The “Microflora Hypothesis” of Allergic Disease

  • Andrew Shreiner
  • Gary B. Huffnagle
  • Mairi C. Noverr
Part of the Advances in Experimental Medicine and Biology book series (volume 635)


Predisposition to allergic disease is a complex function of an individual’s genetic background and, as is the case with multi-gene traits, environmental factors have important phenotypic consequences. Over a span of decades, a dramatic increase in the prevalence of allergic disease in westernized populations suggests the occurrence of critical changes in environmental pressures. Recently, it has been shown that the microbiota (i.e. microflora) of allergic individuals differs from that of non-allergic ones and that differences are detectable prior to the onset of atopy, consistent with a possible causative role. Features of the westernized lifestyle that are known to alter the microbiota, such as antibiotics and diet, are also associated with allergy in humans. In this chapter, we discuss the “Microflora Hypothesis” for allergy which predicts that an “unhealthy” microbiota composition, now commonly found within westernized communities, contributes to the development of allergy and conversely, that restoring a “healthy” microbiota, perhaps through probiotic supplementation, may prevent the development of allergy or even treat existing disease. In testing this hypothesis, our laboratory has recently reported that mice can develop allergic airway responses if their microbiota is altered at the time of first allergen exposure.


Atopic Dermatitis Allergic Disease Atopic Disease Intestinal Microflora Oral Tolerance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Mannino DM, Homa DM, Pertowski CA et al. Surveillance for asthma-United States, 1960–1995. MMWR CDC Surveill Summ 1998; 47(1):1–27.PubMedGoogle Scholar
  2. 2.
    Beasley R, Crane J, Lai CK et al. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000; 105(2 Pt 2):S466–472.CrossRefGoogle Scholar
  3. 3.
    Burney PG, Luczynska C, Chinn S et al. The European Community Respiratory Health Survey. Eur Respir J 1994; 7(5):954–960.PubMedGoogle Scholar
  4. 4.
    Asher MI, Keil U, Anderson HR et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8(3):483–491.PubMedCrossRefGoogle Scholar
  5. 5.
    Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases. Clin Exp Allergy 2005; 35(12):1511–1520.PubMedCrossRefGoogle Scholar
  6. 6.
    Upton MN, McConnachie A, McSharry C et al. Intergenerational 20 year trends in the prevalence of asthma and hay fever in adults: the Midspan family study surveys of parents and offspring. BMJ 2000; 321(7253):88–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Peat JK, van den Berg RH, Green WF et al. Changing prevalence of asthma in Australian children. BMJ 1994; 308(6944):1591–1596.PubMedGoogle Scholar
  8. 8.
    Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998; 12(2):315–335.CrossRefGoogle Scholar
  9. 9.
    Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351(9111):1225–1232.Google Scholar
  10. 10.
    Gerrard JW, Geddes CA, Reggin PL et al. Serum IgE levels in white and metis communities in Saskatchewan. Ann Allergy 1976; 37(2):91–100.PubMedGoogle Scholar
  11. 11.
    Strachan DP. Hay fever, hygiene and household size. BMJ 1989; 299(6710):1259–1260.PubMedGoogle Scholar
  12. 12.
    Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347(12):911–920.PubMedCrossRefGoogle Scholar
  13. 13.
    Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001; 1(1):69–75.PubMedCrossRefGoogle Scholar
  14. 14.
    Umetsu DT, McIntire JJ, Akbari O et al. Asthma: an epidemic of dysregulated immunity. Nat Immunol 2002; 3(8):715–720.PubMedCrossRefGoogle Scholar
  15. 15.
    Rook GA, Brunet LR. Give us this day our daily germs. Biologist (London) 2002; 49(4):145–149.Google Scholar
  16. 16.
    Rook GA, Brunet LR. Old friends for breakfast. Clin Exp Allergy 2005; 35(7):841–842.PubMedCrossRefGoogle Scholar
  17. 17.
    Bjorksten B. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 2004; 25(3–4):257–270.PubMedCrossRefGoogle Scholar
  18. 18.
    Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol 2004; 12(12):562–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Noverr MC, Noggle RM, Toews GB et al. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect Immun 2004; 72(9):4996–5003.PubMedCrossRefGoogle Scholar
  20. 20.
