Features of the intestinal microbiota composition in multiple sclerosis patients receiving oral disease-modifying therapy

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Abstract

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.

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About the authors

Elena A. Tarasova

Institute of Experimental Medicine

Email: tarasovahellen@mail.ru
ORCID iD: 0000-0003-0160-9590
Scopus Author ID: 25937494300
ResearcherId: J-6990-2018

Research Associate, Pavlov Department of Physiology

Russian Federation, 12, Academician Pavlov Str., Saint Petersburg, 197376

Victoria I. Lioudyno

Institute of Experimental Medicine

Email: vlioudyno@mail.ru
ORCID iD: 0000-0002-1449-7754
SPIN-code: 8980-8497
Scopus Author ID: 6504455988
ResearcherId: E-3797-2014 H-6

Cand. Sci. (Biol.), Senior Research Associate, Pavlov Department of Physiology

Russian Federation, 12, Academician Pavlov Str., Saint Petersburg, 197376

Anna V. Matsulevich

Institute of Experimental Medicine

Email: cat_fly@bk.ru
ORCID iD: 0000-0002-0030-9548
SPIN-code: 8464-1814
Scopus Author ID: 57190964381
ResearcherId: J-8280-2018

Research Associate, Pavlov Department of Physiology

Russian Federation, 12, Academician Pavlov Str., Saint Petersburg, 197376

Irina G. Negoreeva

N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences

Email: nip@ihb.spb.ru
ORCID iD: 0000-0002-1497-7109
SPIN-code: 7742-7720
Scopus Author ID: 23498576100

MD, Cand. Sci. (Med.), Research Associate, Laboratory of Neuroimmunology

Russian Federation, Saint Petersburg

Aleksandr G. Ilves

N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences

Email: ailves@hotmail.com
ORCID iD: 0000-0002-9822-5982
SPIN-code: 1068-7281
Scopus Author ID: 36113684700
ResearcherId: AAO-7683-2021

MD, Cand. Sci. (Med.), Senior Research Associate, Laboratory of Neuroimmunology

Russian Federation, Saint Petersburg

Elena V. Ivashkova

N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences

Email: ivashkova@ihb.spb.ru
ORCID iD: 0000-0002-0201-0136
SPIN-code: 5861-9531
Scopus Author ID: 6507961979

MD, Cand. Sci. (Med.), Research Associate, Laboratory of Neuroimmunology

Russian Federation, Saint Petersburg

Galina G. Shkilnyuk

N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences

Email: galinakima@mail.ru
ORCID iD: 0000-0001-7175-668X
Scopus Author ID: 57193109310
ResearcherId: AAZ-3672-2020

MD, Cand. Sci. (Med.), Research Associate, Laboratory of Neuroimmunology

Russian Federation, Saint Petersburg

Irina N. Abdurasulova

Institute of Experimental Medicine

Author for correspondence.
Email: i_abdurasulova@mail.ru
ORCID iD: 0000-0003-1010-6768
Scopus Author ID: 22233604700
ResearcherId: J-6887-2018 H-3

Cand. Sci. (Biol.), Head of Laboratory, Pavlov Department of Physiology

Russian Federation, 12, Academician Pavlov Str., Saint Petersburg, 197376

References

  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. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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.
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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.
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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.
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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

Supplementary files

Supplementary Files
Action
1. Fig. 1. Proportion of multiple sclerosis patients according to number of symptoms. UT — untreated; FG — Fingolomod-treated; TF — Teriflunomide-treated; 0 S — without symptoms; 2 S, 3 S, 4 S, >5 S — two, three, fore, and five and more symptoms GIT disorders from table 2

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2. Fig. 2. The level of symbiotic (a) and opportunistic (b) bacterial species in intestinal microbiota of multiple sclerosis patients with Fingolimod or Teriflunomide therapy (culture method). Data represented as mean ± standard error. In Y axis – the bacterial level in lg colony forming units (CFU) on fecal g; in Х axis – bacterial species found; UT – untreated, FG – Fingolimod-treated, TF – Teriflunomide-treated. ANOVA with post-hoc HSD for unequal N, * difference between FG and TF groups, •differences from UT and TF groups, # differences from UT group, p < 0.05. N — normal, A — atypical

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3. Fig. 3. Changes in bacterial levels in Fingolimod- and Teriflunomide-treated patients with multiple sclerosis (PCR method). Data represented as mean ± standard error. In Y axis — the bacterial level in lg colony forming units (CFU) on fecal g; in Х axis — bacterial species; UT — untreated, FG — Fingolimod-treated, TF — Teriflunomide-treated. ANOVA with post-hoc HSD for unequal N, * differences between FG and TF groups, • differences from UT and TF groups, # differences from UT group, p < 0.05

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Copyright (c) 2021 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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