Advertisement

The microbial environment and its influence on asthma prevention in early life

  • Erika von Mutius
    Correspondence
    Corresponding author: Erika von Mutius, MD, MSc, Department of Pediatrics, Dr von Hauner Children's Hospital of Ludwig Maximilian University of Munich, Lindwurmstrasse 4, D-80337 Munich, Germany.
    Affiliations
    Department of Pediatrics, Dr von Hauner Children's Hospital of Ludwig Maximilian University of Munich, Munich, Germany
    Search for articles by this author
Published:January 22, 2016DOI:https://doi.org/10.1016/j.jaci.2015.12.1301
      There is accumulating evidence to suggest that the environmental microbiome plays a significant role in asthma development. The very low prevalence of asthma in populations highly exposed to microbial environments (farm children and Amish populations) highlights its preventive potential. This microbial diversity might be necessary to instruct a well-adapted immune response and regulated inflammatory responses to other inhaled and ingested environmental elements, such as allergens, particles, and viruses. Like the internal gut microbiome, which is increasingly recognized as an important instructor of immune maturation, the external environmental microbiome might shape immune responses on the skin, airway mucosal surfaces, and potentially also the gut early in life. The diversity of the external microbial world will ensure that of the many maladapted pathways leading to asthma development, most, if not all, will be counterbalanced. Likewise, important contributors to asthma, such as allergen sensitization and allergic manifestations early in life, are being suppressed. Thus the facets of innate immunity targeted by microbes and their compounds and metabolites might be the master switch to asthma and allergy protection, which has been found in environments rich in microbial exposures.

      Key words

      Abbreviations used:

      ALEX (Protection Against the Development of Atopy: Relevant Factors from Farming Environments), aOR (Adjusted odds ratio), EPS (Extracellular polysaccharide), PAMP (Pathogen-associated molecular pattern), PARSIFAL (Prevention of Allergy–Risk Factors for Sensitisation in Children Related to Farming and Anthroposophic Lifestyle)
      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Journal of Allergy and Clinical Immunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barberan A.
        • Dunn R.R.
        • Reich B.J.
        • Pacifici K.
        • Laber E.B.
        • Menninger H.L.
        • et al.
        The ecology of microscopic life in household dust.
        Proc Biol Sci. 2015; 282
        • Rappe M.S.
        • Giovannoni S.J.
        The uncultured microbial majority.
        Annu Rev Microbiol. 2003; 57: 369-394
        • van Strien R.T.
        • Engel R.
        • Holst O.
        • Bufe A.
        • Eder W.
        • Waser M.
        • et al.
        Microbial exposure of rural school children, as assessed by levels of n-acetyl-muramic acid in mattress dust, and its association with respiratory health.
        J Allergy Clin Immunol. 2004; 113: 860-867
        • Schram-Bijkerk D.
        • Doekes G.
        • Douwes J.
        • Boeve M.
        • Riedler J.
        • Ublagger E.
        • et al.
        Bacterial and fungal agents in house dust and wheeze in children: the PARSIFAL study.
        Clin Exp Allergy. 2005; 35: 1272-1278
        • Woese C.R.
        • Fox G.E.
        Phylogenetic structure of the prokaryotic domain: the primary kingdoms.
        Proc Natl Acad Sci U S A. 1977; 74: 5088-5090
        • Legatzki A.
        • Rosler B.
        • von Mutius E.
        Microbiome diversity and asthma and allergy risk.
        Curr Allergy Asthma Rep. 2014; 14: 466
        • Turnbaugh P.J.
        • Hamady M.
        • Yatsunenko T.
        • Cantarel B.L.
        • Duncan A.
        • Ley R.E.
        • et al.
        A core gut microbiome in obese and lean twins.
        Nature. 2009; 457: 480-484
      1. A framework for human microbiome research.
        Nature. 2012; 486: 215-221
        • Costello E.K.
        • Lauber C.L.
        • Hamady M.
        • Fierer N.
        • Gordon J.I.
        • Knight R.
        Bacterial community variation in human body habitats across space and time.