    Rautava S, Kalliomaki M, Isolauri E. New therapeutic strategy for combating the increasing burden of allergic disease: Probiotics-A Nutrition, Allergy, Mucosal Immunology and Intestinal Microbiota (NAMI) Research Group report. J Allergy Clin Immunol 2005; 1161):31–37.PubMedCrossRefGoogle Scholar
  21. 21.
    Bjorksten B, Naaber P, Sepp E et al. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999; 29(3):342–346.PubMedCrossRefGoogle Scholar
  22. 22.
    Bjorksten B, Sepp E, Julge K et al. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001; 108(4):516–520.PubMedCrossRefGoogle Scholar
  23. 23.
    He F, Ouwehand AC, Isolauri E et al. Comparison of mucosal adhesion and species identification of bifidobacteria isolated from healthy and allergic infants. FEMS Immunol Med Microbiol 2001; 30(1):43–47.PubMedCrossRefGoogle Scholar
  24. 24.
    Kalliomaki M, Kirjavainen P, Eerola E et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001; 107(1):129–134.PubMedCrossRefGoogle Scholar
  25. 25.
    Kirjavainen PV, Apostolou E, Arvola T et al. Characterizing the composition of intestinal microflora as a prospective treatment target in infant allergic disease. FEMS Immunol Med Microbiol 2001; 32(1):1–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Ouwehand AC, Isolauri E, He F et al. Differences in Bifidobacterium flora composition in allergic and healthy infants. J Allergy Clin Immunol 2001; 108(1):144–145.PubMedCrossRefGoogle Scholar
  27. 27.
    Watanabe S, Narisawa Y, Arase S et al. Differences in fecal microflora between patients with atopic dermatitis and healthy control subjects. J Allergy Clin Immunol 2003; 111(3):587–591.PubMedCrossRefGoogle Scholar
  28. 28.
    Sepp E, Julge K, Mikelsaar M et al. Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children. Clin Exp Allergy 2005; 35(9):1141–1146.PubMedCrossRefGoogle Scholar
  29. 29.
    Mah KW, Bjorksten B, Lee BW et al. Distinct pattern of commensal gut microbiota in toddlers with eczema. Int Arch Allergy Immunol 2006; 140(2):157–163.PubMedCrossRefGoogle Scholar
  30. 30.
    Bottcher MF, Nordin EK, Sandin A et al. Microflora-associated characteristics in faeces from allergic and non-allergic infants. Clin Exp Allergy 2000; 30(11):1590–1596.PubMedCrossRefGoogle Scholar
  31. 31.
    Woodcock A, Moradi M, Smillie FI et al. Clostridium difficile, atopy and wheeze during the first year of life. Pediatr Allergy Immunol 2002; 13(5):357–360.PubMedCrossRefGoogle Scholar
  32. 32.
    Murray CS, Tannock GW, Simon MA et al. Fecal microbiota in sensitized wheezy and nonsensitized nonwheezy children: a nested case-control study. Clin Exp Allergy 2005; 35(2):741–745.PubMedCrossRefGoogle Scholar
  33. 33.
    Voor T, Julge K, Bottcher MF et al. Atopic sensitization and atopic dermatitis in Estonian and Swedish infants. Clin Exp Allergy 2005; 35(2):153–159.PubMedCrossRefGoogle Scholar
  34. 34.
    Fanaro S, Chierici R, Guerrini P et al. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 2003; 91(441):48–55.PubMedGoogle Scholar
  35. 35.
    Tannock GW. Normal Microflora: An Introduction to Microbes Inhabiting the Human Body. London: Chapman and Hall, 1995.Google Scholar
  36. 36.
    Hooper LV. Bacterial contributions to mammalian gut development. Trends Microbiol 2004; 12(3):129–134.PubMedCrossRefGoogle Scholar
  37. 37.
    Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 2004; 4(6):478–485.PubMedCrossRefGoogle Scholar
  38. 38.
    Xu J, Chiang HC, Bjursell MK et al. Message from a human gut symbiont: sensitivity is a prerequisite for sharing. Trends Microbiol 2004; 12(1):21–28.PubMedCrossRefGoogle Scholar
  39. 39.
    Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect Dis 2001; 1(2):101–114.PubMedCrossRefGoogle Scholar
  40. 40.
    Orrhage K, Nord CE. Bifidobacteria and lactobacilli in human health Drugs Exp Clin Res 2000; 26(3):95–111.PubMedGoogle Scholar
  41. 41.
    Sjovall J, Huitfeldt B, Magni L et al. Effect of beta-lactam prodrugs on human intestinal microflora. Scand J Infect Dis Suppl 1986; 49:73–84.PubMedGoogle Scholar
  42. 42.
    Lidbeck A, Nord CE. Lactobacilli and the normal human anaerobic microflora. Clin Infect Dis 1993; 16(Suppl 4):S181–187.PubMedGoogle Scholar
  43. 43.
    van der Waaij D. The ecology of the human intestine and its consequences for overgrowth by pathogens such as Clostridium difficile. Annu Rev Microbiol 1989; 43:69–87.PubMedCrossRefGoogle Scholar
  44. 44.
    Payne S, Gibson G, Wynne A et al. In vitro studies on colonization resistance of the human gut microbiota to Candida albicans and the effects of tetracycline and Lactobacillus plantarum LPK. Curr Issues Intest Microbiol 2003; 4(1):1–8.PubMedGoogle Scholar
  45. 45.
    Guggenbichler JP, Kofler J, Allerberger F. The influence of third-generation cephalosporins on the aerobic intestinal flora. Infection 1985; 13(Suppl 1):S137–139.PubMedCrossRefGoogle Scholar
  46. 46.
    Mulligan ME, Citron DM, McNamara BT et al. Impact of cefoperazone therapy on fecal flora. Antimicrob Agents Chemother 1982; 22(2):226–230.PubMedGoogle Scholar
  47. 47.
    Samonis G, Gikas A, Anaissie EJ et al. Prospective evaluation of effects of broad-spectrum antibiotics on gastrointestinal yeast colonization of humans. Antimicrob Agents Chemother 1993; 37(1):51–53.PubMedGoogle Scholar
  48. 48.
    Tannock GW. Analysis of the intestinal microflora using molecular methods. Eur J Clin Nutr 2002; 56(Suppl 4):S44–49.PubMedCrossRefGoogle Scholar
  49. 49.
    Farooqi IS, Hopkin JM. Early childhood infection and atopic disorder. Thorax 1998; 53(11):927–932.PubMedCrossRefGoogle Scholar
  50. 50.
    von Mutius E, Illi S, Hirsch T et al. Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children. Eur Respir J 1999; 14(1):4–11.CrossRefGoogle Scholar
  51. 51.
    Wjst M, Hoelscher B, Frye C et al. Early antibiotic treatment and later asthma. Eur J Med Res 2001; 6(6):263–271.PubMedGoogle Scholar
  52. 52.
    McKeever TM, Lewis SA, Smith C et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J Allergy Clin Immunol 2002; 109(1):43–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Cullinan P, Harris J, Mills P et al. Early prescriptions of antibiotics and the risk of allergic disease in adults: a cohort study. Thorax 2004; 59(1):11–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Ahn KM, Lee MS, Hong SJ et al. Fever, use of antibiotics and acute gastroenteritis during infancy as risk factors for the development of asthma in Korean school-age children. J Asthma 2005; 42(9):745–750.PubMedCrossRefGoogle Scholar
  55. 55.
    Celedon JC, Fuhlbrigge A, Rifas-Shiman S et al. Antibiotic use in the first year of life and asthma in early childhood. Clin Exp Allergy 2004; 34(7):1011–1016.PubMedCrossRefGoogle Scholar
  56. 56.
    Illi S, tvon Mutius E, Lau S et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 2001; 322(7283):390–395.PubMedCrossRefGoogle Scholar
  57. 57.
    Wickens K, Pearce N, Crane J et al. Antibiotic use in early childhood and the development of asthma. Clin Exp Allergy 1999; 29(6):766–771.PubMedCrossRefGoogle Scholar
  58. 58.
    Droste JH, Wieringa MH, Weyler JJ et al. Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease? Clin Exp Allergy 2000; 30(11):1547–1553.PubMedCrossRefGoogle Scholar
  59. 59.
