Acta Neuropathologica

, Volume 123, Issue 5, pp 639–651 | Cite as

Commensal gut flora and brain autoimmunity: a love or hate affair?

  • Kerstin Berer
  • Gurumoorthy Krishnamoorthy


Multiple sclerosis (MS) and other chronic inflammatory autoimmune diseases represent major public health challenges in industrialised Western society. MS results from an autoimmune attack against myelin structures by self-reactive lymphocytes, which are normal components of the healthy immune repertoire. The nature of the triggers that convert the innocuous self-reactive lymphocytes into an autoaggressive phenotype is poorly understood. In the past, it was primarily suspected that pathogenic infections trigger MS. However, so far, none of the incriminated pathogenic microbes were firmly associated with the disease. A growing body of evidence in animal models of MS implicates the gut microbiota in the induction of central nervous system (CNS) autoimmunity. The mammalian gut harbors a diverse population of microbial organisms which are essential for our well being. There is an increasing understanding that the gut microbiota not only modulates the local immune functions but also affects the systemic immune system. We are only just beginning to understand the nature of the interactions of the gut microbiota with the host’s immune system especially in the context of autoimmune diseases. This review will address the influence of intestinal microbiota on immune homeostasis and on the development of autoimmune responses at sites distal to the intestine with a particular emphasis placed on a discussion about CNS autoimmunity.


Gut microbiota Commensals Multiple sclerosis EAE Autoimmune disease 



This work was supported by DFG-SFB 571 (Project B6), the German Competence Network on Multiple Sclerosis (KKNMS), ARSEP (France) and by the Max Planck Society.


  1. 1.
    Abdollahi-Roodsaz S, Joosten LAB, Koenders MI et al (2008) Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 118:205–216PubMedCrossRefGoogle Scholar
  2. 2.
    Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174:4453–4460PubMedGoogle Scholar
  3. 3.
    Alam C, Bittoun E, Bhagwat D et al (2011) Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 54:1398–1406PubMedCrossRefGoogle Scholar
  4. 4.
    Atarashi K, Nishimura J, Shima T et al (2008) ATP drives lamina propria TH17 cell differentiation. Nature 455:808–812PubMedCrossRefGoogle Scholar
  5. 5.
    Atarashi K, Tanoue T, Shima T et al (2011) Induction of colonic regulatory T cells by indigenous clostridium species. Science 331:337–341PubMedCrossRefGoogle Scholar
  6. 6.
    Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ (2000) Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1:113–118PubMedCrossRefGoogle Scholar
  7. 7.
    Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920PubMedCrossRefGoogle Scholar
  8. 8.
    Bain CC, Mowat AM (2011) Intestinal macrophages—specialised adaptation to a unique environment. Eur J Immunol 41:2494–2498PubMedCrossRefGoogle Scholar
  9. 9.
    Baken KA, Ezendam J, Gremmer ER et al (2006) Evaluation of immunomodulation by Lactobacillus casei Shirota: immune function, autoimmunity and gene expression. Int J Food Microbiol 112:8–18PubMedCrossRefGoogle Scholar
  10. 10.
    Bauer H, Horowitz RE, Popper H, Levenson SM (1963) Response of lymphatic tissue to microbial flora—studies on germfree mice. Am J Pathol 42:471–483PubMedGoogle Scholar
  11. 11.
    Benson A, Pifer R, Behrendt CL, Hooper LV, Yarovinsky F (2009) Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe 6:187–196PubMedCrossRefGoogle Scholar
  12. 12.
    Benson AK, Kelly SA, Legge R et al (2010) Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc Natl Acad Sci USA 107:18933–18938PubMedCrossRefGoogle Scholar
  13. 13.
    Berer K, Mues M, Koutroulos M et al (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479:538–541PubMedCrossRefGoogle Scholar
  14. 14.
    Bergstrom KSB, Kissoon-Singh V, Gibson DL et al (2010) Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathogens 6:e1000902PubMedCrossRefGoogle Scholar
  15. 15.
    Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedCrossRefGoogle Scholar
  16. 16.
