The Use of Microbes and Their Products in Allergy Prevention and Therapy

  • Paolo Maria Matricardi
Part of the Allergy Frontiers book series (ALLERGY, volume 6)


Epidemiological and experimental studies have led to the hypothesis that stimulation of the immune system by certain microbial products may prevent or treat allergic diseases. The effects of probiotics, mycobacteria, oligodesoxynucleotides (ISS-ODN), engineered bacteria, lipopolysaccharide derived molecules and helminthic products against allergic diseases have been therefore actively investigated. The term "Probiotics" is referred to living or inactivated organisms that are claimed to exert beneficial effects on health when ingested. The probiotics most commonly used against allergic diseases are lactobacilli and bifidobacteria. Natural exposure to environmental mycobacteria has been suggested as being able to promote Th1-type cytokine responses and has, therefore, been suggested to possibly prevent allergy. It has been hypothesized that administration of saprophytic mycobacteria in childhood could therefore help to prevent or treat allergy. Bacterial and viral genomic DNA is enriched, compared to that of mammals, in unmethylated sequences of cytosine and guanine (CpG motifs). These motifs are recognized by the innate immune system through the Toll-Like-Receptor-9. This stimulation is able to prevent and treat allergic reactions in animal models, and has been tested in trials in humans. Lipopolysaccharide derivatives are molecules obtained by modification of LPS isolated by the outer membranes of gram negative bacteria. A molecule originated from LPS of Salmonella minnesota R595, the Monophosphoryl Lipid A (MPL), has been proposed as an adjuvant for vaccine antigens, and utilized in trials against allergic diseases. Larvae of Trichuris suis have been successfully used to treat an immune disorder, such as inflammatory bowel disease, associated with a disregulation of the immune response at intestinal level and is being examined as a therapy against respiratory allergies. Unfortunately, the outcomes of many of the attempts to translate the hygiene hypothesis in preventive and therapeutic strategies are quite discouraging. The reason for disappointing effects may be our lack of clear understanding of all the events preceding and causing allergic diseases.


Atopic Dermatitis Allergic Disease Allergy Clin Immunol Allergic Conjunctivitis Peanut Protein 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nicaise P, Gleizes A, Sandre C, et al. 1998. Influence of intestinal microflora on murine bone marrow and spleen macrophage precursors. Scand J Immunol 48, 585–591CrossRefPubMedGoogle Scholar
  2. 2.
    Sudo N, Sawamura S, Tanaka K, Kubo C, Koga Y, 1997. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159, 1739–1745PubMedGoogle Scholar
  3. 3.
    Strachan DP, 1989. Hay fever, hygiene and household size. Br Med J 299, 1259–1260CrossRefGoogle Scholar
  4. 4.
    Holt PG, 1995. Environmental factors and primary T-cell sensitisation to inhalant allergens in infancy: reappraisal of the role of infections and air pollution. Pediatr Allergy Immunol 6, 1–10CrossRefPubMedGoogle Scholar
  5. 5.
    Matricardi PM, 1997. Infections preventing atopy: facts and new questions. Allergy 52, 879–882CrossRefPubMedGoogle Scholar
  6. 6.
    Romagnani S, 1994. Regulation of the development of type 2 T-helper cells in allergy. Curr Opin Immunol 6, 838–846CrossRefPubMedGoogle Scholar
  7. 7.
    Yazdanbakhsh M, Kremsner PG, van Ree R, 2002. Allergy, parasites and the hygiene hypothesis. Science 296, 490–494CrossRefPubMedGoogle Scholar
  8. 8.
    Mills KH, McGuirk P, 2004. Antigen-specific regulatory T cells—their induction and role in infection. Semin Immunol 16, 107–117CrossRefPubMedGoogle Scholar
  9. 9.
    EAACI Task Force 7, 2003. Microbial products in allergy prevention and therapy. Allergy 58, 461–471CrossRefGoogle Scholar
  10. 10.
    Shirakawa T, Enomoto T, Shimazu S, Hopkin JM, 1997. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79CrossRefPubMedGoogle Scholar
  11. 11.
    Matricardi PM, Yazdanbakhsh M, 2003. Mycobacteria and atopy, 6 years later: a fascinating, still unfinished, business. Clin Exp Allergy 33, 717–720CrossRefPubMedGoogle Scholar
  12. 12.
    Gruber C, Paul KP, 2002. Tuberculin reactivity and allergy. Allergy 57, 277–280CrossRefPubMedGoogle Scholar
  13. 13.
    Rook GA, Stanford JL, 1998. Give us this day our daily germs. Immunol Today 19, 113–116CrossRefPubMedGoogle Scholar
  14. 14.
    Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C, 2002. Suppression of airway eosinophilia by killed Mycobacterium vac-cae-induced allergen-specific regulatory T-cells. Nat Med 8, 625–629CrossRefPubMedGoogle Scholar
  15. 15.
    Arkwright PD, David TJ, 2003. Effect of Mycobacterium vaccae on atopic dermatitis in children of different ages. Br J Dermatol 149, 1029–1034CrossRefPubMedGoogle Scholar
  16. 16.
    Hunt JR, Martinelli R, Adams VC, Rook GA, Brunet LR, 2005. Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model. Clin Exp Allergy 35, 685–690CrossRefPubMedGoogle Scholar
  17. 17.
    Herz U, Gerhold K, Gruber C, Braun A, Wahn U, Renz H, Paul K, 1998. BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. J Allergy Clin Immunol 102, 867–874CrossRefPubMedGoogle Scholar
  18. 18.
    Erb KJ, Holloway JW, Sobeck A, Moll H, Le Gros G, 1998. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J Exp Med 187, 561–189CrossRefPubMedGoogle Scholar
  19. 19.
    Tukenmez F, Bahceciler NN, Barlan IB, Basaran MM, 1999. Effect of pre-immunization by killed Mycobacterium bovis and vaccae on immunoglobulin E response in ovalbumin-sensi-tized newborn mice. Pediatr Allergy Immunol 10, 107–111CrossRefPubMedGoogle Scholar
  20. 20.
    Ozdemir C, Akkoc T, Bahceciler NN, Kucukercan D, Barlan IB, Basaran MM, 2003. Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma. Clin Exp Allergy 33, 266–270CrossRefPubMedGoogle Scholar
  21. 21.
    Arkwright PD, David TJ, 2001. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 107, 531–534CrossRefPubMedGoogle Scholar
  22. 22.
    Berth-Jones J, Arkwright PD, Marasovic D, Savani N, Aldridge CR, Leech SN, Morgan C, Clark SM, Ogilvie S, Chopra S, Harper JI, Smith CH, Rook GA, Friedmann PS, 2006. Killed Mycobacterium vaccae suspension in children with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial. Clin Exp Allergy 36, 1115–1121CrossRefPubMedGoogle Scholar
  23. 23.
    Shirtcliffe PM, Easthope SE, Cheng S, Weatherall M, Tan PL, Le Gros G, Beasley R, 2001. The effect of delipidated deglycolipidated (DDMV) and heat-killed Mycobacterium vaccae in asthma. Am J Respir Crit Care Med 163, 1410–1414PubMedGoogle Scholar
  24. 24.
    Shirtcliffe PM, Goldkorn A, Weatherall M, Tan PL, Beasley R, 2003. Pilot study of the safety and effect of intranasal delipidated acid-treated Mycobacterium vaccae in adult asthma. Respirology 8, 497–503CrossRefPubMedGoogle Scholar
  25. 25.
    Cavallo GP, Elia M, Giordano D, Baldi C, Cammarota R, 2002. Decrease of specific and total IgE levels in allergic patients after BCG vaccination: preliminary report. Arch Otolaryngol Head Neck Surg 128, 1058–1060PubMedGoogle Scholar
  26. 26.
    Choi IS, Koh YI, 2002. Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial. Ann Allergy Asthma Immunol 88, 584–591PubMedCrossRefGoogle Scholar
  27. 27.
    Choi IS, Koh YI, 2003. Effects of BCG revaccination on asthma. Allergy 58, 1114–1116CrossRefPubMedGoogle Scholar
  28. 28.
    Shirtcliffe PM, Easthope SE, Weatherall M, Beasley R, 2004. Effect of repeated intradermal injections of heat-inactivated Mycobacterium bovis bacillus Calmette-Guerin in adult asthma. Clin Exp Allergy 34, 207–212CrossRefPubMedGoogle Scholar
  29. 29.
    Schrezenmeier J, de Vrese M, 2001. Probiotics, prebiotics, and synbiotics – approaching a definition. Am J Clin Nutr 73, 361S–364SGoogle Scholar
  30. 30.
    Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E, 2001. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 107, 129–134CrossRefPubMedGoogle Scholar
  31. 31.
    Watanabe S, Narisawa Y, Arase S, Okamatsu H, Ikenaga T, Tajiri Y, Kumemura M, 2003. Differences in fecal microflora between patients with atopic dermatitis and healthy control subjects. J Allergy Clin Immunol 111, 587–591CrossRefPubMedGoogle Scholar
  32. 32.
