/1352458518823940.
  • Tarlinton RE, Khaibullin T, Granatov E, Martynova E, Rizvanov A, Khaiboullina S. The interaction between viral and environmental risk factors in the pathogenesis of multiple sclerosis. IJMS. 2019;20(2):303. doi:10.3390/ijms20020303.
  • Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Sci. 2022;375(6578):296–301. doi:10.1126/science.abj8222.
  • Yin JX, Tang Z, Gan Y, Li L, Shi F, Coons S, Shi J. Pertussis toxin modulates microglia and T cell profile to protect experimental autoimmune encephalomyelitis. Neuropharmacology. 2014;81:1–5. doi:10.1016/j.neuropharm.2014.01.027.
  • Marchesi JR, Ravel J. The vocabulary of microbiome research: a proposal. Microbiome. 2015;3(1):31. doi:10.1186/s40168-015-0094-5.
  • Ghezzi L, Cantoni C, Pinget GV, Zhou Y, Piccio L. Targeting the gut to treat multiple sclerosis. J Clin Invest. 2021;131(13). doi:10.1172/JCI143774.
  • Shahi SK, Freedman SN, Mangalam AK. Gut microbiome in multiple sclerosis: the players involved and the roles they play. Gut Microbes. 2017;8(6):607–615. doi:10.1080/19490976.2017.1349041.
  • Maglione A, Zuccala M, Tosi M, Clerico M, Rolla S. Host genetics and gut microbiome: perspectives for multiple sclerosis. Genes (Basel). 2021;12(8):1181. doi:10.3390/genes12081181.
  • Shahi SK, Ali S, Jaime CM, Guseva NV, Mangalam AK. HLA class II polymorphisms modulate gut microbiota and experimental autoimmune encephalomyelitis phenotype. Immunohorizons. 2021;5(8):627–646. doi:10.4049/immunohorizons.2100024.
  • Montgomery TL, Künstner A, Kennedy JJ, Fang Q, Asarian L, Culp-Hill R, D’Alessandro A, Teuscher C, Busch H, Krementsov DN, et al. Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity. Proc Natl Acad Sci U S A. 2020;117(44):27516–27527. doi:10.1073/pnas.2002817117.
  • Wang J, Thingholm LB, Skiecevičienė J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen F-A, Rühlemann MC, Szymczak S, et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet. 2016;48(11):1396–1406. doi:10.1038/ng.3695.
  • Ghareghani M, Reiter RJ, Zibara K, Farhadi NL, Vitamin D. Melatonin, and gut microbiota act in concert to initiate multiple sclerosis: a New mechanistic pathway. Front Immunol. 2018;9:2484. doi:10.3389/fimmu.2018.02484.
  • Boziki MK, Kesidou E, Theotokis P, Mentis AFA, Karafoulidou E, Melnikov M, Sviridova A, Rogovski V, Boyko A, Grigoriadis N, et al. Microbiome in multiple sclerosis; where are we, what we know and do not know. Brain Sci. 2020;10(4):234. doi:10.3390/brainsci10040234.
  • Inojosa H, Proschmann U, Akgun K, Ziemssen T. The need for a strategic therapeutic approach: multiple sclerosis in check. Ther Adv Chronic Dis. 2022;13:20406223211063032. doi:10.1177/20406223211063032.
  • Weld-Blundell IV, Grech L, Learmonth YC, Marck CH. Lifestyle and complementary therapies in multiple sclerosis guidelines: systematic review. Acta Neurol Scand. 2022;145(4):379–392. doi:10.1111/ane.13574.
  • Rumah KR, Linden J, Fischetti VA, Vartanian T, Esteban FJ. Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease. PloS One. 2013;8(10):e76359. doi:10.1371/journal.pone.0076359.
  • Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, Kanner R, Bencosme Y, Lee YK, Hauser SL, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114(40):10713–10718. doi:10.1073/pnas.1711235114.
  • Baum K, Rejmus R, Dorffel Y. Commensal gut flora in MS: spatial organization and composition. Mult Scler. 2015;21:458–159.
  • Levi I, Gurevich M, Perlman G, Magalashvili D, Menascu S, Bar N, Godneva A, Zahavi L, Chermon D, Kosower N, et al. Potential role of indolelactate and butyrate in multiple sclerosis revealed by integrated microbiome-metabolome analysis. Cell Rep Med. 2021;2(4):100246. doi:10.1016/j.xcrm.2021.100246.
  • Swidsinski A, Dörffel Y, Loening-Baucke V, Gille C, Göktas Ö, Reißhauer A, Neuhaus J, Weylandt K-H, Guschin A, Bock M, et al. Reduced Mass and diversity of the colonic microbiome in patients with multiple sclerosis and their improvement with Ketogenic Diet. Front Microbiol. 2017;8:1141. doi:10.3389/fmicb.2017.01141.
  • Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F, et al. High frequency of intestinal T H 17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3(7):e1700492. doi:10.1126/sciadv.1700492.
  • Miyake S, Kim S, Suda W, Oshima K, Nakamura M, Matsuoka T, Chihara N, Tomita A, Sato W, Kim S-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. doi:10.1371/journal.pone.0137429.
  • Cantarel BL, Waubant E, Chehoud C, Kuczynski J, DeSantis TZ, Warrington J, Venkatesan A, Fraser CM, Mowry EM. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. Journal Of Investigative Medicine. 2015;63(5):729–734. doi:10.1097/JIM.0000000000000192.
  • Ling Z, Cheng Y, Yan X, Shao L, Liu X, Zhou D, Zhang L, Yu K, Zhao L, et al. Alterations of the fecal microbiota in Chinese patients with multiple sclerosis. Front Immunol. 2020;11:590783. doi:10.3389/fimmu.2020.590783.
  • Storm-Larsen C, Myhr K-M, Farbu E, Midgard R, Nyquist K, Broch L, Berg-Hansen P, Buness A, Holm K, Ueland T, et al. Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis – a pilot trial. Mult Scler J Exp Transl Clin. 2019;5(4):2055217319888767. doi:10.1177/2055217319888767.
  • Ventura RE, Iizumi T, Battaglia T, Liu M, Perez-Perez GI, Herbert J, Blaser MJ. Gut microbiome of treatment-naïve MS patients of different ethnicities early in disease course. Sci Rep. 2019;9(1):16396. doi:10.1038/s41598-019-52894-z.
  • Oezguen N, Yalcinkaya N, Kücükali CI, Dahdouli M, Hollister EB, Luna RA, Türkoglu R, Kürtüncü M, Eraksoy M, Savidge TC, et al. Microbiota stratification identifies disease-specific alterations in neuro-Behçet’s disease and multiple sclerosis. Clin Exp Rheumatol. 2019;37 Suppl 121(6):58–66.
  • Saresella M, Marventano I, Barone M, La Rosa F, Piancone F, Mendozzi L, d’Arma A, Rossi V, Pugnetti L, Roda G, et al. Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis. Front Immunol. 2020;11:1390. doi:10.3389/fimmu.2020.01390.
  • Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L, Xia Z, Liu C, Klotz L, Stauffer U, Baranzini SE, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;114(40):10719–10724. doi:10.1073/pnas.1711233114.
  • Cox LM, Maghzi AH, Liu S, Tankou SK, Dhang FH, Willocq V, Song A, Wasén C, Tauhid S, Chu R, et al. Gut microbiome in progressive multiple sclerosis. Ann Neurol. 2021;89(6):1195–1211. doi:10.1002/ana.26084.
  • Takewaki D, Suda W, Sato W, Takayasu L, Kumar N, Kimura K, Kaga N, Mizuno T, Miyake S, Hattori M, et al. Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis. Proc Natl Acad Sci U S A. 2020;117(36):22402–22412. doi:10.1073/pnas.2011703117.
  • Cekanaviciute E, Debelius, JW, Singh S, Runia T, Nelson C, Yoo B, Kanner R, Crabtree-Hartman E, Mazmanian S, Knight R et al. Gut dysbiosis is a feature of MS and it is characterized by bacteria able to regulate lymphocyte differentiation in vitro. Mult Scler. 2016;22(S3):58–59.
  • Zeng Q, Gong J, Liu X, Chen C, Sun X, Li H, Zhou Y, Cui C, Wang Y, Yang Y, 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. doi:10.1016/j.neuint.2019.104468.
  • Forbes JD, Chen C-Y, Knox NC, Marrie R-A, El-Gabalawy H, de Kievit T, Alfa M, Bernstein CN, Van Domselaar G. A comparative study of the gut microbiota in immune-mediated inflammatory diseases—does a common dysbiosis exist? Microbiome. 2018;6(1):221. doi:10.1186/s40168-018-0603-4.
  • Kozhieva M, Naumova N, Alikina T, Boyko A, Vlassov V, Kabilov MR. Primary progressive multiple sclerosis in a Russian cohort: relationship with gut bacterial diversity. BMC Microbiol. 2019;19(1):309. doi:10.1186/s12866-019-1685-2.
  • Choileain SN, Kleinewietfeld M, Raddassi K, Hafler DA, Ruff WE, Longbrake EE. CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome. J Transl Autoimmunity. 2020;3:100032. doi:10.1016/j.jtauto.2019.100032.
  • Reynders T, Devolder L, Valles‐Colomer M, Van Remoortel A, Joossens M, De Keyser J, Nagels G, D’hooghe M, Raes J. Gut microbiome variation is associated to multiple sclerosis phenotypic subtypes. Ann Clin Transl Neurol. 2020;7(4):406–419. doi:10.1002/acn3.51004.
  • Zhou X, Singh S, Baumann R, Barba P, Landefeld J, Casaccia P, Sand IK, Xia Z, Weiner H, Chitnis T, et al. Household paired design reduces variance and increases power in multi-city gut microbiome study in multiple sclerosis. Mult Scler. 2021;27(3):366–379. doi:10.1177/1352458520924594.
  • Zhou X, Baumann R, Gao X, Mendoza M, Singh S, Katz Sand I, Xia Z, Cox LM, Chitnis T, Yoon H. iMSMS & consortium. Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course. Cell. 2022;185(19):3467–3486.e16. doi:10.1016/j.cell.2022.08.021.
  • Johanson DM 2nd, Goertz JE, Marin IA, Costello J, Overall CC, Gaultier A. Experimental autoimmune encephalomyelitis is associated with changes of the microbiota composition in the gastrointestinal tract. Science Reports. 2020;10(1):15183. doi:10.1038/s41598-020-72197-y.
  • Gandy KAO, Zhang J, Nagarkatti P, Nagarkatti M. The role of gut microbiota in shaping the relapse-remitting and chronic-progressive forms of multiple sclerosis in mouse models. Sci Rep. 2019;9(1):6923. doi:10.1038/s41598-019-43356-7.
  • Moles L, Egimendia A, Osorio-Querejeta I, Iparraguirre L, Alberro A, Suárez J, Sepúlveda L, Castillo-Triviño T, Muñoz-Culla M, Ramos-Cabrer P, et al. Gut microbiota changes in experimental autoimmune encephalomyelitis and cuprizone mice models. ACS Chem Neurosci. 2021;12(5):893–905. doi:10.1021/acschemneuro.0c00695.
  • Colpitts SL, Kasper EJ, Keever A, Liljenberg C, Kirby T, Magori K, Kasper LH, Ochoa-Repáraz J. A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis. Gut Microbes. 2017;8(6):561–573. doi:10.1080/19490976.2017.1353843.
  • Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2011;Suppl 108(supplement_1):4615–4622. doi:10.1073/pnas.1000082107.
  • Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide a expression. The Journal Of Immunology. 2010;185(7):4101–4108. doi:10.4049/jimmunol.1001443.
  • Telesford KM, Yan W, Ochoa-Reparaz J, Pant A, Kircher C, Christy MA, Begum-Haque S, Kasper DL, Kasper LH. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39 + Foxp3 + T cells and T reg function. Gut Microbes. 2015;6(4):234–242. doi:10.1080/19490976.2015.1056973.
  • Yamashita M, Ukibe K, Matsubara Y, Hosoya T, Sakai F, Kon S, Arima Y, Murakami M, Nakagawa H, Miyazaki T, et al. Lactobacillus helveticus SBT2171 attenuates experimental autoimmune encephalomyelitis in mice. Front Microbiol. 2017;8:2596. doi:10.3389/fmicb.2017.02596.
  • Lavasani S, Dzhambazov B, Nouri M, Fåk F, Buske S, Molin G, Thorlacius H, Alenfall J, Jeppsson B, Weström B, 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. doi:10.1371/journal.pone.0009009.
  • He B, Hoang TK, Tian X, Taylor CM, Blanchard E, Luo M, Bhattacharjee MB, Freeborn J, Park S, Couturier J, et al. Lactobacillus reuteri reduces the severity of experimental autoimmune encephalomyelitis in mice by modulating gut microbiota. Front Immunol. 2019;10:385. doi:10.3389/fimmu.2019.00385.
  • Consonni A, Cordiglieri C, Rinaldi E, Marolda R, Ravanelli I, Guidesi E, Elli M, Mantegazza R, Baggi F. Administration of bifidobacterium and lactobacillus strains modulates experimental myasthenia gravis and experimental encephalomyelitis in Lewis rats. Oncotarget. 2018;9(32):22269–22287. doi:10.18632/oncotarget.25170.
  • Ezendam J, de Klerk A, Gremmer ER, van Loveren H. Effects of Bifidobacterium animalis administered during lactation on allergic and autoimmune responses in rodents. Clin Exp Immunol. 2008;154(3):424–431. doi:10.1111/j.1365-2249.2008.03788.x.
  • Kwon HK, Kim G-C, Kim Y, Hwang W, Jash A, Sahoo A, Kim J-E, Nam JH, Im S-H. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clinical Immunology. 2013;146(3):217–227. doi:10.1016/j.clim.2013.01.001.