    Brandl K, Plitas G, Mihu CN et al (2008) Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455:804–807PubMedCrossRefGoogle Scholar
  17. 17.
    Breban MA, Moreau MC, Fournier C, Ducluzeau R, Kahn MF (1993) Influence of the bacterial-flora on collagen-induced arthritis in susceptible and resistant strains of rats. Clin Exp Rheumatol 11:61–64PubMedGoogle Scholar
  18. 18.
    Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J (2011) Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Acta Diabetol 48:257–273PubMedCrossRefGoogle Scholar
  19. 19.
    Bush WS, Sawcer SJ, De Jager PL et al (2010) Evidence for polygenic susceptibility to multiple sclerosis—the shape of things to come. Am J Hum Genet 86:621–625PubMedCrossRefGoogle Scholar
  20. 20.
    Calcinaro F, Dionisi S, Marinaro M et al (2005) Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48:1565–1575PubMedCrossRefGoogle Scholar
  21. 21.
    Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313:1126–1130PubMedCrossRefGoogle Scholar
  22. 22.
    Cerutti A, Rescigno M (2008) The biology of intestinal immunoglobulin A responses. Immunity 28:740–750PubMedCrossRefGoogle Scholar
  23. 23.
    Chieppa M, Rescigno M, Huang AYC, Germain RN (2006) Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J Exp Med 203:2841–2852PubMedCrossRefGoogle Scholar
  24. 24.
    Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu YM, Weiser JN (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16:228–231PubMedCrossRefGoogle Scholar
  25. 25.
    Coombes JL, Siddiqui KRR, Aranciba-Cárcamo CV et al (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β- and retinoic acid-dependent mechanism. J Exp Med 204:1757–1764PubMedCrossRefGoogle Scholar
  26. 26.
    Cyster JG (2010) B cell follicles and antigen encounters of the third kind. Nat Immunol 11:989–996PubMedCrossRefGoogle Scholar
  27. 27.
    De Filippo C, Cavalieri D, Di Paola M et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 107:14691–14696PubMedCrossRefGoogle Scholar
  28. 28.
    De Vos AF, Van Meurs M, Brok HP et al (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169:5415–5423PubMedGoogle Scholar
  29. 29.
    Dicksved J, Halfvarson J, Rosenquist M et al (2008) Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. ISME J 2:716–727PubMedCrossRefGoogle Scholar
  30. 30.
    Duan JY, Chung H, Troy E, Kasper DL (2010) Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing γ/δ T cells. Cell Host Microbe 7:140–150PubMedCrossRefGoogle Scholar
  31. 31.
    Eckburg PB, Bik EM, Bernstein CN et al (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638PubMedCrossRefGoogle Scholar
  32. 32.
    Ezendam J, de KA, Gremmer ER, van Loveren H (2008) Effects of Bifidobacterium animalis administered during lactation on allergic and autoimmune responses in rodents. Clin Exp Immunol 154:424–431PubMedCrossRefGoogle Scholar
  33. 33.
    Ezendam J, van Loveren H (2008) Lactobacillus casei Shirota administered during lactation increases the duration of autoimmunity in rats and enhances lung inflammation in mice. Br J Nutr 99:83–90PubMedCrossRefGoogle Scholar
  34. 34.
    Fagarasan S, Honjo T (2003) Intestinal IgA synthesis: regulation of front-line body defences. Nat Rev Immunol 3:63–72PubMedCrossRefGoogle Scholar
  35. 35.
    Falk PG, Hooper LV, Midtvedt T, Gordon JI (1998) Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol Mol Biol Rev 62:1157–1170PubMedGoogle Scholar
  36. 36.
    Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the Forkhead transcription factor Foxp3. Immunity 22:329–341PubMedCrossRefGoogle Scholar
  37. 37.
    Gaboriau-Routhiau V, Rakotobe S, Lévuyer E et al (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–689PubMedCrossRefGoogle Scholar
  38. 38.
    Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72:551–560PubMedCrossRefGoogle Scholar
  39. 39.