    Johnson CC, Ownby DR, Alford SH et al. Antibiotic exposure in early infancy and risk for childhood atopy. J Allergy Clin Immunol 2005; 115(6):1218–1224.PubMedCrossRefGoogle Scholar
  60. 60.
    Cohet C, Cheng S, MacDonald C et al. Infections, medication use and the prevalence of symptoms of asthma, rhinitis and eczema in childhood. J Epidemiol Community Health 2004; 58(10):852–857.PubMedCrossRefGoogle Scholar
  61. 61.
    Celedon JC, Litonjua AA, Ryan L et al. Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. Am J Respir Crit Care Med 2002; 166(1):72–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Bremner SA, Carey IM, DeWilde S et al. Early-life exposure to antibacterials and the subsequent development of hayfever in childhood in the UK: case-control studies using the General Practice Research Database and the Doctors’ Independent Network. Clin Exp Allergy 2003; 33(11):1518–1525.PubMedCrossRefGoogle Scholar
  63. 63.
    Rettger LF, Horton GD. A comparitive study of the intestinal flora of white rats kept on experimental and ordinary mixed diets. Zentralbl Bakteriol 1914; 73:362–372.Google Scholar
  64. 64.
    Dubos R, Schaedler R, Stephens M. The effect of antibacterial drugs on the fecal flora of mice. J Exp Med 1963; 117:231–243.CrossRefPubMedGoogle Scholar
  65. 65.
    Dubos R. Man Adapting. New Haven: Yale University Press, 1971.Google Scholar
  66. 66.
    Fogarty A, Britton J. Nutritional issues and asthma. Curr Opin Pulm Med 2000; 6(1):86–89.PubMedCrossRefGoogle Scholar
  67. 67.
    Greene LS. Asthma, oxidant stress and diet. Nutrition 1999; 15(11–12):899–907.PubMedCrossRefGoogle Scholar
  68. 68.
    Black PN. The prevalence of allergic disease and linoleic acid in the diet. J Allergy Clin Immunol 1999; 103(2 Pt 1):351–352.PubMedCrossRefGoogle Scholar
  69. 69.
    La Vecchia C, Decarli A, Pagano R. Vegetable consumption and risk of chronic disease. Epidemiology Mar 1998; 9(2):208–210.CrossRefGoogle Scholar
  70. 70.
    Weiland SK, von Mutius E, Husing A et al. Intake of trans fatty acids and prevalence of childhood asthma and allergies in Europe. ISAAC Steering Committee. Lancet 1999; 353(9169):2040–2041.PubMedCrossRefGoogle Scholar
  71. 71.
    Strom K, Janzon L, Mattisson I et al. Asthma but not smoking-related airflow limitation is associated with a high fat diet in men: results from the population study “Men born in 1914”, Malmo, Sweden. Monaldi Arch Chest Dis 1996; 51(1):16–21.PubMedGoogle Scholar
  72. 72.
    Morotomi M, Kawai Y, Mutai M. Intestinal microflora in rats: isolation and characterization of strictly anaerobic bacteria requiring long-chain fatty acids. Appl Environ Microbiol 1976; 31(4):475–480.PubMedGoogle Scholar
  73. 73.
    Eyssen H, Parmentier G. Biohydrogenation of sterols and fatty acids by the intestinal microflora. Am J Clin Nutr 1974; 27(11):1329–1340.PubMedGoogle Scholar
  74. 74.
    Eyssen H, Piessens-Denef M, Parmentier G. Role of the cecum in maintaing 5 steroid-and fatty acid-reducing activity of the rat intestinal microflora. J Nutr 1972; 102(11):1501–1511.PubMedGoogle Scholar
  75. 75.
    Eyssen H. Role of the gut microflora in metabolism of lipids and sterols. Proc Nutr Soc 1973; 32(2):59–63.PubMedCrossRefGoogle Scholar
  76. 76.
    Martindale S, McNeill G, Devereux G et al. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 2005; 17(2):121–128.Google Scholar
  77. 77.
    Alm JS, Swartz J, Lilja G et al. Atopy in children of families with an anthroposophic lifestyle. Lancet 1999; 353(9163):1485–1488.PubMedCrossRefGoogle Scholar
  78. 78.