    Sepp E, Julge K, Mikelsaar M, Bjorksten B, 2005. Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children. Clin Exp Allergy 35, 1141–1146CrossRefPubMedGoogle Scholar
  33. 33.
    Laiho K, Ouwehand A, Salminen S, Isolauri E, 2002. Inventing probiotic functional foods for patients with allergic disease. Ann Allergy Asthma Immunol 89(6 Suppl 1), 75–82PubMedGoogle Scholar
  34. 34.
    Adlerberth I, Strachan DP, Matricardi PM, Ahrné S, Orfei L, Åberg N, Perkin MR, Tripodi S, Hesselmar B, Saalman H, Coates AR, Bonnano CL, Panetta V, Wold AE 2007. Gut microbiota and development of atopic eczema in three European birth cohorts. J Allergy Clin Immunol 120:343–350CrossRefPubMedGoogle Scholar
  35. 35.
    Matricardi PM, 2002. Probiotics against allergy: data, doubts, and perspectives. Allergy 57, 185–187CrossRefPubMedGoogle Scholar
  36. 36.
    Global Strategy for Asthma Management and Prevention. Washington DC: National Institutes of Health, National Heart, Lung, and Blood Institute, 2002: NIH Publication No. 02-3659, p.99Google Scholar
  37. 37.
    Flohr C, Pascoe D, Williams HC, 2005. Atopic dermatitis and the hygiene hypothesis: too clean to be true? Br J Dermatol 152, 202–216CrossRefPubMedGoogle Scholar
  38. 38.
    Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M, 2007. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 119, 192–198CrossRefPubMedGoogle Scholar
  39. 39.
    Taylor AL, Dunstan JA, Prescott SL, 2007. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 119, 184–191CrossRefPubMedGoogle Scholar
  40. 40.
    Rosenfeldt V, Benfeldt E, Nielsen SD, Michaelsen KF, Jeppesen DL, Valerius A, Paerregaard A, 2003. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol 111, 389–395CrossRefPubMedGoogle Scholar
  41. 41.
    Viljanen M, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M, 2005. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy 60, 494–500CrossRefPubMedGoogle Scholar
  42. 42.
    Grüber C, Wendt M, Lau S, Kulig M, Wahn U, Werfel T, Niggemann B, 2005. Randomized placebo-controlled trial of Lactobacillus rhamnosus GG as treatment of mild to moderate atopic dermatitis in infancy. J Allergy Clin Immunol 117, S239CrossRefGoogle Scholar
  43. 43.
    Weston S, Halbert A, Richmond P, Prescott SL, 2005. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child 90, 892–897CrossRefPubMedGoogle Scholar
  44. 44.
    Brouwer ML, Wolt-Plompen SA, Dubois AE, van der Heide S, Jansen DF, Hoijer MA, Kauffman HF, Duiverman EJ, 2006. No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial. Clin Exp Allergy 36(7), 899–906CrossRefPubMedGoogle Scholar
  45. 45.
    Lee TT, Morisset M, Astier C, Moneret-Vautrin DA, Cordebar V, Beaudouin E, Codreanu F, Bihain BE, Kanny G, 2007. Contamination of probiotic preparations with milk allergens can cause anaphylaxis in children with cow's milk allergy. J Allergy Clin Immunol 119, 746–747CrossRefPubMedGoogle Scholar
  46. 46.
    Raz E, Tighe H, Sato Y, Corr M, Dudler JA, Roman M, et al. 1996. Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc Natl Acad Sci U S A 93, 5141–5145CrossRefPubMedGoogle Scholar
  47. 47.
    Krieg AM, 2002. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20, 709–760CrossRefPubMedGoogle Scholar
  48. 48.
    Iwasaki A, Medzhitov R, 2004. Toll-like receptor control of the adaptive immune responses. Nat Immunol 5, 987–995CrossRefPubMedGoogle Scholar
  49. 49.
    Horner AA, Van Uden JH, Zubeldia JM, Broide D, Raz E, 2001. DNA-based immunothera-peutics for the treatment of allergic disease. Immunology Reviews 179, 102–118CrossRefGoogle Scholar
  50. 50.
    Horner AA, Nguyen MD, Ronaghy A, Cinman N, Verbeek S, Raz E, 2000. DNA-based vaccination reduces the risk of lethal anaphylactic hypersensitivity in mice. J Allergy Clin Immunol 106, 349–356CrossRefPubMedGoogle Scholar
  51. 51.
    Magone MT, Chan CC, Beck L, Whitcup SM, Raz E, 2000. Systemic or mucosal administration of immunostimulatory DNA inhibits early and late phases of murine allergic conjunctivitis. Eur J Immunol 30, 1841–1850CrossRefPubMedGoogle Scholar
  52. 52.
