Features of the intestinal microbiota composition in multiple sclerosis patients receiving oral disease-modifying therapy
Elena A. Tarasova , Victoria I. Lioudyno , Anna V. Matsulevich , Irina G. Negoreeva , Aleksandr G. Ilves , Elena V. Ivashkova , Galina G. Shkilnyuk , Irina N. Abdurasulova
Medical academic journal ›› 2021, Vol. 21 ›› Issue (4) : 47 -56.
Features of the intestinal microbiota composition in multiple sclerosis patients receiving oral disease-modifying therapy
BACKGROUND: Heterogeneous dysbiosis of the intestinal microbiome is a common hallmark of multiple sclerosis. In this pilot study, we compared the level of some gut bacteria in multiple sclerosis patients receiving oral disease-modifying therapy versus untreated.
MATERIALS AND METHODS: Subjects were patients with relapsing-remitting or secondary and primary progressive multiple sclerosis. Multiple sclerosis patients were treated by Fingolimod (n = 31), Teriflunomide (n = 21) or were untreated (n = 31). The bacterial levels in stool samples were analyzed by cultivation method and real time PCR.
RESULTS: The levels of symbiotic and opportunistic bacterial species in the fecal samples of multiple sclerosis patients receiving disease-modifying therapy were different from those in untreated patients. Also, there was a difference in the spectrum of gastrointestinal tract disorders between these patients. Fingolimod-treated patients showed decreased levels of some bacterial species compared to untreated subjects, including Escherichia coli with regular enzymatic activity, Sutterella wadsworthensis (phylum Proteobacteria), butyrate-producing bacteria Roseburia spp., Faecalibacterium prausnitzii, and Ruminococcus spp. (phylum Firmicutes, class Clostridia). Teriflunomide-treated patients demonstrated decreased levels of Lactobacillus spp. and Enterococcus spp. (phylum Firmicutes, class Bacilli) and Ruminococcus spp. Increased levels of Bifidobacterium spp. were observed in treated and untreated multiple sclerosis patients with higher EDSS scores.
CONCLUSIONS: This study shows the negative effect of oral disease-modifying therapy on intestinal microbiota composition and gastrointestinal tract disorders. However, more extensive studies are needed to confirm these preliminary results and develop ways to normalize intestinal dysbiosis in multiple sclerosis patients.
multiple sclerosis / dysbiosis / intestinal microbiota / disease-modifying therapy / fingolimod / teriflunomide
| [1] |
Stratton C.W., Wheldon D.B. Multiple sclerosis: An infectious syndrome involving Chlamydophila pneumoniae // Trends Microbiol. 2006. Vol. 14, No. 11. P. 474–479. DOI: 10.1016/j.tim.2006.09.002 |
| [2] |
Stratton CW, Wheldon DB. Multiple sclerosis: An infectious syndrome involving Chlamydophila pneumoniae. Trends Microbiol. 2006;14(11):474–479. DOI: 10.1016/j.tim.2006.09.002 |
| [3] |
Berer K., Krishnamoorthy G. Microbial view of central nervous system autoimmunity // FEBS Lett. 2014. Vol. 588, No. 22. P. 4207–4213. DOI: 10.1016/j.febslet.2014.04.007 |
| [4] |
Berer K, Krishnamoorthy G. Microbial view of central nervous system autoimmunity. FEBS Lett. 2014;588(22):4207–4213. DOI: 10.1016/j.febslet.2014.04.007 |
| [5] |
Hill D.A., Artis D. Intestinal bacteria and the regulation of immune cell homeostasis // Annu. Rev. Immunol. 2010. Vol. 28. P. 623–667. DOI: 10.1146/annurev-immunol-030409-101330 |
| [6] |
Hill DA, Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol. 2010;28:623–667. DOI: 10.1146/annurev-immunol-030409-101330 |
| [7] |
Atarashi K., Tanoue T., Shima T. et al. Induction of colonic regulatory T cells by indigenous Clostridium species // Science. 2011. Vol. 331, No. 6015. P. 337–341. DOI: 10.1126/science.1198469 |
| [8] |
Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331(6015):337–341. DOI: 10.1126/science.1198469 |
| [9] |