    Alm JS, Swartz J, Bjorksten B et al. An anthroposophic lifestyle and intestinal microflora in infancy. Pediatr Allergy Immunol 2002; 13(6):402–411.PubMedCrossRefGoogle Scholar
  79. 79.
    Chase MW. Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol 1946; 61:257–259.Google Scholar
  80. 80.
    Boyaka PN, Tafaro A, Fischer R et al. Therapeutic manipulation of the immune system: enhancement of innate and adaptive mucosal immunity. Curr Pharm Des 2003; 9(24):1965–1972.PubMedCrossRefGoogle Scholar
  81. 81.
    Macaubas C, DeKruyff RH, Umetsu DT. Respiratory tolerance in the protection against asthma. Curr Drug Targets Inflamm Allergy 2003; 2(2):175–186.PubMedCrossRefGoogle Scholar
  82. 82.
    Mayer L, Shao L. Therapeutic potential of oral tolerance. Nat Rev Immunol 2004; 4(6):407–419.PubMedCrossRefGoogle Scholar
  83. 83.
    Sudo N, Sawamura S, Tanaka K et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997; 159(4):1739–1745.PubMedGoogle Scholar
  84. 84.
    Kiyono H, Fukuyama S. NALT-versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol 2004; 4(9):699–710.PubMedCrossRefGoogle Scholar
  85. 85.
    Eberl G. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat Rev Immunol 2005; 5(5):413–420.PubMedCrossRefGoogle Scholar
  86. 86.
    Bauer H, Horowitz RE, Levenson SM et al. The response of the lymphatic tissue to the microbial flora. Studies on germfree mice. Am J Pathol 1963; 42:471–483.PubMedGoogle Scholar
  87. 87.
    Manolios N, Geczy CL, Schrieber L. High endothelial venule morphology and function are inducible in germ-free mice: a possible role for interferon-gamma. Cell Immunol 1988; 117(1):136–151.PubMedCrossRefGoogle Scholar
  88. 88.
    Hamada H, Hiroi T, Nishiyama Y et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J Immunol 2002; 168(1):57–64.PubMedGoogle Scholar
  89. 89.
    Fukuyama S, Hiroi T, Yokota Y et al. Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR and NIK signaling pathways but requires the Id2 gene and CD3(−) CD4(+) CD45(+) cells. Immunity 2002; 17(1):31–40.PubMedCrossRefGoogle Scholar
  90. 90.
    Rescigno M, Urbano M, Valzasina B et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001; 2(4):361–367.PubMedCrossRefGoogle Scholar
  91. 91.
    Kerneis S, Bogdanova A, Kraehenbuhl JP et al. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 1997; 277(5328):949–952.PubMedCrossRefGoogle Scholar
  92. 92.
    Mowat AM. Dendritic cells and immune responses to orally administered antigens. Vaccine 2005; 23(15):1797–1799.PubMedCrossRefGoogle Scholar
  93. 93.
    Reis e Sousa C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin Immunol 2004; 16(1):27–34.PubMedCrossRefGoogle Scholar
  94. 94.
    Bashir ME, Louie S, Shi HN et al. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J Immunol 2004; 172(11):6978–6987.PubMedGoogle Scholar
  95. 95.
    Mellor AL, Baban B, Chandler PR et al. Cutting edge: CpG oligonucleotides induce splenic CD19+dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T-cell regulatory functions via IFN Type 1 signaling. J Immunol 2005; 175(9):5601–5605.PubMedGoogle Scholar
  96. 96.
    Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+T-cell-mediated suppression by dendritic cells. Science 2003; 299(5609):1033–1036.PubMedCrossRefGoogle Scholar
  97. 97.
    Csencsits KL, Jutila MA, Pascual DW. Nasal-associated lymphoid tissue: phenotypic and functional evidence for the primary role of peripheral node addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site. J Immunol 1999; 163(3):1382–1389.PubMedGoogle Scholar
  98. 98.
    Spalding DM, Griffin JA. Different pathways of differentiation of pre B-cell lines are induced by dendritic cells and T-cells from different lymphoid tissues. Cell 1986; 44(3):507–515.PubMedCrossRefGoogle Scholar
  99. 99.