    Gray DHD, Gavanescu I, Benoist C, Mathis D (2007) Danger-free autoimmune disease in Aire-deficient mice. Proc Natl Acad Sci USA 104:18193–18198PubMedCrossRefGoogle Scholar
  40. 40.
    Hall JA, Bouladoux N, Sun CM et al (2008) Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29:637–649PubMedCrossRefGoogle Scholar
  41. 41.
    Hase K, Takahashi D, Ebisawa M, Kawano S, Itoh K, Ohno H (2009) Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease. Plos One 3:e3033CrossRefGoogle Scholar
  42. 42.
    Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G (2010) Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464:908–912PubMedCrossRefGoogle Scholar
  43. 43.
    Hill DA, Artis D (2010) Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol 28:623–667PubMedCrossRefGoogle Scholar
  44. 44.
    Hill JA, Hall JA, Sun CM et al (2008) Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29:758–770PubMedCrossRefGoogle Scholar
  45. 45.
    Ivanov II, Atarashi K, Manel N et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498PubMedCrossRefGoogle Scholar
  46. 46.
    Ivanov II, De Llanos Frutos R, Manel N et al (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–349PubMedCrossRefGoogle Scholar
  47. 47.
    Iwata M, Hirakiyama A, Eshima Y, Kageshima H, Kato C, Song S-Y (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538PubMedCrossRefGoogle Scholar
  48. 48.
    Jia W, Li HK, Zhao LP, Nicholson JK (2008) Gut microbiota: a potential new territory for drug targeting. Nat Rev Drug Discov 7:123–129PubMedCrossRefGoogle Scholar
  49. 49.
    Johansson ME, Hansson GC (2008) Mucus protects the colon by separating bacteria from the epithelium. Gastroenterology 134:A516CrossRefGoogle Scholar
  50. 50.
    Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA 105:15064–15069PubMedCrossRefGoogle Scholar
  51. 51.
    Johansson-Lindbom B, Svensson M, Pabst O et al (2005) Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med 202:1063–1073PubMedCrossRefGoogle Scholar
  52. 52.
    King C, Sarvetnick N (2011) The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. Plos One 6:e17049PubMedCrossRefGoogle Scholar
  53. 53.
    Kira J-I, Yamasaki K, Horiuchi I, Ohyagi Y, Taniwaki T, Kawano Y (1999) Changes in the clinical phenotypes of multiple sclerosis during the past 50 years in Japan. J Neurol Sci 166:53–57PubMedCrossRefGoogle Scholar
  54. 54.
    Kohashi O, Kuwata J, Umehara K, Uemura F, Takahashi T, Ozawa A (1979) Susceptibility to adjuvant-induced arthritis among germfree, specific-pathogen-free, and conventional rats. Infect Immun 26:791–794PubMedGoogle Scholar
  55. 55.
    Krishnamoorthy G, Holz A, Wekerle H (2007) Experimental models of spontaneous autoimmune disease in the central nervous system. J Mol Med 85:1161–1173PubMedCrossRefGoogle Scholar
  56. 56.
    Krishnamoorthy G, Lassmann H, Wekerle H, Holz A (2006) Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest 116:2385–2392PubMedCrossRefGoogle Scholar
  57. 57.
    Kuwahara T, Ogura Y, Oshima K et al (2011) The lifestyle of the segmented filamentous bacterium: a non-culturable gut-associated immunostimulating microbe inferred by whole-genome sequencing. DNA Res 18:291–303PubMedCrossRefGoogle Scholar
  58. 58.
    Lampropoulou V, Hoehlig K, Roch T et al (2008) TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol 180:4763–4773PubMedGoogle Scholar
  59. 59.
    Lauer K (1997) Diet and multiple sclerosis. Neurology 49:S55–S61PubMedGoogle Scholar
  60. 60.
    Lavasani S, Dzhambazov B, Nouri M et al (2010) A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. Plos One 5:e9009PubMedCrossRefGoogle Scholar
  61. 61.
    Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 108:4615–4622PubMedCrossRefGoogle Scholar
  62. 62.
    Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–848PubMedCrossRefGoogle Scholar
  63. 63.
    Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin MA (2008) Mucins in the mucosal barrier to infection. Mucosal Immunol 1:183–197PubMedCrossRefGoogle Scholar
  64. 64.
    MacPherson AJ, Harris NL (2004) Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4:478–485PubMedCrossRefGoogle Scholar
  65. 65.
    Maldonado MA, Kakkanaiah V, MacDonald GC et al (1999) The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. J Immunol 162:6322–6330PubMedGoogle Scholar
  66. 66.
    Manicassamy S, Reizis B, Ravindran R et al (2010) Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329:849–853PubMedCrossRefGoogle Scholar
  67. 67.
    Maslowski KM, Vieira AT, Ng AW et al (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–1286PubMedCrossRefGoogle Scholar
  68. 68.
    Matsushita T, Yanaba K, Bouaziz J-D, Fujimoto M, Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118:3420–3430PubMedGoogle Scholar
  69. 69.
    Matsuzaki T, Nagata Y, Kado S et al (1997) Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei. APMIS 105:643–649PubMedCrossRefGoogle Scholar
  70. 70.
    Matteoli G, Mazzini E, Iliev ID et al (2010) Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 59:595–604PubMedCrossRefGoogle Scholar
  71. 71.
    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118PubMedCrossRefGoogle Scholar
  72. 72.
    Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625PubMedCrossRefGoogle Scholar
  73. 73.
    Mezrich JD, Fechner JH, Zhang XJ, Johnson BP, Burlingham WJ, Bradfield CA (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. J Immunol 185:3190–3198PubMedCrossRefGoogle Scholar
  74. 74.
    Mizutani A, Shaheen VM, Yoshida H et al (2005) Pristane-induced autoimmunity in germ-free mice. Clin Immunol 114:110–118PubMedCrossRefGoogle Scholar
  75. 75.
    Mowat AM (2003) Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3:331–341PubMedCrossRefGoogle Scholar
  76. 76.
    Nell S, Suerbaum S, Josenhans C (2010) The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat Rev Microbiol 8:564–577PubMedCrossRefGoogle Scholar
  77. 77.
    Niess JH, Leithauser F, Adler G, Reimann J (2008) Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J Immunol 180:559–568PubMedGoogle Scholar
  78. 78.
    Nieuwenhuis EES, Matsumoto T, Lindenbergh D et al (2009) Cd1d-dependent regulation of bacterial colonization in the intestine of mice. J Clin Invest 119:1241–1250PubMedCrossRefGoogle Scholar
  79. 79.
    O’Mahony C, Scully P, O’Mahony D et al (2008) Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation. PLoS Pathogens 4:e1000112PubMedCrossRefGoogle Scholar
  80. 80.
    Ochoa-Repáraz J, Mielcarz DW, Ditrio LE et al (2010) Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 185:4101–4108PubMedCrossRefGoogle Scholar
  81. 81.
    Ochoa-Repáraz J, Mielcarz DW, Ditrio LE et al (2009) Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 183:6041–6050PubMedCrossRefGoogle Scholar
  82. 82.
    Ochoa-Repáraz J, Mielcarz DW, Haque-Begum S, Kasper LH (2010) Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes 1:103–108PubMedCrossRefGoogle Scholar
  83. 83.
    Ochoa-Repáraz J, Mielcarz DW, Wang Y et al (2010) A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol 3:487–495PubMedCrossRefGoogle Scholar
  84. 84.
    Perdew GH, Babbs CF (1991) Production of Ah receptor ligands in rat fecal suspensions containing tryptophan or indole-3-carbinol. Nutr Cancer 16:209–218PubMedCrossRefGoogle Scholar
  85. 85.
    Peterson DA, Frank DN, Pace NR, Gordon JI (2008) Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 3:417–427PubMedCrossRefGoogle Scholar
  86. 86.
    Petnicki-Ocwieja T, Hrncir T, Liu YJ et al (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 106:15813–15818PubMedCrossRefGoogle Scholar
  87. 87.