  • Salehipour Z, Haghmorad D, Sankian M, Rastin M, Nosratabadi R, Soltan Dallal MM, Tabasi N, Khazaee M, Nasiraii LR, Mahmoudi M, et al. Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance. Biomed Pharmacother. 2017;95:1535–1548. doi:10.1016/j.biopha.2017.08.117.
  • Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, Choung RS, Ju J, Sompallae R, Gibson-Corley K, et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep. 2017;20(6):1269–1277. doi:10.1016/j.celrep.2017.07.031.
  • Carrillo-Salinas FJ, Mestre L, Mecha M, Feliú A, Del Campo R, Villarrubia N, Espejo C, Montalbán X, Álvarez-Cermeño JC, Villar LM, et al. Gut dysbiosis and neuroimmune responses to brain infection with Theiler’s murine encephalomyelitis virus. Sci Rep. 2017;7(1):44377. doi:10.1038/srep44377.
  • Omura S, Sato F, Park A-M, Fujita M, Khadka S, Nakamura Y, Katsuki A, Nishio K, Gavins FNE, Tsunoda I, et al. 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. 2020;11:1138. doi:10.3389/fimmu.2020.01138.
  • Wang X, Chang L, Wan X, Tan Y, Qu Y, Shan J, Yang Y, Ma L, Hashimoto K. (R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: a role of gut–microbiota–brain axis. Neurobiology Of Disease. 2022;165:105635. doi:10.1016/j.nbd.2022.105635.
  • Wang X, Eguchi A, Yang Y, Chang L, Wan X, Shan J, Qu Y, Ma L, Mori C, Yang J, et al. Key role of the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain. Neurobiol Dis. 2023;176:105951. doi:10.1016/j.nbd.2022.105951.
  • Liu S, Rezende RM, Moreira TG, Tankou SK, Cox LM, Wu M, Song A, Dhang FH, Wei Z, Costamagna G, et al. Oral administration of miR-30d from feces of MS patients suppresses MS-like symptoms in mice by expanding Akkermansia muciniphila. Cell Host & Microbe. 2019;26(6):779–794.e8. doi:10.1016/j.chom.2019.10.008.
  • Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee D-H, May C, Wilck N, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity. 2015;43(4):817–829. doi:10.1016/j.immuni.2015.09.007.
  • Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Dawin E, Bader V, Haase S, Kaisler J, David C, et al. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell. 2020;180(6):1067–1080.e16. doi:10.1016/j.cell.2020.02.035.
  • Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, Korecka A, Bakocevic N, Ng LG, Kundu P, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158. doi:10.1126/scitranslmed.3009759.
  • Mossad O, Erny D. The microbiota–microglia axis in central nervous system disorders. Brain Pathology. 2020;30(6):1159–1177. doi:10.1111/bpa.12908.
  • Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Paz Soldan MM, Luckey DH, Marietta EV, Jeraldo PR, Chen X, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6(1):28484. doi:10.1038/srep28484.
  • Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, Patel B, Mazzola MA, Liu S, Glanz BL, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7(1):12015. doi:10.1038/ncomms12015.
  • Hughes LE, Bonell S, Natt RS, Wilson C, Tiwana H, Ebringer A, Cunningham P, Chamoun V, Thompson EJ, Croker J, et al. Antibody responses to Acinetobacter spp. And Pseudomonas aeruginosa in multiple sclerosis: prospects for diagnosis using the myelin-acinetobacter-neurofilament antibody index. Clin Diagn Lab Immunol. 2001;8(6):1181–1188. doi:10.1128/CDLI.8.6.1181-1188.2001.
  • Farrokhi V, Nemati R, Nichols FC, Yao X, Anstadt E, Fujiwara M, Grady J, Wakefield D, Castro W, Donaldson J, et al. Bacterial lipodipeptide, lipid 654, is a microbiome-associated biomarker for multiple sclerosis. Clin & Trans Imm. 2013;2(11):e8. doi:10.1038/cti.2013.11.
  • Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122(1):107–118. doi:10.1016/j.cell.2005.05.007.
  • Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, Lynch S, Waubant E, Aaen G, Belman A, et al. Gut microbiota composition and relapse risk in pediatric MS: a pilot study. J Neurol Sci. 2016;363:153–157. doi:10.1016/j.jns.2016.02.042.
  • Cady N, Peterson SR, Freedman SN, Mangalam AK. Beyond metabolism: the complex interplay between dietary phytoestrogens, gut bacteria, and cells of nervous and immune systems. Front Neurol. 2020;11:150. doi:10.3389/fneur.2020.00150.
  • Freedman SN, Shahi SK, Mangalam AK. The “gut feeling”: breaking down the role of gut microbiome in multiple sclerosis. Neurotherapeutics. 2018;15(1):109–125. doi:10.1007/s13311-017-0588-x.
  • Cocchi M, Mondo E, Romeo M, Traina G. The inflammatory conspiracy in multiple sclerosis: a crossroads of clues and insights through mast cells, platelets, inflammation, gut microbiota, mood disorders and stem cells. Int J Mol Sci. 2022;23(6):3253. doi:10.3390/ijms23063253.
  • Garabatos N, Santamaria P. Gut microbial antigenic mimicry in autoimmunity. Front Immunol. 2022;13:873607. doi:10.3389/fimmu.2022.873607.
  • Elsayed NS, Aston P, Bayanagari VR, Shukla SK. The gut microbiome molecular mimicry piece in the multiple sclerosis puzzle. Front Immunol. 2022;13:972160. doi:10.3389/fimmu.2022.972160.
  • Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278(13):11312–11319. doi:10.1074/jbc.M211609200.
  • Liu J, Li H, Gong T, Chen W, Mao S, Kong Y, Yu J, Sun J. Anti-neuroinflammatory effect of short-chain fatty acid acetate against Alzheimer’s disease via upregulating GPR41 and inhibiting ERK/JNK/NF-κB. J Agric Food Chem. 2020;68(27):7152–7161. doi:10.1021/acs.jafc.0c02807.
  • Chevalier AC, Rosenberger TA. Increasing acetyl-CoA metabolism attenuates injury and alters spinal cord lipid content in mice subjected to experimental autoimmune encephalomyelitis. J Neurochem. 2017;141(5):721–737. doi:10.1111/jnc.14032.
  • Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic T reg cell homeostasis. Sci. 2013;341(6145):569–573. doi:10.1126/science.1241165.
  • Hoyles L, Snelling T, Umlai U-K, Nicholson JK, Carding SR, Glen RC, McArthur S. Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier. Microbiome. 2018;6(1). doi:10.1186/s40168-018-0439-y.
  • Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–450. doi:10.1038/nature12721.
  • Kespohl M, Vachharajani N, Luu M, Harb H, Pautz S, Wolff S, Sillner N, Walker A, Schmitt-Kopplin P, Boettger T, et al. The microbial metabolite butyrate induces expression of Th1-associated factors in CD4(+) T cells. Front Immunol. 2017;8:1036. doi:10.3389/fimmu.2017.01036.
  • Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247–2252. doi:10.1073/pnas.1322269111.
  • Chen T, Noto D, Hoshino Y, Mizuno M, Miyake S. Butyrate suppresses demyelination and enhances remyelination. J Neuroinflammation. 2019;16(1):165. doi:10.1186/s12974-019-1552-y.
  • Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451–455. doi:10.1038/nature12726.
  • Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Raifer H, Vachharajani N, Carrascosa LC, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun. 2019;10(1):760. doi:10.1038/s41467-019-08711-2.
  • 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):8837. doi:10.1038/s41598-019-45311-y.
  • Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–977. doi:10.1038/nn.4030.
  • Wenzel TJ, Gates EJ, Ranger AL, Klegeris A. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Mol Cell Neurosci. 2020;105:103493. doi:10.1016/j.mcn.2020.103493.
  • Sundaram TS, Giromini C, Rebucci R, Baldi A. Omega-3 Polyunsaturated fatty acids counteract inflammatory and oxidative damage of non-transformed porcine enterocytes. Anim (Basel). 2020;10(6):956. doi:10.3390/ani10060956.
  • Denys A, Hichami A, Khan NA. N-3 PUFAs modulate T-cell activation via protein kinase C-α and -ε and the NF-κB signaling pathway. J Lipid Res. 2005;46(4):752–758. doi:10.1194/jlr.M400444-JLR200.
  • Djuricic I, Calder PC. Beneficial outcomes of omega-6 and omega-3 Polyunsaturated fatty acids on human health: an update for 2021. Nutrients. 2021;13(7):2421. doi:10.3390/nu13072421.
  • Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, Tong C, Xu K. Associations among dietary omega-3 Polyunsaturated fatty acids, the gut microbiota, and intestinal immunity. Mediators Of Inflammation. 2021;2021:1–11. doi:10.1155/2021/8879227.
  • Montgomery TL, Eckstrom K, Lile KH, Caldwell S, Heney ER, Lahue KG, D’Alessandro A, Wargo MJ, Krementsov DN. Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity. Microbiome. 2022;10(1):198. doi:10.1186/s40168-022-01408-7.
  • Rothhammer V, Borucki DM, Garcia Sanchez MI, Mazzola MA, Hemond CC, Regev K, Paul A, Kivisäkk P, Bakshi R, Izquierdo G, et al. Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e359. doi:10.1212/NXI.0000000000000359.
  • Sonner JK, Keil M, Falk-Paulsen M, Mishra N, Rehman A, Kramer M, Deumelandt K, Röwe J, Sanghvi K, Wolf L, et al. Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology. Nat Commun. 2019;10(1):4877. doi:10.1038/s41467-019-12776-4.
  • Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, Haase S, Mähler A, Balogh A, Markó L, et al. Salt-responsive gut commensal modulates T(H)17 axis and disease. Nature. 2017;551(7682):585–589. doi:10.1038/nature24628.
  • Zelante T, Iannitti R, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D’Angelo C, Massi-Benedetti C, Fallarino F, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39(2):372–385. doi:10.1016/j.immuni.2013.08.003.
  • Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet A, Qiu Z, Maher L, Redinbo M, Phillips R, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4. Immunity. 2014;41(2):296–310. doi:10.1016/j.immuni.2014.06.014.
  • Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao C-C, Patel B, Yan R, Blain M, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22(6):586–597. doi:10.1038/nm.4106.
  • Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao C-C, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557(7707):724–728. doi:10.1038/s41586-018-0119-x.
  • Owe-Young R, Webster NL, Mukhtar M, Pomerantz RJ, Smythe G, Walker D, Armati PJ, Crowe SM, Brew BJ. Kynurenine pathway metabolism in human blood–brain–barrier cells: implications for immune tolerance & neurotoxicity. J Neurochem. 2008;105(4):1346–1357. doi:10.1111/j.1471-4159.2008.05241.x.
  • Lim CK, Bilgin A, Lovejoy DB, Tan V, Bustamante S, Taylor BV, Bessede A, Brew BJ, Guillemin GJ. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Sci Rep-Uk. 2017;7(1). doi:10.1038/srep41473.
  • Guillemin GJ, Smythe G, Takikawa O, Brew BJ. Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia. 2005;49(1):15–23. doi:10.1002/glia.20090.
  • Rothhammer V, Kenison JE, Li Z, Tjon E, Takenaka MC, Chao C-C, Alves de Lima K, Borucki DM, Kaye J, Quintana FJ, et al. Aryl hydrocarbon receptor activation in astrocytes by laquinimod ameliorates autoimmune inflammation in the CNS. Neurol Neuroimmunol Neuroinflamm. 2021;8(2):e946. doi:10.1212/NXI.0000000000000946.
  • Haase S, Haghikia A, Wilck N, Muller DN, Linker RA. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018;154(2):230–238. doi:10.1111/imm.12933.
  • Calvo-Barreiro L, Eixarch H, Ponce-Alonso M, Castillo M, Lebrón-Galán R, Mestre L, Guaza C, Clemente D, Del Campo R, Montalban X, et al. A commercial probiotic induces tolerogenic and reduces pathogenic responses in experimental autoimmune encephalomyelitis. Cells. 2020;9(4):906. doi:10.3390/cells9040906.
  • San Hernandez AM, Singh C, Valero DJ, Nisar J, Trujillo Ramirez JI, Kothari KK, Isola S, Gordon DK. Multiple sclerosis and serotonin: potential therapeutic applications. Cureus. 2020;12:e11293. doi:10.7759/cureus.11293.
  • Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell. 2021;184(16):4168–4185.e21. doi:10.1016/j.cell.2021.05.045.
  • Carriche GM, Almeida L, Stüve P, Velasquez L, Dhillon-LaBrooy A, Roy U, Lindenberg M, Strowig T, Plaza-Sirvent C, Schmitz I, et al. Regulating T-cell differentiation through the polyamine spermidine. J Allergy Clin Immun. 2021;147(1):335–348.e11. doi:10.1016/j.jaci.2020.04.037.
  • Yang Q, Zheng C, Cao J, Cao G, Shou P, Lin L, Velletri T, Jiang M, Chen Q, Han Y, et al. Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages. Cell Death Differ. 2016;23(11):1850–1861. doi:10.1038/cdd.2016.71.
  • Guo X, Harada C, Namekata K, Kimura A, Mitamura Y, Yoshida H, Matsumoto Y, Harada T. Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis. Invest Ophthalmol Vis Sci. 2011;52(5):2696–2703. doi:10.1167/iovs.10-6015.
  • Soda K, Kano Y, Nakamura T, Kasono K, Kawakami M, Konishi F. Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. The Journal Of Immunology. 2005;175(1):237–245. doi:10.4049/jimmunol.175.1.237.
  • Zhang S, Al-Maghout T, Cao H, Pelzl L, Salker MS, Veldhoen M, Cheng A, Lang F, Singh Y. Gut bacterial metabolite Urolithin a (UA) mitigates Ca(2+) entry in T cells by regulating miR-10a-5p. Front Immunol. 2019;10:1737. doi:10.3389/fimmu.2019.01737.