    Shikina T, Hiroi T, Iwatani K et al. IgA class switch occurs in the organized nasopharynx-and gut-associated lymphoid tissue, but not in the diffuse lamina propria of airways and gut. J Immunol 2004; 172(10):6259–6264.PubMedGoogle Scholar
  100. 100.
    Bowman EP, Kuklin NA, Youngman KR et al. The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells. J Exp Med 2002; 195(2):269–275.PubMedCrossRefGoogle Scholar
  101. 101.
    Fagarasan S, Muramatsu M, Suzuki K et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 2002; 298(5597):1424–1427.PubMedCrossRefGoogle Scholar
  102. 102.
    Masopust D, Vezys V, Marzo AL et al. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291(5512):2413–2417.PubMedCrossRefGoogle Scholar
  103. 103.
    Reinhardt RL, Khoruts A, Merica R et al. Visualizing the generation of memory CD4 T-cells in the whole body. Nature 2001; 410(6824):101–105.PubMedCrossRefGoogle Scholar
  104. 104.
    Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 1988; 140(2):440–445.PubMedGoogle Scholar
  105. 105.
    Homann D, Dyrberg T, Petersen J et al. Insulin in oral immune “tolerance”: a one-amino acid change in the B chain makes the difference. J Immunol 1999; 163(4):1833–1838.PubMedGoogle Scholar
  106. 106.
    Nagler-Anderson C, Bober LA, Robinson ME et al. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci USA 1986; 83(19):7443–7446.PubMedCrossRefGoogle Scholar
  107. 107.
    Russo M, Nahori MA, Lefort J et al. Suppression of asthma-like responses in different mouse strains by oral tolerance. Am J Respir Cell Mol Biol 2001; 24(5):518–526.PubMedGoogle Scholar
  108. 108.
    Husby S, Mestecky J, Moldoveanu Z et al. Oral tolerance in humans. T-cell but not B-cell tolerance after antigen feeding. J Immunol 1994; 152(9):4663–4670.PubMedGoogle Scholar
  109. 109.
    Eyles JE, Spiers ID, Williamson ED et al. Tissue distribution of radioactivity following intranasal administration of radioactive microspheres. J Pharm Pharmacol 2001; 53(5):601–607.PubMedCrossRefGoogle Scholar
  110. 110.
    Pickett TE, Pasetti MF, Galen JE et al. In vivo characterization of the murine intranasal model for assessing the immunogenicity of attenuated Salmonella enterica serovar Typhi strains as live mucosal vaccines and as live vectors. Infect Immun 2000; 68(1):205–213.PubMedGoogle Scholar
  111. 111.
    Southam DS, Dolovich M, O’Byrne PM et al. Distribution of intranasal instillations in mice: effects of volume, time, body position and anesthesia. Am J Physiol Lung Cell Mol Physiol 2002; 282(4):L833–839.PubMedGoogle Scholar
  112. 112.
    Maeda Y, Noda S, Tanaka K et al. The failure of oral tolerance induction is functionally coupled to the absence of T-cells in Peyer’s patches under germfree conditions. Immunobiology 2001; 204(4):442–457.PubMedCrossRefGoogle Scholar
  113. 113.
    Sudo N, Yu XN, Aiba Y et al. An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy 2002; 32(7):1112–1116.PubMedCrossRefGoogle Scholar
  114. 114.
    Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci USA 1994; 91(14):6688–6692.PubMedCrossRefGoogle Scholar
  115. 115.
    Mitchison NA. Induction of Immunological Paralysis in Two Zones of Dosage. Proc R Soc Lond B Biol Sci 1964; 161:275–292.PubMedGoogle Scholar
  116. 116.
    Barone KS, Jain SL, Michael JG. Effect of in vivo depletion of CD4+ and CD8+ cells on the induction and maintenance of oral tolerance. Cell Immunol 1995; 163(1):19–29.PubMedCrossRefGoogle Scholar
  117. 117.
    Garside P, Steel M, Liew FY et al. CD4+ but not CD8+ T-cells are required for the induction of oral tolerance. Int Immunol 1995; 7(3):501–504.PubMedCrossRefGoogle Scholar
  118. 118.