Gaboriau-Routhiau V., Rakotobe S., Lécuyer E. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses // Immunity. 2009. Vol. 31, No. 4. P. 677–689. DOI: 10.1016/j.immuni.2009.08.020 |
| [10] |
Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity. 2009;31(4):677–689. DOI: 10.1016/j.immuni.2009.08.020 |
| [11] |
Ivanov I.I., Frutos R de L., Manel N. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine // Cell Host Microbe. 2008. Vol. 4, No. 4. P. 337–349. DOI: 10.1016/j.chom.2008.09.009 |
| [12] |
Ivanov II, Frutos Rde L, Manel N, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008;4(4):337–349. DOI: 10.1016/j.chom.2008.09.009 |
| [13] |
Buscarinu M.C., Cerasoli B., Annibali V. et al. Altered intestinal permeability in patients with relapsing-remitting multiple sclerosis: A pilot study // Mult. Scler. 2017. Vol. 23, No. 3. P. 442–446. DOI: 10.1177/1352458516652498 |
| [14] |
Buscarinu MC, Cerasoli B, Annibali V, et al. Altered intestinal permeability in patients with relapsing-remitting multiple sclerosis: A pilot study. Mult Scler. 2017;23(3):442–446. DOI: 10.1177/1352458516652498 |
| [15] |
Camara-Lemarroy C.R., Metz L., Meddings J.B. et al. The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics // Brain. 2018. Vol. 141, No. 7. P. 1900–1916. DOI: 10.1093/brain/awy131 |
| [16] |
Camara-Lemarroy CR, Metz L, Meddings JB, et al. The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics. Brain. 2018;141(7):1900–1916. DOI: 10.1093/brain/awy131 |
| [17] |
Braniste V., Al-Asmakh M., Kowal C. et al. The gut microbiota influences blood-brain barrier permeability in mice // Sci. Transl. Med. 2014. Vol. 6, No. 263. P. 263ra158. DOI: 10.1126/scitranslmed.3009759 |
| [18] |
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. DOI: 10.1126/scitranslmed.3009759 |
| [19] |
Hoban A.E., Stilling R.M., Ryan F.J. et al. Regulation of prefrontal cortex myelination by the microbiota // Transl. Psychiatry. 2016. Vol. 6, No. 4. P. e774. DOI: 10.1038/tp.2016.42 |
| [20] |
Hoban AE, Stilling RM, Ryan FJ, et al. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry. 2016;6(4):e774. DOI: 10.1038/tp.2016.42 |
| [21] |
Miyake S., Kim S., Suda W. et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonginf to Clostridia XIVa and IV clusters // PLoS One. 2015. Vol. 10, No. 9. P. e0137429. DOI: 10.1371/journal.pone.0137429 |
| [22] |
Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonginf to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429. DOI: 10.1371/journal.pone.0137429 |
| [23] |
Jangi S., Gandhi R., Cox L.M. et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015. DOI: 10.1038/ncomms12015 |
| [24] |
Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015. DOI: 10.1038/ncomms12015 |
| [25] |
Chen J., Chia N., Kalari K.R. et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls // Sci. Rep. 2016. Vol. 6. P. 28484. DOI: 10.1038/srep28484 |
| [26] |
Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6:28484. DOI: 10.1038/srep28484 |
| [27] |
Абдурасулова И.Н., Тарасова Е.А., Ермоленко Е.И. и др. При рассеянном склерозе изменяется качественный и количественный состав микробиоты кишечника // Медицинский академический журнал. 2015. Т. 15, № 3. С. 55–67. |
| [28] |
Abdurasulova IN, Tarasova EA, Ermolenko EI, et al. Multiple sclerosis is associated with altered quantitative and qualitative composition of intestinal microbiota. Medical Academic Journal. 2015;15(3):55–67. (In Russ.) |
| [29] |
Levinthal D.J., Rahman F., Nusrat S. et al. Adding to the burden: gastrointestinal symptoms and syndromes in multiple sclerosis // Mult. Scler. Int. 2013. Vol. 2013. P. 319201. DOI: 10.1155/2013/319201 |
| [30] |
Levinthal DJ, Rahman F, Nusrat S, et al. Adding to the burden: gastrointestinal symptoms and syndromes in multiple sclerosis. Mult Scler Int. 2013;2013:319201. DOI: 10.1155/2013/319201 |
| [31] |