  • Shen PX, Li X, Deng S-Y, Zhao L, Zhang Y-Y, Deng X, Han B, Yu J, Li Y, Wang Z-Z, et al. Urolithin a ameliorates experimental autoimmune encephalomyelitis by targeting aryl hydrocarbon receptor. EBioMedicine. 2021;64:103227. doi:10.1016/j.ebiom.2021.103227.
  • Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019;10(1). doi:10.1038/s41467-018-07859-7.
  • Gong Z, Huang J, Xu B, Ou Z, Zhang L, Lin X, Ye X, Kong X, Long D, Sun X, et al. Urolithin a attenuates memory impairment and neuroinflammation in APP/PS1 mice. J Neuroinflammation. 2019;16(1):62. doi:10.1186/s12974-019-1450-3.
  • DaSilva NA, Nahar PP, Ma H, Eid A, Wei Z, Meschwitz S, Zawia NH, Slitt AL, Seeram NP. Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro. Nutritional Neuroscience. 2019;22(3):185–195. doi:10.1080/1028415X.2017.1360558.
  • Busto R, Serna J, Perianes-Cachero A, Quintana-Portillo R, García-Seisdedos D, Canfrán-Duque A, Paino CL, Lerma M, Casado ME, Martín-Hidalgo A, et al. Ellagic acid protects from myelin-associated sphingolipid loss in experimental autoimmune encephalomyelitis. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(9):958–967. doi:10.1016/j.bbalip.2018.05.009.
  • Chen P, Chen FC, Lei JX, Wang GH, Zhou BH. The gut microbiota metabolite Urolithin B improves cognitive deficits by Inhibiting Cyt C-Mediated apoptosis and promoting the survival of neurons through the PI3K pathway in aging mice. Front Pharmacol. 2021;12:768097. doi:10.3389/fphar.2021.768097.
  • Castillo-Alvarez F, Perez-Matute P, Oteo JA, Marzo-Sola ME. The influence of interferon β-1b on gut microbiota composition in patients with multiple sclerosis. Neurología (English Ed). 2021;36(7):495–503. doi:10.1016/j.nrleng.2020.05.006.
  • Katz Sand I, Zhu Y, Ntranos A, Clemente JC, Cekanaviciute E, Brandstadter R, Crabtree-Hartman E, Singh S, Bencosme Y, Debelius J, et al. Disease-modifying therapies alter gut microbial composition in MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(1):e517. doi:10.1212/NXI.0000000000000517.
  • Abdurasulova IN, Tarasova EA, Nikiforova IG, Il’ves AG, Ivashkova EV, Matsulevich AV, Tatarinov AE, Shangina LV, Ermolenko EI, Klimenko VM, et al. The intestinal microbiota composition in patients with multiple sclerosis receiving different disease-modifying therapies DMT. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(8):62–69. doi:10.17116/jnevro201811808262.
  • Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, Graves J, Lynch S, Waubant E. Gut microbiota in early pediatric multiple sclerosis: a case−control study. Euro J Of Neurology. 2016;23(8):1308–1321. doi:10.1111/ene.13026.
  • Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, Spencer CM, Lynch SV, Zamvil SS, Waubant E, et al. Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls. BMC Neurol. 2016;16(1):182. doi:10.1186/s12883-016-0703-3.
  • Shahi SK, Freedman SN, Murra AC, Zarei K, Sompallae R, Gibson-Corley KN, Karandikar NJ, Murray JA, Mangalam AK. Prevotella histicola, a human gut commensal, is as potent as COPAXONE® in an animal model of multiple sclerosis. Front Immunol. 2019;10:462. doi:10.3389/fimmu.2019.00462.
  • Rumah KR, Vartanian TK, Fischetti VA. Oral multiple sclerosis drugs inhibit the in vitro growth of epsilon toxin producing gut bacterium, Clostridium perfringens. Front Cell Infect Microbiol. 2017;7:11. doi:10.3389/fcimb.2017.00011.
  • Li QR, Wang CY, Tang C, He Q, Li N, Li JS. Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys after alemtuzumab treatment. Am J Transplant. 2013;13(4):899–910. doi:10.1111/ajt.12148.
  • Diebold M, Meola M, Purushothaman S, Siewert LK, Pössnecker E, Roloff T, Lindberg RL, Kuhle J, Kappos L, Derfuss T, et al. Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis. Gut Microbes. 2022;14(1):2147055. doi:10.1080/19490976.2022.2147055.
  • Dehghani F, Abdollahi S, Shidfar F, Clark CCT, Soltani S. Probiotics supplementation and brain-derived neurotrophic factor (BDNF): a systematic review and meta-analysis of randomized controlled trials. Nutr Neurosci. 2022;1–11. doi:10.1080/1028415X.2022.2110664.
  • Valizadeh S, Majdi Seghinsara A, Maleki Chollou K, Bahadori A, Abbaszadeh S, Taghdir M, Behniafar H, Riahi SM. The efficacy of probiotics in experimental autoimmune encephalomyelitis (an animal model for MS): a systematic review and meta-analysis. Lett Appl Microbiol. 2021;73(4):408–417. doi:10.1111/lam.13543.
  • Kap YS, Bus-Spoor C, van Driel N, Dubbelaar ML, Grit C, Kooistra SM, Fagrouch ZC, Verschoor EJ, Bauer J, Eggen BJL, et al. Targeted diet modification reduces multiple sclerosis–like disease in adult marmoset monkeys from an outbred colony. J Immunol. 2018;201(11):3229–3243. doi:10.4049/jimmunol.1800822.
  • Mestre L, Carrillo-Salinas FJ, Feliú A, Mecha M, Alonso G, Espejo C, Calvo-Barreiro L, Luque-García JL, Estevez H, Villar LM, et al. How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process. Gut Microbes. 2020;12(1):1813532. doi:10.1080/19490976.2020.1813532.
  • Delgado S, Sanchez B, Margolles A, Ruas-Madiedo P, Ruiz L. Molecules produced by probiotics and intestinal microorganisms with immunomodulatory activity. Nutrients. 2020;12(2):391. doi:10.3390/nu12020391.
  • Moravejolahkami AR, Paknahad Z, Chitsaz A. Dietary intake of energy and fiber in MS patients; an approach to prebiotics role. Nutr Food Sci. 2019;49(6):1039–1050. doi:10.1108/NFS-01-2019-0001.
  • Mirashrafi S, Hejazi Taghanaki SZ, Sarlak F, Moravejolahkami AR, Hojjati Kermani MA, Haratian M. Effect of probiotics supplementation on disease progression, depression, general health, and anthropometric measurements in relapsing-remitting multiple sclerosis patients: a systematic review and meta-analysis of clinical trials. Int J Clin Pract. 2021;75(11):e14724. doi:10.1111/ijcp.14724.