        Science. 2009; 326: 1694-1697
        • Barberan A.
        • Ladau J.
        • Leff J.W.
        • Pollard K.S.
        • Menninger H.L.
        • Dunn R.R.
        • et al.
        Continental-scale distributions of dust-associated bacteria and fungi.
        Proc Natl Acad Sci U S A. 2015; 112: 5756-5761
        • Maier R.M.
        • Palmer M.W.
        • Andersen G.L.
        • Halonen M.J.
        • Josephson K.C.
        • Maier R.S.
        • et al.
        Environmental determinants of and impact on childhood asthma by the bacterial community in household dust.
        Appl Environ Microbiol. 2010; 76: 2663-2667
        • Kettleson E.M.
        • Adhikari A.
        • Vesper S.
        • Coombs K.
        • Indugula R.
        • Reponen T.
        Key determinants of the fungal and bacterial microbiomes in homes.
        Environ Res. 2015; 138: 130-135
        • Giovannangelo M.
        • Gehring U.
        • Nordling E.
        • Oldenwening M.
        • Terpstra G.
        • Bellander T.
        • et al.
        Determinants of house dust endotoxin in three European countries—the AIRALLERG study.
        Indoor Air. 2007; 17: 70-79
        • Rullo V.E.
        • Rizzo M.C.
        • Arruda L.K.
        • Sole D.
        • Naspitz C.K.
        Daycare centers and schools as sources of exposure to mites, cockroach, and endotoxin in the city of Sao Paulo.
        Brazil. J Allergy Clin Immunol. 2002; 110: 582-588
        • Wouters I.M.
        • Douwes J.
        • Doekes G.
        • Thorne P.S.
        • Brunekreef B.
        • Heederik D.J.
        Increased levels of markers of microbial exposure in homes with indoor storage of organic household waste.
        Appl Environ Microbiol. 2000; 66: 627-631
        • Normand A.C.
        • Sudre B.
        • Vacheyrou M.
        • Depner M.
        • Wouters I.M.
        • Noss I.
        • et al.
        Airborne cultivable microflora and microbial transfer in farm buildings and rural dwellings.
        Occup Environ Med. 2011; 68: 849-855
        • Waser M.
        • Schierl R.
        • von Mutius E.
        • Maisch S.
        • Carr D.
        • Riedler J.
        • et al.
        Determinants of endotoxin levels in living environments of farmers' children and their peers from rural areas.
        Clin Exp Allergy. 2004; 34: 389-397
        • Hilty M.
        • Burke C.
        • Pedro H.
        • Cardenas P.
        • Bush A.
        • Bossley C.
        • et al.
        Disordered microbial communities in asthmatic airways.
        PLoS One. 2010; 5: e8578
        • Charlson E.S.
        • Bittinger K.
        • Haas A.R.
        • Fitzgerald A.S.
        • Frank I.
        • Yadav A.
        • et al.
        Topographical continuity of bacterial populations in the healthy human respiratory tract.
        Am J Respir Crit Care Med. 2011; 184: 957-963
        • Morris A.
        • Beck J.M.
        • Schloss P.D.
        • Campbell T.B.
        • Crothers K.
        • Curtis J.L.
        • et al.
        Comparison of the respiratory microbiome in healthy nonsmokers and smokers.
        Am J Respiratory Crit Care Med. 2013; 187: 1067-1075
        • Huang Y.J.
        • Nelson C.E.
        • Brodie E.L.
        • Desantis T.Z.
        • Baek M.S.
        • Liu J.
        • et al.
        Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma.
        J Allergy Clin Immunol. 2011; 127 (e1-3): 372-381
        • Cardenas P.A.
        • Cooper P.J.
        • Cox M.J.
        • Chico M.
        • Arias C.
        • Moffatt M.F.
        • et al.
        Upper airways microbiota in antibiotic-naive wheezing and healthy infants from the tropics of rural Ecuador.
        PLoS One. 2012; 7: e46803
        • Green B.J.
        • Wiriyachaiporn S.
        • Grainge C.
        • Rogers G.B.
        • Kehagia V.