Arnason B.G. Long-term experience with interferon beta-1b (Betaferon) in multiple sclerosis // J. Neurol. 2005. Vol. 252 Suppl 3. P. iii28–iii33. DOI: 10.1007/s00415-005-2014-2 |
| [32] |
Arnason BG. Long-term experience with interferon beta-1b (Betaferon) in multiple sclerosis. J Neurol. 2005;252 Suppl 3: iii28–iii33. DOI: 10.1007/s00415-005-2014-2 |
| [33] |
Weinstock-Guttman B., Nair K.V., Glajch J.L. et al. Two decades of glatiramer acetate: From initial discovery to the current development of generics // J. Neurol. Sci. 2017. Vol. 376. P. 255–259. DOI: 10.1016/j.jns.2017.03.030 |
| [34] |
Weinstock-Guttman B, Nair KV, Glajch JL, et al. Two decades of glatiramer acetate: From initial discovery to the current development of generics. J Neurol Sci. 2017;376:255–259. DOI: 10.1016/j.jns.2017.03.030 |
| [35] |
Cantarel B.L., Waubant E., Chehoud C. et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators // J. Investig. Med. 2015. Vol. 63, No. 5. P. 729–734. DOI: 10.1097/JIM.0000000000000192 |
| [36] |
Cantarel BL, Waubant E, Chehoud C, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med. 2015;63(5):729–734. DOI: 10.1097/JIM.0000000000000192 |
| [37] |
Абдурасулова И.Н., Тарасова Е.А., Никифорова И.Г. и др. Особенности состава микробиоты кишечника у пациентов с рассеянным склерозом, получающих препараты, изме-няющие течение рассеянного склероза // Журнал неврологии и психиатрии им. C.C. Корсакова. 2018. Т. 118, № 8–2. С. 62–69. DOI: 10.17116/jnevro201811808262 |
| [38] |
Abdurasulova IN, Tarasova EA, Nikiforova IG, et al. The intestinal microbiota composition in patients with multiple sclerosis receiving different disease-modifying therapies DMT. S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(8–2): 62–69. (In Russ.). DOI: 10.17116/jnevro201811808262 |
| [39] |
Castillo-Alvarez F., Perez-Matute P., Oteo J.A., Marzo-Sola M.E. The influence of interferon β-1b on gut microbiota composition in patients with multiple sclerosis // Neurologia (Engl Ed). 2021. Vol. 36, No. 7. P. 495–503. DOI: 10.1016/j.nrl.2018.04.006 |
| [40] |
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. Neurologia (Engl Ed). 2021;36(7):495–503. DOI: 10.1016/j.nrl.2018.04.006 |
| [41] |
Абдурасулова И.Н., Ермоленко Е.И., Мацулевич А.В. и др. Влияние пробиотических энтерококков и глатирамера ацетата на тяжесть экспериментального аллергического энцефаломиелита у крыс // Российский физиологический журнал им. И.М. Сеченова. 2016. Т. 102, № 4. С. 463–479. |
| [42] |
Abdurasulova IN, Ermolenko EI, Matsulevich AV, et al. Effects of probiotic Enterococci and Glatiramer Acetate on the severity of experimental allergic encephalomyelitis in rats. J. Neurosci Behav Physiol. 2017;47(7):866–876. DOI: 10.1007/s11055-017-0484-1 |
| [43] |
Nwankwo E., Allington D.R., Rivey M.P. Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis // Degener. Neurol. Neuromuscul. Dis. 2012. Vol. 2. P. 15–28. DOI: 10.2147/DNND.S29022 |
| [44] |
Nwankwo E, Allington DR, Rivey MP. Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis. Degener Neurol Neuromuscul Dis. 2012;2:15–28. DOI: 10.2147/DNND.S29022 |
| [45] |
Portaccio E. Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis // Core Evid. 2011. Vol. 6. P. 13–21. DOI: 10.2147/CE.S10101 |
| [46] |
Portaccio E. Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis. Core Evid. 2011;6:13–21. DOI: 10.2147/CE.S10101 |
| [47] |
Storm-Larsen C., Myhr K.-M., Farbu E. 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. Vol. 5, No. 4. P. 2055217319888767. DOI: 10.1177/2055217319888767 |
| [48] |
Storm-Larsen C, Myhr K-M, Farbu E, 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 |
| [49] |
Krogh K., Christensen P., Sabroe S., Laurberg S. Neurogenic bowel dysfunction score // Spinal Cord. 2006. Vol. 44, No. 10. P. 625–631. DOI:10.1038/sj.sc.3101887 |
| [50] |