  • Jiang J, Chu C, Wu C, Wang C, Zhang C, Li T, Zhai Q, Yu L, Tian F, Chen W, et al. Efficacy of probiotics in multiple sclerosis: a systematic review of preclinical trials and meta-analysis of randomized controlled trials. Food Funct. 2021;12(6):2354–2377. doi:10.1039/D0FO03203D.
  • Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Daneshvar Kakhaki R, Akbari E, Tajabadi-Ebrahimi M, Jafari P, Asemi Z. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr. 2017;36(5):1245–1249. doi:10.1016/j.clnu.2016.08.015.
  • Tankou SK, Regev K, Healy BC, Tjon E, Laghi L, Cox LM, Kivisäkk P, Pierre IV, Hrishikesh L, Gandhi R, et al. A probiotic modulates the microbiome and immunity in multiple sclerosis. Ann Neurol. 2018;83(6):1147–1161. doi:10.1002/ana.25244.
  • Zeraati M, Enayati M, Kafami L, Shahidi SH, Salari AA. Gut microbiota depletion from early adolescence alters adult immunological and neurobehavioral responses in a mouse model of multiple sclerosis. Neuropharmacology. 2019;157:107685. doi:10.1016/j.neuropharm.2019.107685.
  • Bianchimano P, Britton GJ, Wallach DS, Smith EM, Cox LM, Liu S, Iwanowski K, Weiner HL, Faith JJ, Clemente JC, et al. Mining the microbiota to identify gut commensals modulating neuroinflammation in a mouse model of multiple sclerosis. Microbiome. 2022;10(1):174. doi:10.1186/s40168-022-01364-2.
  • Chen H, Ma X, Liu Y, Ma L, Chen Z, Lin X, Si L, Ma X, Chen X. Gut microbiota interventions with Clostridium butyricum and norfloxacin modulate immune response in experimental autoimmune encephalomyelitis mice. Front Immunol. 2019;10:1662. doi:10.3389/fimmu.2019.01662.
  • Yokote H, Miyake S, Croxford JL, Oki S, Mizusawa H, Yamamura T. NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora. The American Journal Of Pathology. 2008;173(6):1714–1723. doi:10.2353/ajpath.2008.080622.
  • Miyauchi E, Kim S-W, Suda W, Kawasumi M, Onawa S, Taguchi-Atarashi N, Morita H, Taylor TD, Hattori M, Ohno H, et al. Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature. 2020;585(7823):102–106. doi:10.1038/s41586-020-2634-9.
  • McMurran CE, Guzman de la Fuente A, Penalva R, Ben Menachem-Zidon O, Dombrowski Y, Falconer J, Gonzalez GA, Zhao C, Krause FN, Young AMH, et al. The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination. Proc Natl Acad Sci U S A. 2019;116(50):25311–25321. doi:10.1073/pnas.1905787116.
  • Suleiman L, Waubant E, Aaen G, Belman A, Benson L, Candee M, Chitnis T, Gorman M, Goyal M, Greenberg B, et al. Early infectious exposures are not associated with increased risk of pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2018;22:103–107. doi:10.1016/j.msard.2018.03.015.
  • Baldin E, Zenesini C, Antonazzo IC, Bartolomei I, Caniatti L, Costa M, Curti E, Ferraro D, Foschi M, Granella F, et al. Antibiotic use and risk of multiple sclerosis: a nested case-control study in Emilia-Romagna region, Italy. Neuroepidemiology. 2021;55(3):224–231. doi:10.1159/000515682.
  • Metz LM, Li D, Traboulsee A, Myles ML, Duquette P, Godin J, Constantin M, Yong VW. Glatiramer acetate in combination with minocycline in patients with relapsing—remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler. 2009;15(10):1183–1194. doi:10.1177/1352458509106779.
  • Sorensen PS, Sellebjerg F, Lycke J, Färkkilä M, Créange A, Lund CG, Schluep M, Frederiksen JL, Stenager E, Pfleger C, et al. Minocycline added to subcutaneous interferon β-1a in multiple sclerosis: randomized RECYCLINE study. Eur J Neurol. 2016;23(5):861–870. doi:10.1111/ene.12953.
  • Parks NE, Jackson-Tarlton CS, Vacchi L, Merdad R, Johnston BC. Dietary interventions for multiple sclerosis-related outcomes. Cochrane Database Syst Rev. 2020;2020(5):CD004192. doi:10.1002/14651858.CD004192.pub4.
  • Sanchez JMS, DePaula-Silva AB, Libbey JE, Fujinami RS. Role of diet in regulating the gut microbiota and multiple sclerosis. Clin Immunol. 2022;235:108379. doi:10.1016/j.clim.2020.108379.
  • Valburg C, Sonti A, Stern JN, Najjar S, Harel A. Dietary factors in experimental autoimmune encephalomyelitis and multiple sclerosis: a comprehensive review. Mult Scler. 2021;27(4):494–502. doi:10.1177/1352458520923955.
  • Bhargava P, Cassard S, Steele SU, Azevedo C, Pelletier D, Sugar EA, Waubant E, Mowry EM. The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. Contemporary Clinical Trials. 2014;39(2):288–293. doi:10.1016/j.cct.2014.10.004.
  • Rosjo E, Steffensen LH, Jørgensen L, Lindstrøm JC, Šaltytė Benth J, Michelsen AE, Aukrust P, Ueland T, Kampman MT, Torkildsen Ø, et al. Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. J Neurol. 2015;262(12):2713–2721. doi:10.1007/s00415-015-7902-5.
  • Fitzgerald KC, Munger KL, Köchert K, Arnason BGW, Comi G, Cook S, Goodin DS, Filippi M, Hartung H-P, Jeffery DR, et al. Association of vitamin D levels with multiple sclerosis activity and progression in patients receiving interferon beta-1b. JAMA Neurol. 2015;72(12):1458–1465. doi:10.1001/jamaneurol.2015.2742.
  • Shieh A, Lee, SM, Lagishetty V, Gottleib C, Jacobs, JP, Adams, JS. Pilot trial of vitamin D3 and calcifediol in healthy vitamin D deficient adults: does it change the fecal microbiome? J Clin Endocrinol Metab. 2021;106(12):3464–3476. doi:10.1210/clinem/dgab573.
  • Naderpoor N, Mousa A, Fernanda Gomez Arango L, Barrett HL, Dekker Nitert M, de Courten B. Effect of vitamin D supplementation on faecal microbiota: a randomised clinical trial. Nutrients. 2019;11(12):2888. doi:10.3390/nu11122888.
  • Enam F, Mansell TJ. Prebiotics: tools to manipulate the gut microbiome and metabolome. J Ind Microbiol Biotechnol. 2019;46(9–10):1445–1459. doi:10.1007/s10295-019-02203-4.
  • Berer K, Martínez I, Walker A, Kunkel B, Schmitt-Kopplin P, Walter J, Krishnamoorthy G. Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and immune status. Sci Rep. 2018;8(1):10431. doi:10.1038/s41598-018-28839-3.
