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The Gut Microbiome in Multiple Sclerosis

Opinion statement

The gut microbiome is made up of a wide range of (chiefly) bacterial species that colonize the small and large intestine. The human gut microbiome contains a subset of thousands of bacterial species, with up to 1014 total bacteria. Studies examining this bacterial content have shown wide variations in which species are present between individuals. The gut microbiome has been shown to have profound effects on the development and maintenance of immune system in both animal models and in humans. A growing body of evidence has implicated the human gut microbiome in a range of disorders, including obesity, inflammatory bowel diseases, and cardiovascular disease. Animal studies present compelling evidence that the gut microbiome plays a significant role in the progression of demyelinating disease, and that modulation of the microbiome can lead to either exacerbation or amelioration of symptoms. Differences in diet, vitamin D insufficiency, smoking, and alcohol use have all been implicated as risk factors in MS, and all have the ability to affect the composition of the gut microbiota. Preliminary clinical trials aimed at modulating the gut microbiota in MS patients are underway and may prove to be a promising and lower-risk treatment option in the future.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938–52.

  2. 2.

    Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol. 2009;65:239–48.

  3. 3.

    Krumbholz M, Derfuss T, Hohlfeld R, Meinl E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol. 2012;8:13–623.

  4. 4.

    Fazekas F, Enzinger C, Wallner-Blazek M, Ropele S, Pluta-Fuerst A, Fuchs S. Gender differences in MRI studies on multiple sclerosis. J Neurol Sci. 2009;286:28–30.

  5. 5.

    Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–17.

  6. 6.

    Sawcer S. The complex genetics of multiple sclerosis: pitfalls and prospects. Brain. 2008;131:3118–31.

  7. 7.

    Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet. 2008;9:516–26.

  8. 8.•

    International Multiple Sclerosis Genetics Consortium et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9. Study confirming several genetic factors associated with MS.

  9. 9.

    Simpson Jr S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82:1132–41.

  10. 10.

    Trojano M et al. Geographical variations in sex ratio trends over time in multiple sclerosis. PLoS ONE. 2012;7:e48078.

  11. 11.

    Joscelyn J, Kasper LH. Digesting the emerging role for the gut microbiome in central nervous system demyelination. Mult Scler. 2014;20:1553–9.

  12. 12.

    Royal 3rd W, Mia Y, Li H, Naunton K. Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis. J Neuroimmunol. 2009;213:135–41.

  13. 13.•

    Kang SW et al. 1,25-dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol. 2012;188:5276–82. Evidence for role of Vitamin D in Treg function.

  14. 14.

    Matarese G et al. Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur J Immunol. 2001;31:1324–32.

  15. 15.

    Matarese G et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol. 2001;166:5909–16.

  16. 16.

    Lock C et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8:500–8.

  17. 17.

    Matarese G et al. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2005;102:5150–5.

  18. 18.

    Sanna V, Di Giacomo A, La Cava A, Lechler RI, Fontana S, Zappacosta S, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest. 2003;111:241–50.

  19. 19.

    Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000;55 Suppl 1:S2–10.

  20. 20.•

    Correale J. Helminth/parasite treatment of multiple sclerosis. Curr Treat Options Neurol. 2014;16:296. Review of Helminth treatment of MS, which is related to the gut microflora.

  21. 21.

    Fabis Pedrini MJ, et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. J Neurol Neurosurg Psychiatry. 2015.

  22. 22.•

    Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014;38:1–12. In depth review focusing on the microbiome and CNS disorders beyod MS.

  23. 23.

    Ochoa-Reparaz J, Kasper LH. Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett. 2014;588:4214–22.

  24. 24.•

    Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837–48. Gut microbiota can exacerbate EAE.

  25. 25.

    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.

  26. 26.

    Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011;479:538–41.

  27. 27.••

    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009;183:6041–50. Antibiotic treatment prevents EAE induction, and gut microflora reconstitution enables it.

  28. 28.

    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. Am J Pathol. 2008;173:1714–23.

  29. 29.••

    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol. 2010;185:4101–8. Demonstrates that a single polysaccharide from a member of the gut microflora can protect against EAE.

  30. 30.

    Ochoa-Reparaz J, Mielcarz DW, Haque-Begum S, Kasper LH. Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes. 2010;1:103–8.

  31. 31.

    Ochoa-Reparaz J, Mielcarz DW, Wang Y, Begum-Haque S, Dasgupta S, Kasper DL, et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 2010;3:487–95.

  32. 32.

    Wang Y et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun. 2014;5:4432.

  33. 33.

    Wang Y et al. A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes. 2014;5:552–61.

  34. 34.

    Jun S, Ochoa-Reparaz J, Zlotkowska D, Hoyt T, Pascual DW. Bystander-mediated stimulation of proteolipid protein-specific regulatory T (Treg) cells confers protection against experimental autoimmune encephalomyelitis (EAE) via TGF-beta. J Neuroimmunol. 2012;245:39–47.

  35. 35.

    Ochoa-Reparaz J, Riccardi C, Rynda A, Jun S, Callis G, Pascual DW. Regulatory T cell vaccination without autoantigen protects against experimental autoimmune encephalomyelitis. J Immunol. 2007;178:1791–9.

  36. 36.