    Yoshida H, Hachimura S, Hirahara K et al. Induction of oral tolerance in splenocyte-reconstituted SCID mice. Clin Immunol Immunopathol 1998; 87(3):282–291.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang X, Izikson L, Liu L et al. Activation of CD25(+)CD4(+) regulatory T-cells by oral antigen administration. J Immunol 2001; 167(8):4245–4253.PubMedGoogle Scholar
  120. 120.
    von Boehmer H. Mechanisms of suppression by suppressor T-cells. Nat Immunol 2005; 6(4):338–344.CrossRefGoogle Scholar
  121. 121.
    Viney JL, Mowat AM, O’Malley JM et al. Expanding dendritic cells in vivo enhances the induction of oral tolerance. J Immunol 1998;160(12):5815–5825.PubMedGoogle Scholar
  122. 122.
    Hall G., Houghton CG, Rahbek JU et al. Suppression of allergen reactive Th2 mediated responses and pulmonary eosinophilia by intranasal administration of an immunodominant peptide is linked to IL-10 production. Vaccine 2003; 21(5–6):549–561.PubMedCrossRefGoogle Scholar
  123. 123.
    Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001; 2(8):725–731.PubMedCrossRefGoogle Scholar
  124. 124.
    de Heer HJ, Hammad H, Soullie T et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 2004; 200(1):89–98.PubMedCrossRefGoogle Scholar
  125. 125.
    Bennett CL, Christie J, Ramsdell F et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27(1):20–21.PubMedCrossRefGoogle Scholar
  126. 126.
    Chatila TA, Blaeser F, Ho N et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 2000; 106(12):R75–81.PubMedCrossRefGoogle Scholar
  127. 127.
    Wildin RS, Ramsdell F, Peake J et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27(1):18–20.PubMedCrossRefGoogle Scholar
  128. 128.
    Bellinghausen I, Klostermann B, Knop J et al. Human CD4+CD25+ T-cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J Allergy Clin Immunol 2003; 111(4):862–868.PubMedCrossRefGoogle Scholar
  129. 129.
    Grindebacke H, Wing K, Andersson AC et al. Defective suppression of Th2 cytokines by CD4CD25 regulatory T-cells in birch allergics during birch pollen season. Clin Exp Allergy 2004; 34(9):1364–1372.PubMedCrossRefGoogle Scholar
  130. 130.
    Ling EM, Smith T, Nguyen XD et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 2004; 363(9409):608–615.PubMedCrossRefGoogle Scholar
  131. 131.
    Calderone RA, ed. Candida and Candidiasis. Washington, DC: ASM Press, 2001:472.Google Scholar
  132. 132.
    Giuliano M, Barza M, Jacobus NV et al. Effect of broad-spectrum parenteral antitiotics on composition of intestinal microflora of humans. Antimicrob Agents Chemother 1987; 31(2):202–206.PubMedGoogle Scholar
  133. 133.
    Huang MY, Wang JH. Impact of antibiotic use on fungus colonization in patients hospitalized due to fever. J Microbiol Immunol Infect 2003; 36(2):123–128.PubMedGoogle Scholar
  134. 134.
    Maraki S, Margioris AN, Orfanoudaki E et al. Effects of doxycycline, metronidazole and their combination on Candida species colonization of the human oropharynx, intestinal lumen and vagina. J Chemother 2003; 15(4):369–373.PubMedGoogle Scholar
  135. 135.
    Hoberg KA, Cihlar RL, Calderone RA. Inhibitory effect of cerulenin and sodium butyrate on germination of Candida albicans. Antimicrob Agents Chemother 1983; 24(3):401–408.PubMedGoogle Scholar
  136. 136.
    Noverr MC, Huffnagle GB. Regulation of Candida albicans morphogenesis by fatty acid metabolites. Infect Immun 2004; 72(11):6206–6210.PubMedCrossRefGoogle Scholar
  137. 137.
    Sjogren J, Magnusson J, Broberg A et al. Antifungal 3-hydroxy fatty acids from Lactobacillus plantarum MiLAB 14. Appl Environ Microbiol 2003; 69(12):7554–7557.PubMedCrossRefGoogle Scholar
  138. 138.