        • Lau L.
        • et al.
        Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma.
        PLoS One. 2014; 9: e100645
        • Marri P.R.
        • Stern D.A.
        • Wright A.L.
        • Billheimer D.
        • Martinez F.D.
        Asthma-associated differences in microbial composition of induced sputum.
        J Allergy Clin Immunol. 2013; 131 (e1-3): 346-352
        • Bisgaard H.
        • Hermansen M.N.
        • Buchvald F.
        • Loland L.
        • Halkjaer L.B.
        • Bonnelykke K.
        • et al.
        Childhood asthma after bacterial colonization of the airway in neonates.
        N Engl J Med. 2007; 357: 1487-1495
        • Vissing N.H.
        • Chawes B.L.
        • Bisgaard H.
        Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates.
        Am J Respir Crit Care Med. 2013; 188: 1246-1252
        • Singer F.
        • Luchsinger I.
        • Inci D.
        • Knauer N.
        • Latzin P.
        • Wildhaber J.H.
        • et al.
        Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma.
        Allergy. 2013; 68: 531-538
        • Ursell L.K.
        • Clemente J.C.
        • Rideout J.R.
        • Gevers D.
        • Caporaso J.G.
        • Knight R.
        The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites.
        J Allergy Clin Immunol. 2012; 129: 1204-1208
        • Arnold I.C.
        • Dehzad N.
        • Reuter S.
        • Martin H.
        • Becher B.
        • Taube C.
        • et al.
        Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells.
        J Clin Invest. 2011; 121: 3088-3093
        • Trompette A.
        • Gollwitzer E.S.
        • Yadava K.
        • Sichelstiel A.K.
        • Sprenger N.
        • Ngom-Bru C.
        • et al.
        Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.
        Nat Med. 2014; 20: 159-166
        • Mazmanian S.K.
        • Liu C.H.
        • Tzianabos A.O.
        • Kasper D.L.
        An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.
        Cell. 2005; 122: 107-118
        • Steinmeyer S.
        • Lee K.
        • Jayaraman A.
        • Alaniz R.C.
        Microbiota metabolite regulation of host immune homeostasis: a mechanistic missing link.
        Curr Allergy Asthma Rep. 2015; 15: 24
        • Fujimura K.E.
        • Demoor T.
        • Rauch M.
        • Faruqi A.A.
        • Jang S.
        • Johnson C.C.
        • et al.
        House dust exposure mediates gut microbiome lactobacillus enrichment and airway immune defense against allergens and virus infection.
        Proc Natl Acad Sci U S A. 2014; 111: 805-810
        • von Mutius E.
        Allergies, infections and the hygiene hypothesis—the epidemiological evidence.
        Immunobiology. 2007; 212: 433-439
        • Genuneit J.
        • Strachan D.P.
        • Buchele G.
        • Weber J.
        • Loss G.
        • Sozanska B.
        • et al.
        The combined effects of family size and farm exposure on childhood hay fever and atopy.
        Pediatr Allergy Immunol. 2013; 24: 293-298
        • Krämer U.
        • Heinrich J.
        • Wjst M.
        • Wichmann H.E.
        Age of entry to day nursery and allergy in later childhood.
        Lancet. 1999; 353: 450-454
        • Ball T.M.
        • Castro-Rodriguez J.A.
        • Griffith K.A.
        • Holberg C.J.
        • Martinez F.D.
        • Wright A.L.
        Siblings, day-care attendance, and the risk of asthma and wheezing during childhood.
        N Engl J Med. 2000; 343: 538-543
        • Celedon J.C.
        • Milton D.K.
        • Ramsey C.D.
        • Litonjua A.A.
        • Ryan L.
        • Platts-Mills T.A.
        • et al.
        Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood.
        J Allergy Clin Immunol. 2007; 120: 144-149
        • Chen C.M.
        • Gehring U.
        • Wickman M.
        • Hoek G.
        • Giovannangelo M.
        • Nordling E.
        • et al.
        Domestic cat allergen and allergic sensitisation in young children.