    Jun S, Gilmore W, Callis G, Rynda A, Haddad A, Pascual DW. A live diarrheal vaccine imprints a Th2 cell bias and acts as an anti-inflammatory vaccine. J Immunol. 2005;175:6733–40.

  37. 37.

    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;154:424–31.

  38. 38.

    Lavasani S 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:e9009.

  39. 39.

    Takata K et al. The lactic acid bacterium Pediococcus acidilactici suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells. PLoS ONE. 2011;6:e27644.

  40. 40.

    Maassen CB, Claassen E. Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity. Vaccine. 2008;26:2056–7.

  41. 41.

    Kwon HK 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.

  42. 42.

    Rezende RM et al. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells. J Autoimmun. 2013;40:45–57.

  43. 43.••

    Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268–73. Excellent review on the manners in which the gut microbiota and immune system interact.

  44. 44.

    Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4:478–85.

  45. 45.

    Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr. 1999;69:1035S–45.

  46. 46.

    Braniste V et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6:263ra158.

  47. 47.

    Begum-Haque S, Christy M, Ochoa-Reparaz J, Nowak EC, Mielcarz D, Haque A, et al. Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J Neuroimmunol. 2011;232:136–44.

  48. 48.

    Tzianabos AO, Kasper DL, Onderdonk AB. Structure and function of Bacteroides fragilis capsular polysaccharides: relationship to induction and prevention of abscesses. Clin Infect Dis. 1995;20 Suppl 2:S132–40.

  49. 49.

    Pantosti A, Tzianabos AO, Reinap BG, Onderdonk AB, Kasper DL. Bacteroides fragilis strains express multiple capsular polysaccharides. J Clin Microbiol. 1993;31:1850–5.

  50. 50.

    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122:107–18.

  51. 51.

    Mazmanian SK, Kasper DL. The love-hate relationship between bacterial polysaccharides and the host immune system. Nat Rev Immunol. 2006;6:849–58.

  52. 52.

    Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453:620–5.

  53. 53.

    Mazmanian SK. Capsular polysaccharides of symbiotic bacteria modulate immune responses during experimental colitis. J Pediatr Gastroenterol Nutr. 2008;46 Suppl 1:E11–2.

  54. 54.

    Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7.

  55. 55.

    Ochoa-Reparaz J et al. IL-13 production by regulatory T cells protects against experimental autoimmune encephalomyelitis independently of autoantigen. J Immunol. 2008;181:954–68.

  56. 56.

    Kochetkova I, Trunkle T, Callis G, Pascual DW. Vaccination without autoantigen protects against collagen II-induced arthritis via immune deviation and regulatory T cells. J Immunol. 2008;181:2741–52.

  57. 57.

    Mowry E, Waubant E, Chehoud C, DeSantis T, Kuczynski J, Warrington J. Gut bacterial populations in multiple sclerosis and in health (P05.106). Neurology. 2012;78:P05.106.

  58. 58.

    Bhargava P, Mowry EM. Gut microbiome and multiple sclerosis. Curr Neurol Neurosci Rep. 2014;14:492.

  59. 59.

    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:e76359.

  60. 60.•

    Jhangi S et al. Increased Archaea species and changes with therapy in gut microbiome of multiple sclerosis subjects (S24.001). Neurology. 2014;82:S24.001. Largest study to date on the gut microbiome content of MS patients.

  61. 61.

    Tremlett H et al. Gut microbiome in early pediatric multiple sclerosis: a case-control study. Mult Scler. 2014;20:285–496.

  62. 62.

    Telesford K, Wang Y, Ochoa-Reparaz J, Begum-Haque S, Kasper LH. Commensal antigen induction of suppressive human Foxp3+ Tregs. Mult Scler. 2014;20:285–496.

  63. 63.

    Saemann MD et al. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J. 2000;14:2380–2.

  64. 64.

    Kampman MT, Brustad M. Vitamin D: a candidate for the environmental effect in multiple sclerosis—observations from Norway. Neuroepidemiology. 2008;30:140–6.

  65. 65.

    Ly NP, Litonjua A, Gold DR, Celedon JC. Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity? J Allergy Clin Immunol. 2011;127:1087–94. quiz 1095-6.

  66. 66.

    Mai V, McCrary QM, Sinha R, Glei M. Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: an observational study in African American and Caucasian American volunteers. Nutr J. 2009;8:49.

  67. 67.

    Pozuelo-Moyano B, Benito-Leon J, Mitchell AJ, Hernandez-Gallego J. A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis. Neuroepidemiology. 2013;40:147–53.

  68. 68.

    David LA et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

  69. 69.

    Turnbaugh PJ et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4.

  70. 70.

    Piccio L, Stark JL, Cross AH. Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukoc Biol. 2008;84:940–8.

  71. 71.

    Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003;52:2882–7.

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Conflict of Interest

Daniel W. Mielcarz declares no conflict of interest.

Lloyd H. Kasper declares the receipt of grants from Symbiotix Biotherapies, NIH, and NMSS, outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Daniel W. Mielcarz PhD.

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This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders

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Mielcarz, D.W., Kasper, L.H. The Gut Microbiome in Multiple Sclerosis. Curr Treat Options Neurol 17, 18 (2015).

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  • Gut microbiome
  • Multiple sclerosis
  • MS
  • Vitamin D deficiency
  • Hygiene hypothesis
  • Immunity
  • Inflammation
  • Gut microbiota
  • Treatment