Krogh K, Christensen P, Sabroe S, Laurberg S. Neurogenic bowel dysfunction score. Spinal Cord. 2006;44(10): 625–631. DOI:10.1038/sj.sc.3101887 |
| [51] |
Takewaki D., Suda W., Sato W. et al. Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis // Proc. Natl. Acad. Sci. USA. 2020. Vol. 117, No. 36. P. 22402–22412. DOI: 10.1073/pnas.2011703117 |
| [52] |
Takewaki D, Suda W, Sato W, et al. Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis. Proc Natl Acad Sci USA. 2020;117(36):22402–22412. DOI: 10.1073/pnas.2011703117 |
| [53] |
Cekanaviciute E., Yoo B.B., Runia T.F. et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models // Proc. Natl. Acad. Sci. USA. 2017. Vol. 114, No. 40. P. 10713–10718. DOI: 10.1073/pnas.1711235114 |
| [54] |
Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci USA. 2017;114(40):10713–10718. DOI: 10.1073/pnas.1711235114 |
| [55] |
Cekanaviciute E., Pröbstel A.-K., Thornann A. et al. Multiple sclerosis-associated changes in the composition and immune functions of spore-forming bacteria // mSystems. 2018. Vol. 3, No. 6. P. e00083–18. DOI: 10.1128/mSystems.00083-18 |
| [56] |
Cekanaviciute E, Pröbstel A-K, Thornann A, et al. Multiple sclerosis-associated changes in the composition and immune functions of spore-forming bacteria. mSystems. 2018;3(6):e00083–18. DOI: 10.1128/mSystems.00083-18 |
| [57] |
Kozhieva M., Naumova N., Alikina T. et al. Primary progressive multiple sclerosis in a Russian cohort: relationship with gut bacterial diversity // BMC Microbiol. 2019. Vol. 19, No. 1. P. 309. DOI: 10.1186/s12866-019-1685-2 |
| [58] |
Kozhieva M, Naumova N, Alikina T, et al. 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 |
| [59] |
Ventura R.E., Iizumi T., Battaglia T. et al. Gut microbiome of treatment-naïve MS patients of different ethnicities early in disease course // Sci. Rep. 2019. Vol. 9, No. 1. P. 16396. DOI: 10.1038/s41598-019-52894-z |
| [60] |
Ventura RE, Iizumi T, Battaglia T, et al. 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 |
| [61] |
Cox L.M., Maghzi A.H., Liu S. et al. The gut microbiome in progressive multiple sclerosis // Ann. Neurol. 2021. Vol. 89, No. 6. P. 1195–1211. DOI: 10.1002/ana.26084 |
| [62] |
Cox LM, Maghzi AH, Liu S, et al. The gut microbiome in progressive multiple sclerosis. Ann Neurol. 2021;89(6):1195–1211. DOI: 10.1002/ana.26084 |
| [63] |
Reynders T., Devolder L., Valles-Colomer M. et al. Gut microbiome variation is associated to Multiple Sclerosis phenotypic subtypes // Ann. Clin. Transl. Neurol. 2020. Vol. 7, No. 4. P. 406–419. DOI: 10.1002/acn3.51004 |
| [64] |
Reynders T, Devolder L, Valles-Colomer M, et al. Gut microbiome variation is associated to Multiple Sclerosis phenotypic subtypes. Ann Clin Transl Neurol. 2020;7(4):406–419. DOI: 10.1002/acn3.51004 |
| [65] |
Christiansen S.H., Murphy R.A., Juul-Madsen K. et al. The immunomodulatory drug Glatiramer Acetate is also an effective antimicrobial agent that kills gram-negative bacteria // Sci. Rep. 2017. Vol. 7, No. 1. P. 15653. DOI: 10.1038/s41598-017-15969-3 |
| [66] |
Christiansen SH, Murphy RA, Juul-Madsen K, et al. The immunomodulatory drug Glatiramer Acetate is also an effective antimicrobial agent that kills gram-negative bacteria. Sci Rep. 2017;7(1):15653. DOI: 10.1038/s41598-017-15969-3 |
| [67] |
Rumah K.R., Vartanian T.K., Fischetti V.A. Oral multiple sclerosis drugs inhibit the in vitro growth of epsilon toxin producing gut bacterium, Clostridium perfringens // Front. Cell. Infect. Microbiol. 2017. Vol. 7. P. 11. DOI: 10.3389/fcimb.2017.00011 |
| [68] |
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 |
| [69] |
Rumah K.R., Linden J., Fischetti V.A., Vartanian T. 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. Vol. 8, No. 10. P. e76359. DOI: 10.1371/journal.pone.0076359 |
| [70] |
Rumah KR, Linden J, Fischetti VA, Vartanian T. 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 |
| [71] |