    Magnusson J, Strom K, Roos S et al. Broad and complex antifungal activity among environmental isolates of lactic acid bacteria. FEMS Microbiol Lett 2003; 219(1):129–135.PubMedCrossRefGoogle Scholar
  139. 139.
    Hogan DA, Vik A, Kolter R. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol Microbiol 2004; 54(5):1212–1223.PubMedCrossRefGoogle Scholar
  140. 140.
    Bohmig GA, Krieger PM, Saemann MD et al. n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids. Immunology 1997; 92(2):234–243.PubMedCrossRefGoogle Scholar
  141. 141.
    Saemann MD, Bohmig GA, Osterreicher CH 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(15):2380–2382.PubMedGoogle Scholar
  142. 142.
    Cavaglieri CR, Nishiyama A, Fernandes LC et al. Differential effects of short-chain fatty acids on proliferation and production of pro-and anti-inflammatory cytokines by cultured lymphocytes. Life Sci 2003; 73(13):1683–1690.PubMedCrossRefGoogle Scholar
  143. 143.
    Andoh A, Bamba T, Sasaki M. Physiological and anti-inflammatory roles of dietary fiber and butyrate in intestinal functions. JPEN J Parenter Enteral Nutr 1999; 23(5 Suppl):S70–73.PubMedCrossRefGoogle Scholar
  144. 144.
    Saemann MD, Bohmig GA, Zlabinger GJ. Short-chain fatty acids: bacterial mediators of a balanced host-microbial relationship in the human gut. Wien Klin Wochenschr 2002; 114(8–9):289–300.PubMedGoogle Scholar
  145. 145.
    Noverr MC, Huffnagle GB. Regulation of Candida albicans morphogenesis by fatty acid metabolites. Infect Immun 2004; 72(11):6206–10.PubMedCrossRefGoogle Scholar
  146. 146.
    Noverr MC, Falkowski NR, McDonald RA et al. The development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen and IL-13. Infect Immun 2005; 73(1):30–38.PubMedCrossRefGoogle Scholar
  147. 147.
    Hunt JR, Martinelli R, Adams VC et al. Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model. Clin Exp Allergy 2005; 35(5):685–690.PubMedCrossRefGoogle Scholar
  148. 148.
    Adams VC, Hunt JR, Martinelli R et al. Mycobacterium vaccae induces a population of pulmonary CD11c+ cells with regulatory potential in allergic mice. Eur J Immunol 2004; 34(3):631–638.PubMedCrossRefGoogle Scholar
  149. 149.
    Zuany-Amorim C, Sawicka E, Manlius C et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002; 8(6):625–629.PubMedCrossRefGoogle Scholar
  150. 150.
    Kitagaki K, Businga TR, Kline JN. Oral administration of CpG-ODNs suppresses antigen-induced asthma in mice. Clin Exp Immunol 2006; 143(2):249–259.PubMedCrossRefGoogle Scholar
  151. 151.
    Blumer N, Herz U, Wegmann M et al. Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 2005; 35(3):397–402.PubMedCrossRefGoogle Scholar
  152. 152.
    Eisenbarth SC, Piggott DA, Huleatt JW et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T-helper cell type 2 responses to inhaled antigen. J Exp Med 2002; 196(12):1645–1651.PubMedCrossRefGoogle Scholar
  153. 153.
    Gerhold K, Blumchen K, Bock A et al. Endotoxins prevent murine IgE production, T(H) 2 immune responses and development of airway eosinophilia but not airway hyperreactivity. J Allergy Clin Immunol 2002; 110(1):110–116.PubMedCrossRefGoogle Scholar
  154. 154.
    Racila DM, Kline JN. Perspectives in asthma: molecular use of microbial products in asthma prevention and treatment. J Allergy Clin Immunol 2005; 116(6):1202–1205.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Andrew Shreiner
    • 1
  • Gary B. Huffnagle
    • 1
  • Mairi C. Noverr
    • 2
  1. 1.Department of Internal Medicine Division of Pulmonary and Critical Care MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Immunology and MicrobiologyWayne State University DetroitE. CanfieldUSA

Personalised recommendations