    Pöllinger B, Krishnamoorthy G, Berer K et al (2009) Spontaneous relapsing–remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med 206:1303–1316PubMedCrossRefGoogle Scholar
  88. 88.
    Pomare EW, Branch WJ, Cummings JH (1985) Carbohydrate fermentation in the human-colon and its relation to acetate concentrations in venous-blood. J Clin Invest 75:1448–1454PubMedCrossRefGoogle Scholar
  89. 89.
    Pozzilli P, Signore A, Williams AJK, Beales PE (1993) NOD mouse colonies around the world—recent facts and figures. Immunol Today 14:193–196PubMedCrossRefGoogle Scholar
  90. 90.
    Prakash T, Oshima K, Morita H et al (2011) Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of Th17 cell differentiation. Cell Host Microbe 10:273–284PubMedCrossRefGoogle Scholar
  91. 91.
    Quintana FJ, Basso AS, Iglesias AH et al (2008) Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71PubMedCrossRefGoogle Scholar
  92. 92.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118:229–241PubMedCrossRefGoogle Scholar
  93. 93.
    Rehakova Z, Capkova J, Stepankova R et al (2000) Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol 61:555–558PubMedCrossRefGoogle Scholar
  94. 94.
    Rescigno M, Urbano M, Valzasina B et al (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2:361–367PubMedCrossRefGoogle Scholar
  95. 95.
    Rossini AA, Williams RM, Mordes JP, Appel MC, Like AA (1979) Spontaneous diabetes in the gnotobiotic BB-W rat. Diabetes 28:1031–1032PubMedCrossRefGoogle Scholar
  96. 96.
    Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9:313–323PubMedCrossRefGoogle Scholar
  97. 97.
    Round JL, Mazmanian SK (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 107:12204–12209PubMedCrossRefGoogle Scholar
  98. 98.
    Saleh M, Elson CO (2011) Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 34:293–302PubMedCrossRefGoogle Scholar
  99. 99.
    Salvetti M, Ristori G, Bomprezzi R, Pozzilli P, Leslie RDG (2000) Twins: mirrors of the immune system. Immunol Today 21:342–347PubMedCrossRefGoogle Scholar
  100. 100.
    Salzman NH, Hung KC, Haribhai D et al (2010) Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11:76–82PubMedCrossRefGoogle Scholar
  101. 101.
    Sawcer S, Hellenthal G, Pirinen M et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219PubMedCrossRefGoogle Scholar
  102. 102.
    Scher JU, Abramson SB (2011) The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 7:569–578PubMedGoogle Scholar
  103. 103.
    Schulz O, Jaensson E, Persson EK et al (2009) Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med 206:3101–3114PubMedCrossRefGoogle Scholar
  104. 104.
    Sczesnak A, Segata N, Qin X et al (2011) The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10:260–272PubMedCrossRefGoogle Scholar
  105. 105.
    Sinkorova Z, Capkova J, Niederlova J, Stepankova R, Sinkora J (2008) Commensal intestinal bacterial strains trigger ankylosing enthesopathy of the ankle in inbred B10.BR (H-2k) male mice. Hum Immunol 69:845–850PubMedCrossRefGoogle Scholar
  106. 106.
    Slack E, Hapfelmeier S, Stecher B et al (2009) Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325:617–620PubMedCrossRefGoogle Scholar
  107. 107.
    Smith KD, McCoy KD, MacPherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19:59–69PubMedCrossRefGoogle Scholar
  108. 108.
    Sokol H, Pigneur B, Watterlot L et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105:16731–16736PubMedCrossRefGoogle Scholar
  109. 109.
    Spor A, Koren O, Ley R (2011) Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol 9:279–290PubMedCrossRefGoogle Scholar
  110. 110.
    Stecher B, Chaffron S, Kappeli R et al (2010) Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathogens 6:e1000711PubMedCrossRefGoogle Scholar
  111. 111.
    Suzuki K, Meek B, Doi Y et al (2004) Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci USA 101:1981–1986PubMedCrossRefGoogle Scholar
  112. 112.