    Krieg AM, 2006. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5, 471–484CrossRefPubMedGoogle Scholar
  53. 53.
    Parronchi P, Brugnolo F, Annunziato F, Manuelli C, Sampognaro S, Mavilia C, Romagnani S, Maggi E, 1999. Phosphorothioate oligodeoxynucleotides promote the in vitro development of human allergen-specific CD4+ T cells into Th1 effectors. J Immunol 163, 5946–5953PubMedGoogle Scholar
  54. 54.
    Bohle B, Jahn-Schmid B, Maurer D, Kraft D, Ebner C, 1999. Oligodeoxynucleotides containing CpG motifs induce IL-12, IL-18 and IFN-gamma production in cells from allergic individuals and inhibit IgE synthesis in vitro. Eur J Immunol 29, 2344–2353CrossRefPubMedGoogle Scholar
  55. 55.
    Simons FE, Shikishima Y, Van Nest G, Eiden JJ, HayGlass KT, 2004. Selective immune redirection in humans with ragweed allergy by injecting Amb a1 linked to immunostimulatory DNA. J Allergy Clin Immunol 113, 1144–1151CrossRefPubMedGoogle Scholar
  56. 56.
    Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q, 2004. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol 113, 235–241CrossRefPubMedGoogle Scholar
  57. 57.
    Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, Eiden JJ, et al. 2000. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 106, 124–134CrossRefPubMedGoogle Scholar
  58. 58.
    Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D, 2006. Immune tolerance network group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355, 1445–1455Google Scholar
  59. 59.
    Busse W, Gross G, Korenblat P, Nayak N, Tarpay M, Levitt D, 2006. Phase 2/3 study of the novel vaccine Amb a 1 immunostimulatory oligodeoxyribonucleotide conjugate AIC in ragweed allergic adults. J Allergy Clin Immunol 117, S88–S89CrossRefGoogle Scholar
  60. 60.
    Seymour SM, Chowdhury BA, 2007. Immunotherapy with a ragweed vaccine. N Engl J Med 356, 86CrossRefPubMedGoogle Scholar
  61. 61.
    Drachenberg KJ, Wheeler AW, Stuebner P, Horak F, 2001. A well-tolerated grass pollen specific allergy vaccine containing a novel adjuvant, Monophosphoryl Lipid A reduces allergic symptoms after only four preseasonal injections. Allergy 56, 498–505CrossRefPubMedGoogle Scholar
  62. 62.
    von Baehr V, Hermes A, von Baehr R, Scherf HP, Volk HD, Fischer von Weikersthal-Drachenberg KJ, Woroniecki S, 2005. Allergoid-specific T-cell reaction as a measure of the immunological response to specific immunotherapy (SIT) with a Th1-adjuvanted allergy vaccine. J Investig Allergol Clin Immunol 15, 234–241Google Scholar
  63. 63.
    Puggioni F, Durham SR, Francis JN, 2005. Monophosphoryl lipid A (MPL) promotes allergen-induced immune deviation in favour of Th1 responses. Allergy 60, 678–684CrossRefPubMedGoogle Scholar
  64. 64.
    Weinstock J, Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV, 2005. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 128, 825–832CrossRefPubMedGoogle Scholar
  65. 65.
    Wilson MS, Taylor MD, Balic A, Finney CA, Lamb JR, Maizels RM, 2005. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 202, 1199–1212CrossRefPubMedGoogle Scholar
  66. 66.
    Falcone FH, Pritchard DI, 2005. Parasite role and reversal: worms on trial. Trends in Parasitol 21, 157–160CrossRefGoogle Scholar
  67. 67.
    Li XM, Srivastava K, Grishin A, Huang CK, Schofield B, Burks W, Sampson HA, 2003. Persistent protective effect of heat-killed Escherichia coli producing “engineered,” recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol 112, 159–167CrossRefPubMedGoogle Scholar
  68. 68.
    Matricardi PM, Bonini S, 2000. Mimicking microbial ‘education’ of the immune system: a strategy to revert the epidemic trend of atopy and allergic asthma? Respir Res 1, 129–132CrossRefPubMedGoogle Scholar
  69. 69.
    Feleszko W, Jaworska J, Hamelmann E, 2006. Toll-like receptors – novel targets in allergic airway disease (probiotics, friends and relatives). Eur J Pharmacol 533(1–3), 308–318CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Department of Pediatric Pneumology and ImmunologyCharité – UniversitätsmedizinBerlinGermany

Personalised recommendations