        Int J Hyg Environ Health. 2008; 211: 337-344
        • Ownby D.R.
        • Johnson C.C.
        • Peterson E.L.
        Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.
        JAMA. 2002; 288: 963-972
        • Braun-Fahrlander C.
        • Gassner M.
        • Grize L.
        • Neu U.
        • Sennhauser F.H.
        • Varonier H.S.
        • et al.
        Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community. SCARPOL team. Swiss study on childhood allergy and respiratory symptoms with respect to air pollution.
        Clin Exp Allergy. 1999; 29: 28-34
        • Riedler J.
        • Eder W.
        • Oberfeld G.
        • Schreuer M.
        Austrian children living on a farm have less hay fever, asthma and allergic sensitization.
        Clin Exp Allergy. 2000; 30: 194-200
        • Von Ehrenstein O.S.
        • Von Mutius E.
        • Illi S.
        • Baumann L.
        • Bohm O.
        • von Kries R.
        Reduced risk of hay fever and asthma among children of farmers.
        Clin Exp Allergy. 2000; 30: 187-193
        • Riedler J.
        • Braun-Fahrlander C.
        • Eder W.
        • Schreuer M.
        • Waser M.
        • Maisch S.
        • et al.
        Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey.
        Lancet. 2001; 358: 1129-1133
        • von Mutius E.
        • Vercelli D.
        Farm living: effects on childhood asthma and allergy.
        Nat Rev Immunol. 2010; 10: 861-868
        • Ege M.J.
        • Frei R.
        • Bieli C.
        • Schram-Bijkerk D.
        • Waser M.
        • Benz M.R.
        • et al.
        Not all farming environments protect against the development of asthma and wheeze in children.
        J Allergy Clin Immunol. 2007; 119: 1140-1147
        • Fuchs O.
        • Genuneit J.
        • Latzin P.
        • Buchele G.
        • Horak E.
        • Loss G.
        • et al.
        Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide.
        J Allergy Clin Immunol. 2012; 130: 382-388.e6
        • Holbreich M.
        • Genuneit J.
        • Weber J.
        • Braun-Fahrlander C.
        • Waser M.
        • von Mutius E.
        Amish children living in northern indiana have a very low prevalence of allergic sensitization.
        J Allergy Clin Immunol. 2012; 129: 1671-1673
      2. Hrusch CL, Stein MM, Igartua C, Holbreich M, Thorne PS, Vercelli D, et al. Differences in immune regulatory phenotypes in two U.S. farming populations mirror differential asthma and atopy risk: studies in Amish and Hutterite school children. C101 allergic airway inflammation and hyperresponsiveness: novel mechanisms and therapy. American Thoracic Society International Conference, Denver, May 15-20 2015; 2015, p. A5171-A.

        • Radon K.
        • Windstetter D.
        • Eckart J.
        • Dressel H.
        • Leitritz L.
        • Reichert J.
        • et al.
        Farming exposure in childhood, exposure to markers of infections and the development of atopy in rural subjects.
        Clin Exp Allergy. 2004; 34: 1178-1183
        • von Mutius E.
        • Radon K.
        Living on a farm: impact on asthma induction and clinical course.
        Immunol Allergy Clin North Am. 2008; 28 (ix-x): 631-647
        • Douwes J.
        • Travier N.
        • Huang K.
        • Cheng S.
        • McKenzie J.
        • Le Gros G.
        • et al.
        Lifelong farm exposure may strongly reduce the risk of asthma in adults.
        Allergy. 2007; 62: 1158-1165
        • Sozanska B.
        • Blaszczyk M.
        • Pearce N.
        • Cullinan P.
        Atopy and allergic respiratory disease in rural Poland before and after accession to the European union.
        J Allergy Clin Immunol. 2014; 133: 1347-1353
        • Sozanska B.
        • Macneill S.J.
        • Kajderowicz-Kowalik M.
        • Danielewicz H.
        • Wheatley M.
        • Newman Taylor A.J.
        • et al.
        Atopy and asthma in rural Poland: A paradigm for the emergence of childhood respiratory allergies in Europe.