Абдурасулова И.Н., Тарасова Е.А., Кудрявцев И.В. и др. Состав микробиоты кишечника и популяций циркулирующих Th-клеток у пациентов с рассеянным склерозом // Инфекция и иммунитет. 2019. T. 9, ¹ 3–4. C. 504–522. DOI: 10.15789/2220-7619-2019-3-4-504-522 |
| [72] |
Abdurasulova IN, Tarasova EA, Kudryavtsev IV, et al. Intestinal microbiota composition and populations of circulating Th cells in patients with multiple sclerosis. Russian Journal of Infection and Immunity. 2019;9(3–4):504–522. (In Russ.). DOI: 10.15789/2220-7619- 2019-3-4-504-522 |
| [73] |
Ермоленко E.И., Исаков В.А., Ждан-Пушкина С.Х., Тец В.В. Количественная оценка антагонистической активности лактобацилл // Журнал микробиологии, эпидемиологии и иммунобиологии. 2004. ¹ 5. C. 94–98. |
| [74] |
Ermolenko EI, Isakov BA, Zhdan-Pushkina CKh, Tez VV. Quantitative characterization of the antagonistic activity of lactobacilli. Zh Mikrobiol Epidemiol Immunobiol. 2004;5:94–98. (In Russ.) |
| [75] |
Murphy C.T., Hall L.J., Hurley G. et al. The sphingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Сitrobacter rodentium // Infect. Immun. 2012. Vol. 80, No. 8. P. 2712–2723. DOI: 10.1128/IAI.06319-11 |
| [76] |
Murphy CT, Hall LJ, Hurley G, et al. The sphingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Сitrobacter rodentium. Infect Immun. 2012;80(8):2712–2723. DOI: 10.1128/IAI.06319-11 |
| [77] |
Mirza A., Mao-Draayer Y. The gut microbiome and microbial translocation in multiple sclerosis // Clin. Immunol. 2017. Vol. 183. P. 213–224. DOI: 10.1016/j.clim.2017.03.001 |
| [78] |
Mirza A, Mao-Draayer Y. The gut microbiome and microbial translocation in multiple sclerosis. Clin Immunol. 2017;183:213–224. DOI: 10.1016/j.clim.2017.03.001 |
| [79] |
Tecellioglu M., Kamisli O., Kamisli S. et al. Listeria monocytogenes rhombencephalitis in a patient with multiple sclerosis during fingolimod therapy // Mult. Scler. Relat. Disord. 2019. Vol. 27. P. 409–411. DOI: 10.1016/j.msard.2018.11.025 |
| [80] |
Tecellioglu M, Kamisli O, Kamisli S, et al. Listeria monocytogenes rhombencephalitis in a patient with multiple sclerosis during fingolimod therapy. Mult Scler Relat Disord. 2019;27:409–411. DOI: 10.1016/j.msard.2018.11.025 |
| [81] |
Aramideh Khouy R., Karampoor S., Keyvani H. et al. The frequency of varicella-zoster virus infection in patients with multiple sclerosis receiving fingolimod // J. Neuroimmunol. 2019. Vol. 328. P. 94–97. DOI: 10.1016/j.jneuroim.2018.12.009 |
| [82] |
Aramideh Khouy R, Karampoor S, Keyvani H, et al. The frequency of varicella-zoster virus infection in patients with multiple sclerosis receiving fingolimod. J Neuroimmunol. 2019;328:94–97. DOI: 10.1016/j.jneuroim.2018.12.009 |
| [83] |
Ma S.B., Griffin D., Boyd S.C. et al. Cryptococcus neoformans var grubii meningoencephalitis in a patient on fingolimod for relapsing-remitting multiple sclerosis: Case report and review of published cases // Mult. Scler. Relat. Disord. 2020. Vol. 39. P. 101923. DOI: 10.1016/j.msard.2019.101923 |
| [84] |
Ma SB, Griffin D, Boyd SC, et al. Cryptococcus neoformans var grubii meningoencephalitis in a patient on fingolimod for relapsing-remitting multiple sclerosis: Case report and review of published cases. Mult Scler Relat Disord. 2020;39:101923. DOI: 10.1016/j.msard.2019.101923 |
| [85] |
Sand I.K., Zhu Y., Ntranos A. et al. Disease-modifying therapies alter gut microbial composition in MS // Neurol. Neuroimmunol. Neuroinflamm. 2018. Vol. 6, No. 1. P. e517. DOI: 10.1212/NXI.0000000000000517 |
| [86] |
Sand IK, Zhu Y, Ntranos A, et al. Disease-modifying therapies alter gut microbial composition in MS. Neurol Neuroimmunol Neuroinflamm. 2018;6(1):e517. DOI: 10.1212/NXI.0000000000000517 |
Tarasova E.A., Lioudyno V.I., Matsulevich A.V., Negoreeva I.G., Ilves A.G., Ivashkova E.V., Shkilnyuk G.G., Abdurasulova I.N.
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