The role of the gut microbiome in multiple sclerosis

Objective: to study the role of the human gut microbiome in the mechanisms of multiple sclerosis (MS) development and in the formation of response to immunomodulatory therapy.

Material and methods. The study included 100 people – 80 patients with MS, 65 of whom had relapsing-remitting MS (RRMS) and 15 had primary-progressive MS (PPMS), all before being prescribed glucocorticoid therapy, as well as 20 healthy people of the same age. The gut microbiome was studied using 16S rRNA gene analysis. The influence of gender, duration and severity of MS, therapy received, the presence of a risk factor for MS exacerbation (smoking), and the presence of a predisposing factor in the genotype (DR2(15) haplotype) were assessed.

Results. For MS, regardless of gender, disease duration, type of course, treatment received, and other clinical and demographic characteristics, there is generally an increase in the content of rare forms of bacteria of the Verrucomicrobia type and related classes, orders, and families, as well as a decrease in the level of butyrate-producing bacteria of the genus Roseburia, which has an anti-inflammatory effect. The microbiome of male MS patients is more enriched with microorganisms, as in women in the control group, which can be regarded as one of the compensatory anti-inflammatory mechanisms that reduce the spread of MS in men. In cases of short-term MS, the gut microbiome was dominated by bacteria of the classes Erysipelotrichia, Verrucomicrobiae and Deltaproteobacteria, with the latter two being characteristic of all types of MS, indicating their role in the formation of a predisposition to MS; As the duration of MS increased, the content of bacteria of the genus Phascolarctobacterium increased, while the decrease in the level of bacteria of the genus Roseburia and OTU_825 (Roseburia_intestinalis), typical for MS, did not depend on the duration of MS. As the severity of MS increased on the EDSS scale, a predominance of rare forms of the class Verrucomicrobiae, family Verrucomicrobiaceae, was noted. In severe patients with EDSS ≥4.5 points, a predominance of bacteria of the class unc_Bacteroidetes was noted. In PPMS, as a more unfavourable type of MS course, the levels of bacteria of the Desulfovibrionaceae fam- ily, Akkermansia genus and OTU_30 (Akkermansia_muciniphila) were significantly increased (both compared to PPMS and compared to the control), and the level of OTU_825 (Roseburia_intestinalis) are significantly increased (compared to both PPMS and the control group), while the level of OTU_825 (Roseburia_intestinalis) is even lower than in typical relapsing MS, indicating a more unfavourable course of MS with a predominance of the neurodegenerative process.

During exacerbation of PPMS, a statistically significant increase in the presence of Proteobacteria and other classes, families and genera of bacteria associated with inflammation, indicating the involvement of the microbiome not only in the formation of predisposition, but also in a short-term increase in the activity of autoimmune inflammation, leading to an exacerbation of the pathological process in brain tissue.

Many differences between the gut microbiome of MS patients and that of the control group were most significant in the group of smokers. An increase in the presence of Verrucomicrobiaceae bacteria in the gut microbiome in MS was most noticeable in carriers of the HLA-DRB1-2(15) genetic marker, which increases the risk of developing MS.

High-dose IFN therapy may alter the composition of the gut microbiome, possibly due to the growth of anti-inflammatory microbiome, partic- ularly Holdemanella and Megasphaera, as well as butyrate-producing bacteria OTU_33 (unc_Lachnospiraceae).

Conclusion. The gut microbiome plays an important role in shaping the course and response to treatment in MS.

1. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010 Jul;9(7):727-39. doi: 10.1016/S1474-4422(10)70094-6

2. HedstrЪm AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. 2014 Mar;71(3):300-5. doi: 10.1001/jamaneurol.2013.5858

3. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011 May 12;473(7346):174-80. doi: 10.1038/nature09944

4. Sitkin SI, Tkachenko EI, Vakhitov TYa. The philometabolic core of the intestinal microbiota. Almanac of Clinical Medicine. 2015;40:12-34. (In Russ.)

5. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859-904. doi: 10.1152/physrev.00045.2009

6. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. doi: 10.1038/nature08821

7. Rajilic-Stojanovic M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev. 2014 Sep;38(5):996-1047. doi: 10.1111/1574-6976.12075

8. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012 May 9;486(7402):222-7. doi: 10.1038/nature11053

9. Schulze J, Sonnenborn U. Yeasts in the gut: from commensals to infectious agents. Dtsch Arztebl Int. 2009 Dec;106(51-52):837-42. doi: 10.3238/arztebl.2009.0837

10. Reyes A, Haynes M, Hanson N, et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 2010 Jul 15;466(7304):334-8. doi: 10.1038/nature09199

11. Waller AS, Yamada T, Kristensen DM, et al. Classification and quantification of bacteriophage taxa in human gut metagenomes. ISME J. 2014 Jul;8(7):1391-402. doi: 10.1038/ismej.2014.30

12. Chen T, Long W, Zhang C, et al. Fiber-utilizing capacity varies in Prevotella-versus Bacteroides-dominated gut microbiota. Sci Rep. 2017 Jun 1;7(1):2594. doi: 10.1038/s41598-017-02995-4

13. Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016 Jun 27;6:28484. doi: 10.1038/srep28484

14. Tremlett H, Fadrosh DW, Faruqi AA, et al; US Network of Pediatric MS Centers. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016 Aug;23(8):1308-21. doi: 10.1111/ene.13026

15. Jiang H, Ling Z, Zhang Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015;48:186-94. doi: 10.1016/j.bbi.2015.03.016

16. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366

17. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73. doi: 10.1016/S1474-4422(17)30470-2

18. Kozhieva M, Naumova N, Alikina T, et al. Primary progressive multiple sclerosis in a Russian cohort: relationship with gut bacterial diversity. BMC Microbiol. 2019 Dec 30;19(1):309. doi: 10.1186/s12866-019-1685-2

19. Kozhieva M, Naumova N, Alikina N, et al. The Core of Gut Life: Firmicutes Profile in Patients with Relapsing-Remitting Multiple Sclerosis. Life (Basel). 2021 Jan;11(1):55. doi: 10.3390/life11010055

20. Boyko AN, Melnikov MV, Boyko OV, et al. Microbiota markers level in the cerebrospinal fluid of patients with multiple sclerosis and radiologically isolated syndrome. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2021;13(1):27-30. (In Russ.) doi: 10.14412/2074-2711-2021-1S-27-30

21. Boziki MK, Kesidou E, Theotokis P, et al. Microbiome in MS; where are we, what we know and do not know. Brain Sci. 2020 Apr 14;10(4):234. doi: 10.3390/brainsci10040234

22. Saresella M, Mendozzi L, Rossi V, et al. Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study. Front Immunol. 2017 Oct 25;8:1391. doi: 10.3389/fimmu.2017.01391