        Allergy. 2007; 62: 394-400
        • Viinanen A.
        • Munhbayarlah S.
        • Zevgee T.
        • Narantsetseg L.
        • Naidansuren T.
        • Koskenvuo M.
        • et al.
        The protective effect of rural living against atopy in Mongolia.
        Allergy. 2007; 62: 272-280
        • Tse K.
        • Horner A.A.
        Defining a role for ambient TLR ligand exposures in the genesis and prevention of allergic diseases.
        Semin Immunopathol. 2008; 30: 53-62
        • Wickens K.
        • Lane J.M.
        • Fitzharris P.
        • Siebers R.
        • Riley G.
        • Douwes J.
        • et al.
        Farm residence and exposures and the risk of allergic diseases in New Zealand children.
        Allergy. 2002; 57: 1171-1179
        • Illi S.
        • Depner M.
        • Genuneit J.
        • Horak E.
        • Loss G.
        • Strunz-Lehner C.
        • et al.
        Protection from childhood asthma and allergy in alpine farm environments—the GABRIEL advanced studies.
        J Allergy Clin Immunol. 2012; 129: 1470-1477.e6
        • Downs S.H.
        • Marks G.B.
        • Mitakakis T.Z.
        • Leuppi J.D.
        • Car N.G.
        • Peat J.K.
        Having lived on a farm and protection against allergic diseases in Australia.
        Clin Exp Allergy. 2001; 31: 570-575
        • Zekveld C.
        • Bibakis I.
        • Bibaki-Liakou V.
        • Pedioti A.
        • Dimitroulis I.
        • Harris J.
        • et al.
        The effects of farming and birth order on asthma and allergies.
        Eur Respir J. 2006; 28: 82-88
        • Roduit C.
        • Wohlgensinger J.
        • Frei R.
        • Bitter S.
        • Bieli C.
        • Loeliger S.
        • et al.
        Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis.
        J Allergy Clin Immunol. 2011; 127: 179-185.e1
        • Pfefferle P.I.
        • Buchele G.
        • Blumer N.
        • Roponen M.
        • Ege M.J.
        • Krauss-Etschmann S.
        • et al.
        Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: the PASTURE study.
        J Allergy Clin Immunol. 2010; 125 (e1-3): 108-115
        • Ege M.J.
        • Bieli C.
        • Frei R.
        • van Strien R.T.
        • Riedler J.
        • Ublagger E.
        • et al.
        Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children.
        J Allergy Clin Immunol. 2006; 117: 817-823
        • Loss G.
        • Bitter S.
        • Wohlgensinger J.
        • Frei R.
        • Roduit C.
        • Genuneit J.
        • et al.
        Prenatal and early-life exposures alter expression of innate immunity genes: the PASTURE cohort study.
        J Allergy Clin Immunol. 2012; 130: 523-530.e9
        • Perkin M.R.
        • Strachan D.P.
        Which aspects of the farming lifestyle explain the inverse association with childhood allergy?.
        J Allergy Clin Immunol. 2006; 117: 1374-1381
        • Waser M.
        • Michels K.B.
        • Bieli C.
        • Floistrup H.
        • Pershagen G.
        • von Mutius E.
        • et al.
        Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe.
        Clin Exp Allergy. 2007; 37: 661-670
        • Loss G.
        • Apprich S.
        • Waser M.
        • Kneifel W.
        • Genuneit J.
        • Buchele G.
        • et al.
        The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study.
        J Allergy Clin Immunol. 2011; 128: 766-773.e4
        • Loss G.
        • Depner M.
        • Ulfman L.H.
        • van Neerven R.J.
        • Hose A.J.
        • Genuneit J.
        • et al.
        Consumption of unprocessed cow's milk protects infants from common respiratory infections.
        J Allergy Clin Immunol. 2015; 135: 56-62
        • Gehring U.
        • Spithoven J.
        • Schmid S.
        • Bitter S.
        • Braun-Fahrlander C.
        • Dalphin J.C.
        • et al.
        Endotoxin levels in cow's milk samples from farming and non-farming families—the PASTURE study.