  • Moravejolahkami AR, Paknahad Z, Chitsaz A. Dietary intake of energy and fiber in MS patients; an approach to prebiotics role. Nutr Food Sci. 2019;49(6):1039–1050. doi:10.1108/NFS-01-2019-0001.
  • Calvo-Barreiro L, Eixarch H, Cornejo T, Costa C, Castillo M, Mestre L, Guaza C, Martínez-Cuesta MDC, Tanoue T, Honda K, et al. Selected Clostridia strains from the human microbiota and their metabolite, butyrate, improve experimental autoimmune encephalomyelitis. Neurotherapeutics. 2021;18(2):920–937. doi:10.1007/s13311-021-01016-7.
  • Di Biase A, Salvati S, Di Benedetto R, Attorri L, Martinelli A, Malchiodi F. Eicosapentaenoic acid pre-treatment reduces biochemical changes induced in total brain and myelin of weanling wistar rats by cuprizone feeding. Prostaglandins, Leukotrienes And Essential Fatty Acids. 2014;90(4):99–104. doi:10.1016/j.plefa.2013.11.004.
  • Torkildsen Ø, Brunborg LA, Thorsen F, Mørk SJ, Stangel M, Myhr K-M, Bø L. Effects of dietary intervention on MRI activity, de- and remyelination in the cuprizone model for demyelination. Exp Neurol. 2009;215(1):160–166. doi:10.1016/j.expneurol.2008.09.026.
  • Fleck AK, Hucke S, Teipel F, Eschborn M, Janoschka C, Liebmann M, Wami H, Korn L, Pickert G, Hartwig M, et al. Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity. Brain. 2021;144(4):1152–1166. doi:10.1093/brain/awab040.
  • Dong TA, Sandesara PB, Dhindsa DS, Mehta A, Arneson LC, Dollar AL, Taub PR, Sperling LS. Intermittent fasting: a heart healthy dietary pattern? The American Journal Of Medicine. 2020;133(8):901–907. doi:10.1016/j.amjmed.2020.03.030.
  • Catenacci VA, Pan Z, Ostendorf D, Brannon S, Gozansky WS, Mattson MP, Martin B, MacLean PS, Melanson EL, Troy Donahoo W, et al. A randomized pilot study comparing zero-calorie alternate-day fasting to daily caloric restriction in adults with obesity. Obesity (Silver Spring). 2016;24(9):1874–1883. doi:10.1002/oby.21581.
  • Duenas M, Muñoz-González I, Cueva C, Jiménez-Girón A, Sánchez-Patán F, Santos-Buelga C, Moreno-Arribas MV, Bartolomé B. A survey of modulation of gut microbiota by dietary polyphenols. BioMed Research International. 2015;2015:1–15. doi:10.1155/2015/850902.
  • Ginwala R, McTish E, Raman C, Singh N, Nagarkatti M, Nagarkatti P, Sagar D, Jain P, Khan ZK. Apigenin, a natural flavonoid, attenuates EAE severity through the modulation of dendritic cell and other immune cell functions. J Neuroimmune Pharmacol. 2016;11(1):36–47. doi:10.1007/s11481-015-9617-x.
  • Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel P-M, Infante-Duarte C, Brocke S, Zipp F. Green Tea Epigallocatechin-3-Gallate Mediates T Cellular NF-κB inhibition and exerts Neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004;173(9):5794–5800. doi:10.4049/jimmunol.173.9.5794.
  • Haghmorad D, Mahmoudi, MB, Salehipour Z, Jalayer Z, Rastin M, Kokhaei P, Mahmoudi M. Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis. J Neuroimmunol. 2017;302:23–33. doi:10.1016/j.jneuroim.2016.11.009.
  • Verbeek R, van Tol EA, van Noort JM. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol. 2005;70(2):220–228. doi:10.1016/j.bcp.2005.04.041.
  • Sato F, Martinez NE, Shahid M, Rose JW, Carlson NG, Tsunoda I. Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. The American Journal Of Pathology. 2013;183(5):1390–1396. doi:10.1016/j.ajpath.2013.07.006.
  • Ghaiad HR, Nooh MM, El-Sawalhi MM, Shaheen AA. Resveratrol promotes remyelination in cuprizone model of multiple sclerosis: biochemical and histological study. Mol Neurobiol. 2017;54(5):3219–3229. doi:10.1007/s12035-016-9891-5.
  • Dolati S, Babaloo Z, Ayromlou H, Ahmadi M, Rikhtegar R, Rostamzadeh D, Roshangar L, Nouri M, Mehdizadeh A, Younesi V, et al. Nanocurcumin improves regulatory T-cell frequency and function in patients with multiple sclerosis. J Neuroimmunol. 2019;327:15–21. doi:10.1016/j.jneuroim.2019.01.007.
  • Wang C, Huang Z, Yu K, Ding R, Ye K, Dai C, Xu X, Zhou G, Li C. High-salt diet has a certain impact on protein Digestion and gut microbiota: a sequencing and proteome combined study. Front Microbiol. 2017;8:1838. doi:10.3389/fmicb.2017.01838.
  • Ferguson JF, Aden LA, Barbaro NR, Van Beusecum JP, Xiao L, Simons AJ, Warden C, Pasic L, Himmel LE, Washington MK, et al. High dietary salt–induced DC activation underlies microbial dysbiosis-associated hypertension. JCI Insight. 2019;5(13). doi:10.1172/jci.insight.126241.
  • Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J Clin Invest. 2015;125(11):4212–4222. doi:10.1172/JCI81151.
  • Haase S, Wilck N, Haghikia A, Gold R, Mueller DN, Linker RA. The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol. 2020;50(12):1863–1870. doi:10.1002/eji.201847807.
  • Farez MF, Fiol MP, Gaitan MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26–31. doi:10.1136/jnnp-2014-307928.
  • Fitzgerald KC, Munger KL, Hartung H-P, Freedman MS, Montalbán X, Edan G, Wicklein E-M, Radue E-W, Kappos L, Pohl C, et al. Sodium intake and multiple sclerosis activity and progression in BENEFIT. Ann Neurol. 2017;82(1):20–29. doi:10.1002/ana.24965.
  • McDonald J, Graves J, Waldman A, Lotze T, Schreiner T, Belman A, Greenberg B, Weinstock-Guttman B, Aaen G, Tillema J-M, et al. A case-control study of dietary salt intake in pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2016;6:87–92. doi:10.1016/j.msard.2016.02.011.
  • Nourbakhsh B, Graves J, Casper TC, Lulu S, Waldman A, Belman A, Greenberg B, Weinstock-Guttman B, Aaen G, Tillema J-M, et al. Dietary salt intake and time to relapse in paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(12):1350–1353. doi:10.1136/jnnp-2016-313410.
  • Phillips MCL. Fasting as a Therapy in neurological disease. Nutrients. 2019;11(10):2501. doi:10.3390/nu11102501.
  • Storoni M, Plant GT. The therapeutic potential of the ketogenic diet in treating progressive multiple sclerosis. Mult Scler Int. 2015;2015:681289. doi:10.1155/2015/681289.
  • Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross A, Morgan T, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 2016;15(10):2136–2146. doi:10.1016/j.celrep.2016.05.009.
  • Razeghi Jahromi S, Ghaemi A, Alizadeh A, Sabetghadam F, Moradi Tabriz H, Togha M. Effects of intermittent fasting on experimental Autoimune encephalomyelitis in C57BL/6 mice. Iran J Allergy Asthma Immunol. 2016;15:212–219.
  • Bai M, Wang Y, Han R, Xu L, Huang M, Zhao J, Lin Y, Song S, Chen Y. Intermittent caloric restriction with a modified fasting-mimicking diet ameliorates autoimmunity and promotes recovery in a mouse model of multiple sclerosis. J Nutr Biochem. 2021;87:108493. doi:10.1016/j.jnutbio.2020.108493.
  • Cignarella F, Cantoni C, Ghezzi L, Salter A, Dorsett Y, Chen L, Phillips D, Weinstock GM, Fontana L, Cross AH, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab. 2018;27(6):1222–1235.e6. doi:10.1016/j.cmet.2018.05.006.
  • Bahr LS, Bock M, Liebscher D, Bellmann-Strobl J, Franz L, Prüß A, Schumann D, Piper SK, Kessler CS, Steckhan N, et al. Ketogenic diet and fasting diet as nutritional approaches in multiple sclerosis (NAMS): protocol of a randomized controlled study. Trials. 2020;21(1). doi:10.1186/s13063-019-3928-9.
  • Cantoni C, Lin Q, Dorsett Y, Ghezzi L, Liu Z, Pan Y, Chen K, Han Y, Li Z, Xiao H, et al. Alterations of host-gut microbiome interactions in multiple sclerosis. EBioMedicine. 2022;76:103798. doi:10.1016/j.ebiom.2021.103798.
  • Saresella M, Mendozzi L, Rossi V, Mazzali F, Piancone F, LaRosa F, Marventano I, Caputo D, Felis GE, Clerici M, et al. Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: a pilot study. Front Immunol. 2017;8:1391. doi:10.3389/fimmu.2017.01391.
  • Wahls TL, Titcomb TJ, Bisht B, Eyck PT, Rubenstein LM, Carr LJ, Darling WG, Hoth KF, Kamholz J, Snetselaar LG, et al. Impact of the Swank and Wahls elimination dietary interventions on fatigue and quality of life in relapsing-remitting multiple sclerosis: the WAVES randomized parallel-arm clinical trial. Mult Scler J Exp Transl Clin. 2021;7(3):20552173211035399. doi:10.1177/20552173211035399.
  • Irish AK, Erickson CM, Wahls TL, Snetselaar LG, Darling WG. Randomized control trial evaluation of a modified Paleolithic dietary intervention in the treatment of relapsing-remitting multiple sclerosis: a pilot study. Degener Neurol Neuromuscul Dis. 2017;7:1–18. doi:10.2147/DNND.S116949.
  • Yadav V, Marracci G, Kim E, Spain R, Cameron M, Overs S, Riddehough A, Li DKB, McDougall J, Lovera J, et al. Low-fat, plant-based diet in multiple sclerosis: a randomized controlled trial. Mult Scler Relat Disord. 2016;9:80–90. doi:10.1016/j.msard.2016.07.001.
  • Halkjaer SI, Boolsen AW, Gunther S, Christensen AH, Petersen AM. Can fecal microbiota transplantation cure irritable bowel syndrome? World J Gastroenterol. 2017;23(22):4112–4120. doi:10.3748/wjg.v23.i22.4112.
  • Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, Connor S, Ng W, Paramsothy R, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389(10075):1218–1228. doi:10.1016/S0140-6736(17)30182-4.
  • Xue LJ, Yang X-Z, Tong Q, Shen P, Ma S-J, Wu S-N, Zheng J-L, Wang H-G. Fecal microbiota transplantation therapy for Parkinson’s disease: a preliminary study. Med. 2020;99(35):e22035. doi:10.1097/MD.0000000000022035.
  • Mao D, Jiang Q, Sun Y, Mao Y, Guo L, Zhang Y, Man M, Ouyang G, Sheng L. Treatment of intestinal graft-versus-host disease with unrelated donor fecal microbiota transplantation capsules: a case report. Med. 2020;99(38):e22129. doi:10.1097/MD.0000000000022129.
  • Li K, Wei S, Hu L, Yin X, Mai Y, Jiang C, Peng X, Cao X, Huang Z, Zhou H, et al. Protection of fecal microbiota transplantation in a mouse model of multiple sclerosis. Mediators Of Inflammation. 2020;2020:1–13. doi:10.1155/2020/2058272.
  • Makkawi S, Camara-Lemarroy C, Metz L. Fecal microbiota transplantation associated with 10 years of stability in a patient with SPMS. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e459. doi:10.1212/NXI.0000000000000459.
  • Engen PA, Zaferiou A, Rasmussen H, Naqib A, Green SJ, Fogg LF, Forsyth CB, Raeisi S, Hamaker B, Keshavarzian A, et al. Single-arm, non-randomized, time series, single-subject study of fecal microbiota transplantation in multiple sclerosis. Front Neurol. 2020;11:978. doi:10.3389/fneur.2020.00978.
  • Al KF, Craven LJ, Gibbons S, Parvathy SN, Wing AC, Graf C, Parham KA, Kerfoot SM, Wilcox H, Burton JP, et al. Fecal microbiota transplantation is safe and tolerable in patients with multiple sclerosis: a pilot randomized controlled trial. Mult Scler J Exp Transl Clin. 2022;8(2):20552173221086662. doi:10.1177/20552173221086662.
  • Tanasescu R, Tench CR, Constantinescu CS, Telford G, Singh S, Frakich N, Onion D, Auer DP, Gran B, Evangelou N, et al. Hookworm treatment for relapsing multiple sclerosis: a randomized Double-blinded placebo-controlled trial. JAMA Neurol. 2020;77(9):1089–1098. doi:10.1001/jamaneurol.2020.1118.
  • Correale J, Farez MF. The impact of parasite infections on the course of multiple sclerosis. J Neuroimmunol. 2011;233(1–2):6–11. doi:10.1016/j.jneuroim.2011.01.002.
  • Jenkins TP, Pritchard DI, Tanasescu R, Telford G, Papaiakovou M, Scotti R, Cortés A, Constantinescu CS, Cantacessi C. Experimental infection with the hookworm, necator americanus, is associated with stable gut microbial diversity in human volunteers with relapsing multiple sclerosis. BMC Biol. 2021;19(1):74. doi:10.1186/s12915-021-01003-6.
  • Barone M, Mendozzi L, D’Amico F, Saresella M, Rampelli S, Piancone F, La Rosa F, Marventano I, Clerici M, d’Arma A, et al. Influence of a high-impact multidimensional rehabilitation program on the gut microbiota of patients with multiple sclerosis. Int J Mol Sci. 2021;22(13):7173. doi:10.3390/ijms22137173.