Among the different environmental variables that may play a role in the pathogenesis of MS, the influence of the microorganisms living in or on the body (collectively referred to as the microbiota and their genome being the microbiome) has gained significant traction as a critical determinant of autoimmunity.
Seminal studies using the EAE model have previously shown in fact that the incidence of the disease in germ-free and antibiotic-treated mice was significantly lower than in conventional animals [1-3]. But now mechanistic studies have gone beyond proof-of-principle investigations and have begun to dissect how the microbiota can impact the induction and progression of CNS autoimmunity. In these models in fact it has been shown that it was a proinflammatory intestinal environment that promoted brain autoimmunity by enhancing TH17 cell expansion and self-reactive T cell pathogenicity. Myelin-reactive T cells are driven toward a pathogenic TH17 phenotype in the small intestinal mucosa and then migrate to the CNS where they mediate autoimmune damage of the myelin sheath. Some commensal bacterial species that modulate CNS autoimmunity have been characterized and therefore microbiota modulation by probiotics is being developed as the primary EAE therapeutic strategy involving the gut microbiota. For example, Kwon and collaborators have desribed the beneficial effects of a five-strain probiotic on the clinical signs of EAE (4) while in another recent study Haghikia et al showed that short-chain fatty acids, bacterial products produced from the fermentation of dietary fibre, increased the production of IL-10 and Treg and ultimately ameliorated the course of EAE (5).
These observations have motivated clinical studies that have revealed differences in the composition of the gut microbiome of MS patients compared to the unaffected population. Particularly, in a recent study by Cosorich et al (6), the role of the intestinal environment in promoting TH17 cell expansion in MS patients has been validated, and an increased frequency of TH17 cells was shown to be associated with high disease activity and with specific alterations of the gut mucosa-associated microbiota in MS patients. As observed in adult patients, the importance of the gut environment for the development of CNS autoimmunity has been validated also in a pediatric cohort of patients in a work recently published in European Journal of Neurology (7). Tremlett et al in fact has found out that in children with MS specific microbiota species were associated with an increased risk of relapses, and that treated pediatric patients presented a more similar gut microbiota to healthy controls than untreated patients. This is of critical importance because the risk of developing MS is clearly associated also with other environmental factors that could impact gut composition and constitute a bias, but paediatric patients are less likely to have been exposed to MS-specific environmental triggers (e.g., Epstein-Barr virus infection, smoking or adolescent obesity) than adults and this indicates a possible causal role for the commensal microbiota in disease pathogenesis.
The knowledge that the microbiota has diverse effects on host tissues and our rapidly evolving ability to characterize and carefully manipulate microbial communities has the potential to make important advances in the treatment and quality of life of individuals living with MS.
key points:
- experimental autoimmune
- encephalomyelitis
- pathogenesis of MS
- microbiota
[1] Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2011;108(Suppl. 1):4615–22. <link www.ncbi.nlm.nih.gov/pubmed/20660719 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/20660719</link>
[2] Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, et al. Commensal micro biota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011;479:538–41. <link www.ncbi.nlm.nih.gov/pubmed/22031325 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/22031325</link>
[3] Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, et al. Role of gut commensal micro flora in the development of experimental autoimmune encephalomyelitis. J Immunol 2009;183:6041–50. <link www.ncbi.nlm.nih.gov/pubmed/19841183 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/19841183</link>
[4] Kwon HK, Kim GC, Kim Y, Hwang W, Jash A, Sahoo A, et al. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clin Immunol 2013;146:217–27. <link www.ncbi.nlm.nih.gov/pubmed/23416238 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/23416238</link>
[5] Haghikia A, Jorg S, Duscha A, Berg J, Manzel A, Waschbisch A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 2015;43:817–29. <link www.ncbi.nlm.nih.gov/pubmed/26488817 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/26488817</link>
[6] Cosorich, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J et al. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3(7):e1700492. <link www.ncbi.nlm.nih.gov/pubmed/28706993>https://www.ncbi.nlm.nih.gov/pubmed/28706993</link>
[7] Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study.
Eur J Neurol 2016;23:1308–21. <link www.ncbi.nlm.nih.gov/pubmed/27176462 - external-link-new-window "Opens external link in new window">https://www.ncbi.nlm.nih.gov/pubmed/27176462</link>