        Environ Int. 2008; 34: 1132-1136
        • Kirchner B.
        • Pfaffl M.
        • Dumpler J.
        • von Mutius E.
        • Ege M.
        MiRNA in native and processed cow's milk and its implication for the “farm milk effect” on asthma.
        J Allergy Clin Immunol. 2015 Dec 18; (pii: S0091-6749(15)01634-6. [Epub ahead of print])
        • Brick T.
        • Schober Y.
        • Böcking C.
        • Pekkanen J.
        • Genuneit J.
        • Loss G.
        • et al.
        Ω-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk.
        J Allergy Clin Immunol. 2016; ([E-pub ahead of print])
        • Bringolf-Isler B.
        • Graf E.
        • Waser M.
        • Genuneit J.
        • von Mutius E.
        • Loss G.
        • et al.
        Association of physical activity, asthma, and allergies: a cohort of farming and nonfarming children.
        J Allergy Clin Immunol. 2013; 132: 743-746.e4
        • Stocklin L.
        • Loss G.
        • von Mutius E.
        • Weber J.
        • Genuneit J.
        • Horak E.
        • et al.
        Health-related quality of life in rural children living in four European countries: the GABRIEL study.
        Int J Public Health. 2013; 58: 355-366
        • Ege M.J.
        • Herzum I.
        • Buchele G.
        • Krauss-Etschmann S.
        • Lauener R.P.
        • Bitter S.
        • et al.
        Specific ige to allergens in cord blood is associated with maternal immunity to Toxoplasma gondii and rubella virus.
        Allergy. 2008; 63: 1505-1511
        • Ege M.J.
        • Strachan D.P.
        • Cookson W.O.
        • Moffatt M.F.
        • Gut I.
        • Lathrop M.
        • et al.
        Gene-environment interaction for childhood asthma and exposure to farming in central Europe.
        J Allergy Clin Immunol. 2011; 127 (e1-4): 138-144
        • Horak Jr., F.
        • Studnicka M.
        • Gartner C.
        • Veiter A.
        • Tauber E.
        • Urbanek R.
        • et al.
        Parental farming protects children against atopy: longitudinal evidence involving skin prick tests.
        Clin Exp Allergy. 2002; 32: 1155-1159
        • Lampi J.
        • Koskela H.
        • Hartikainen A.L.
        • Ramasamy A.
        • Couto Alves A.
        • Jarvelin M.R.
        • et al.
        Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland.
        BMJ Open. 2015; 5: e007350
        • Lluis A.
        • Depner M.
        • Gaugler B.
        • Saas P.
        • Casaca V.I.
        • Raedler D.
        • et al.
        Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood.
        J Allergy Clin Immunol. 2014; 133: 551-559
        • Schaub B.
        • Liu J.
        • Hoppler S.
        • Schleich I.
        • Huehn J.
        • Olek S.
        • et al.
        Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells.
        J Allergy Clin Immunol. 2009; 123: 774-782.e5
        • Pfefferle P.I.
        • Sel S.
        • Ege M.J.
        • Buchele G.
        • Blumer N.
        • Krauss-Etschmann S.
        • et al.
        Cord blood allergen-specific IgE is associated with reduced IFN-γ production by cord blood cells: the protection against allergy-study in rural environments (PASTURE) study.
        J Allergy Clin Immunol. 2008; 122: 711-716
        • Loss G.J.
        • Depner M.
        • Hose A.J.
        • Genuneit J.
        • Karvonen A.M.
        • Hyvarinen A.
        • et al.
        The early development of wheeze: environmental determinants and genetic susceptibility at 17q21.
        Am J Respir Crit Care Med. 2015; ([Epub ahead of print])
        • Radon K.
        • Windstetter D.
        • Poluda A.L.
        • Mueller B.
        • von Mutius E.
        • Koletzko S.
        • et al.
        Contact with farm animals in early life and juvenile inflammatory bowel disease: a case-control study.
        Pediatrics. 2007; 120: 354-361
        • Timm S.
        • Svanes C.
        • Janson C.
        • Sigsgaard T.