    Takata K, Kinoshita M, Okuno T et al (2011) The lactic acid bacterium Pediococcus acidilactici Suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells. PLoS ONE 6:e27644PubMedCrossRefGoogle Scholar
  113. 113.
    Talham GL, Jiang HQ, Bos NA, Cebra JJ (1999) Segmented filamentous bacteria are potent stimuli of a physiologically normal state of the murine gut mucosal immune system. Infect Immun 67:1992–2000PubMedGoogle Scholar
  114. 114.
    Taurog JD, Richardson JA, Croft JT et al (1994) The germ-free state prevents development of gut and joint jnflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359–2364PubMedCrossRefGoogle Scholar
  115. 115.
    Turnbaugh PJ, Hamady M, Yatsunenko T et al (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484PubMedCrossRefGoogle Scholar
  116. 116.
    Ubeda C, Taur Y, Jenq RR et al (2010) Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest 120:4332–4341PubMedCrossRefGoogle Scholar
  117. 117.
    Umesaki Y, Okada Y, Matsumoto S, Imaoka A, Setoyama H (1995) Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class-II molecules and fucosyl asialo Gm1 glycolipids on the small-intestinal epithelial-cells in the ex-germ-free mouse. Microbiol Immunol 39:555–562PubMedGoogle Scholar
  118. 118.
    Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, Toivanen P (2008) Fecal microbiota in early rheumatoid arthritis. J Rheumatol 35:1500–1505PubMedGoogle Scholar
  119. 119.
    Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host–microbial interface. Proc Natl Acad Sci USA 105:20858–20863PubMedCrossRefGoogle Scholar
  120. 120.
    Vaishnava S, Yamamoto M, Severson KM et al (2011) The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334:255–258PubMedCrossRefGoogle Scholar
  121. 121.
    Van den Broek MF, van Bruggen MC, Koopman JP, Hazenberg MP, Van den Berg WB (1992) Gut flora induces and maintains resistance against streptococcal cell wall-induced arthritis in F344 rats. Clin Exp Immunol 88:313–317PubMedCrossRefGoogle Scholar
  122. 122.
    Van der Sluis M, De Koning BAE, De Bruijn ACJM et al (2006) Muc2-deficient mice spontaneously develop colitis, indicating that Muc2 is critical for colonic protection. Gastroenterology 131:117–129PubMedCrossRefGoogle Scholar
  123. 123.
    Van Zwam M, Huizinga R, Heijmans N et al (2009) Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J Pathol 217:543–551PubMedCrossRefGoogle Scholar
  124. 124.
    Veldhoen M, Hirota K, Westendorf AM et al (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109PubMedCrossRefGoogle Scholar
  125. 125.
    Vijay-Kumar M, Aitken JD, Carvalho FA et al (2010) Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science 328:228–231PubMedCrossRefGoogle Scholar
  126. 126.
    Wen L, Ley RE, Volchkov PY et al (2008) Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455:1109–1113PubMedCrossRefGoogle Scholar
  127. 127.
    Wikoff WR, Anfora AT, Liu J et al (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 106:3698–3703PubMedCrossRefGoogle Scholar
  128. 128.
    Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC (2003) Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 100:12877–12882PubMedCrossRefGoogle Scholar
  129. 129.
    Wolk K, Witte E, Wallace E et al (2006) IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 36:1309–1323PubMedCrossRefGoogle Scholar
  130. 130.
    Wong JM, de SR, Kendall CW, Emam A, Jenkins DJ (2006) Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 40:235–243PubMedCrossRefGoogle Scholar
  131. 131.
    Wu GD, Chen J, Hoffmann C et al (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105–108PubMedCrossRefGoogle Scholar
  132. 132.
    Wu H-J, Ivanov II, Darce D et al (2010) Gut residing filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–823PubMedCrossRefGoogle Scholar
  133. 133.
    Yokote H, Miyake S, Croxford JL, Oki S, Mizusawa H, Yamamura T (2008) NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora. Am J Pathol 173:1714–1723PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of NeuroimmunologyMax Planck Institute of NeurobiologyMartinsriedGermany

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