        • Johannessen A.
        • Gislason T.
        • et al.
        Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in northern Europe.
        Eur J Epidemiol. 2014; 29: 429-437
        • Parks C.G.
        • Cooper G.S.
        • Dooley M.A.
        • Park M.M.
        • Treadwell E.L.
        • Gilkeson G.S.
        Childhood agricultural and adult occupational exposures to organic dusts in a population-based case-control study of systemic lupus erythematosus.
        Lupus. 2008; 17: 711-719
        • Radon K.
        • Windstetter D.
        • Poluda D.
        • Hafner R.
        • Thomas S.
        • Michels H.
        • et al.
        Exposure to animals and risk of oligoarticular juvenile idiopathic arthritis: a multicenter case-control study.
        BMC Musculoskelet Disord. 2010; 11: 73
        • Radon K.
        • Windstetter D.
        • Solfrank S.
        • von Mutius E.
        • Nowak D.
        • Schwarz H.P.
        • et al.
        Exposure to farming environments in early life and type 1 diabetes: a case-control study.
        Diabetes. 2005; 54: 3212-3216
        • Braun-Fahrlander C.
        • Riedler J.
        • Herz U.
        • Eder W.
        • Waser M.
        • Grize L.
        • et al.
        Environmental exposure to endotoxin and its relation to asthma in school-age children.
        N Engl J Med. 2002; 347: 869-877
        • Ege M.J.
        • Mayer M.
        • Normand A.C.
        • Genuneit J.
        • Cookson W.O.
        • Braun-Fahrlander C.
        • et al.
        Exposure to environmental microorganisms and childhood asthma.
        N Engl J Med. 2011; 364: 701-709
        • Hanski I.
        • von Hertzen L.
        • Fyhrquist N.
        • Koskinen K.
        • Torppa K.
        • Laatikainen T.
        • et al.
        Environmental biodiversity, human microbiota, and allergy are interrelated.
        Proc Natl Acad Sci U S A. 2012; 109: 8334-8339
        • Fyhrquist N.
        • Ruokolainen L.
        • Suomalainen A.
        • Lehtimaki S.
        • Veckman V.
        • Vendelin J.
        • et al.
        Acinetobacter species in the skin microbiota protect against allergic sensitization and inflammation.
        J Allergy Clin Immunol. 2014; 134: 1301-1309.e11
        • Rompa S.
        • Janke T.
        • Schwaiger K.
        • Mayer M.
        • Bauer J.
        • Genuneit J.
        • et al.
        Association of childhood asthma and fungal taxa in environmental dust samples.
        Eur Respir J. 2014; 44
        • Debarry J.
        • Garn H.
        • Hanuszkiewicz A.
        • Dickgreber N.
        • Blumer N.
        • von Mutius E.
        • et al.
        Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties.
        J Allergy Clin Immunol. 2007; 119: 1514-1521
        • Conrad M.L.
        • Ferstl R.
        • Teich R.
        • Brand S.
        • Blumer N.
        • Yildirim A.O.
        • et al.
        Maternal tlr signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii f78.
        J Exp Med. 2009; 206: 2869-2877
        • Hagner S.
        • Harb H.
        • Zhao M.
        • Stein K.
        • Holst O.
        • Ege M.J.
        • et al.
        Farm-derived gram-positive bacterium Staphylococcus sciuri w620 prevents asthma phenotype in HDM- and OVA-exposed mice.
        Allergy. 2013; 68: 322-329
        • Peters M.
        • Kauth M.
        • Scherner O.
        • Gehlhar K.
        • Steffen I.
        • Wentker P.
        • et al.
        Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization.
        J Allergy Clin Immunol. 2010; 126 (e1-4): 648-656
        • Mendy A.
        • Gasana J.
        • Vieira E.R.
        • Forno E.
        • Patel J.
        • Kadam P.
        • et al.
        Endotoxin exposure and childhood wheeze and asthma: a meta-analysis of observational studies.
        J Asthma. 2011; 48: 685-693
        • Thorne P.S.
        • Mendy A.
        • Metwali N.
        • Salo P.
        • Co C.
        • Jaramillo R.
        • et al.
        Endotoxin exposure: predictors and prevalence of associated asthma outcomes in the U.S.
        Am J Respir Crit Care Med. 2015; 192: 1287-1297
        • Douwes J.
        • van Strien R.
        • Doekes G.
        • Smit J.
        • Kerkhof M.
        • Gerritsen J.
        • et al.
        Does early indoor microbial exposure reduce the risk of asthma? The prevention and incidence of asthma and mite allergy birth cohort study.
        J Allergy Clin Immunol. 2006; 117: 1067-1073
        • Tischer C.
        • Casas L.
        • Wouters I.M.
        • Doekes G.
        • Garcia-Esteban R.
        • Gehring U.
        • et al.
        Early exposure to bio-contaminants and asthma up to 10 years of age: results of the HITEA study.
        Eur Respir J. 2015; 45: 328-337
        • Lynch S.V.
        • Wood R.A.
        • Boushey H.
        • Bacharier L.B.
        • Bloomberg G.R.
        • Kattan M.
        • et al.
        Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children.
        J Allergy Clin Immunol. 2014; 134: 593-601.e12
        • Mendell M.J.
        • Mirer A.G.
        • Cheung K.
        • Tong M.
        • Douwes J.
        Respiratory and allergic health effects of dampness, mold, and dampness-related agents: a review of the epidemiologic evidence.
        Environ Health Perspect. 2011; 119: 748-756
        • Quansah R.
        • Jaakkola M.S.
        • Hugg T.T.
        • Heikkinen S.A.
        • Jaakkola J.J.
        Residential dampness and molds and the risk of developing asthma: a systematic review and meta-analysis.
        PLoS One. 2012; 7: e47526
        • Kanchongkittiphon W.
        • Mendell M.J.
        • Gaffin J.M.
        • Wang G.
        • Phipatanakul W.
        Indoor environmental exposures and exacerbation of asthma: an update to the 2000 review by the institute of medicine.
        Environ Health Perspect. 2015; 123: 6-20
        • Kercsmar C.M.
        • Dearborn D.G.
        • Schluchter M.
        • Xue L.
        • Kirchner H.L.
        • Sobolewski J.
        • et al.
        Reduction in asthma morbidity in children as a result of home remediation aimed at moisture sources.
        Environ Health Perspect. 2006; 114: 1574-1580
        • Janeway Jr., C.A.
        • Medzhitov R.
        Innate immune recognition.
        Annu Rev Immunol. 2002; 20: 197-216
        • Schaub B.
        • Lauener R.
        • von Mutius E.
        The many faces of the hygiene hypothesis.
        J Allergy Clin Immunol. 2006; 117: 969-977
        • DeMarco M.L.
        • Woods R.J.
        From agonist to antagonist: structure and dynamics of innate immune glycoprotein md-2 upon recognition of variably acylated bacterial endotoxins.
        Mol Immunol. 2011; 49: 124-133
        • Frei R.
        • Roduit C.
        • Bieli C.
        • Loeliger S.
        • Waser M.
        • Scheynius A.
        • et al.
        Expression of genes related to anti-inflammatory pathways are modified among farmers' children.
        PLoS One. 2014; 9: e91097
        • Schuijs M.J.
        • Willart M.A.
        • Vergote K.
        • Gras D.
        • Deswarte K.
        • Ege M.J.
        • et al.
        Farm dust and endotoxin protect against allergy through a20 induction in lung epithelial cells.
        Science. 2015; 349: 1106-1110
        • Schaub B.
        • Vercelli D.
        Environmental protection from allergic diseases: from humans to mice and back.
        Curr Opin Immunol. 2015; 36: 88-93
      3. Gozdz J, Holbreich M, Metwali N, Thorne PS, Sperling AI, Martinez FD, et al. Opposite effects of farming on asthma: mice exposed to Amish and Hutterite environmental products recapitulate asthma protection and risk. B21 translational asthma research. American Thoracic Society International Conference, Denver, May 15-20, 2015; p. A2489-A.