Journal of Infection (2014) xx, 1e3
www.elsevierhealth.com/journals/jinf
The intestinal microbiota and allergic asthma Marie-Claire Arrieta a, Brett Finlay a,b,* Michael Smith Laboratories, 301 e 2185 East Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z4 b Department of Microbiology and Immunology, 2350 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z4 a
Accepted 18 July 2014 Available online - - -
KEYWORDS Asthma; Microbiota; Hygiene hypothesis; Regulatory T cells
Summary There is increasing evidence that environmental changes are involved in the sharp increase in asthma incidence, as well as with other immune-mediated diseases. This increase matches the introduction of modern life advances such as antibiotics and caesarean sections. Several epidemiological studies provide convincing evidence that a lack of exposure to microbes early in life is associated with later development of allergic asthma. In addition, animal studies have shown that early life modulation of the intestinal microbiota with antibiotics has profound effects in the immune cellular mechanisms that lead to asthma. By describing some of the most relevant human and animal studies in this field, we explore the concept that significant perturbations of the intestinal and perhaps the lung microbiota are a cause of allergic asthma. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Asthma and the hygiene hypothesis Asthma is a multifactorial immune-mediated disease consisting of bronchial hyper-responsiveness and chronic airway inflammation. The symptoms of asthma range from mild episodes of airway obstruction to very severe and recurrent symptoms kindred to chronic obstructive pulmonary disease (COPD) that are difficult and costly to treat.1
Asthma affects 5e16% of people worldwide2 and its incidence has steadily increased since the mid 1900s.3 There are several other immune-mediated and autoimmune disorders that, like asthma, have increased in prevalence since the post WWII era. This common feature is one of the main factors that led to the generation of the hygiene hypothesis. This hypothesis, introduced for the first time 25 years ago,4 describes the sharp increase in these disorders
* Corresponding author. 301 e 2185 East Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4. Tel.: þ1 604 822 2210; fax: þ1 604 822 9830. E-mail address: [email protected] (B. Finlay). http://dx.doi.org/10.1016/j.jinf.2014.07.015 0163-4453/ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
2 as a result of modern life advances, such as antibiotics, vaccinations, caesarean sections, increased sanitation, etc. These societal and medical changes have shifted the ecology of our mucosal microbial communities, reduced early childhood infections and led to an imbalanced development of our immune system. The pathogenesis of asthma has genetic and environmental components. Gene wide association studies (GWAS) have reported many gene loci associated with the disease, however, most loci do not explain the largest proportion of the heritability of asthma.5 The genetic component in asthma is considered to be polygenetic, which may explain the heterogeneity of asthma phenotypes in humans.5 Studies regarding the environmental exposures of asthma patients have yielded significant information about the role of the environment in asthma. Children raised in farms within developed countries are significantly less likely to develop asthma than children raised in non-farm rural areas, or in cities.6,7 Young children that attend day care facilities are also less likely to develop asthma during school years.8 These studies are part of an ever-expanding group of research reports that associate early life events that alter the mucosal microbiota (pre and perinatal antibiotics, formula feeding, caesarean sections, perinatal stress, etc.) with an increased risk of atopy or asthma.
What constitutes a healthy microbiota? Although a logical and critically important question to ask, there is very little consensus in terms of the taxonomic composition of the microbiota in the healthy human body. The microbiota e known as the collection of bacteria, archaea, fungi, protozoa and viruses e inhabits our skin surface and mucosae. The human gastrointestinal tract is heavily colonized by 104e1013 cells/ml, with the colon harbouring the majority of cells and the most biodiverse microbial ecosystem.9 There is great intra and inter-individual microbial taxonomic variability, however, metabolomics analysis revealed that the microbial metabolic pathways remain highly conserved between individuals, suggesting that different microbiotas serve similar functions.9 Previously considered a sterile organ, high-throughput sequencing methods have also shown the presence of a resident lung microbiota.10,11 However, the studies that aim to characterize the lung microbiome are scarce and they vary greatly in the methodology used and data obtained, making it very early yet to understand the compositional and functional aspects of the lung microbiome. Until then, it remains speculative e although logical e to consider that the resident lung microbiota may also play an important role in the lung immune development and the pathogenesis of asthma. While it remains very complicated to answer whether a healthy microbiome can be described taxonomically, it may be more likely that the general microbial composition is less important than the balance between certain microbial groups that confer immune homeostasis. In human asthma studies there is evidence of microbial dysbiosis in the intestine12e14 and the lung, even in patients not under corticosteroid treatment.10,11,15 A common observation in these studies is the reduction in intestinal
M.-C. Arrieta, B. Finlay bacterial diversity, as well as the an alteration of the Firmicutes:Bacteroides ratios, two of the most important phyla in the human intestinal microbiota. However, dysbiosis can be a product of the inflammatory response in asthma, and it is through animal studies that a causal relationship between the microbiota and asthma is being explored.
Microbial dysbiosis as a cause of asthma Germ-free animal models of asthma exhibit an exacerbated phenotype16,17 which can be ameliorated upon bacterial colonization.18,19 Studies from our laboratory have shown that treatment with vancomycin, but not streptomycin lead to an increase in asthma severity.20,21 Analysis of the intestinal microbiota of the vancomycin-treated mice revealed a marked increase in Lactobacillaceae family members and a reduction in Bacteroides, suggesting that perhaps the increase in the former group and/or an underrepresentation of the latter group is involved in directing the immune response towards an allergic phenotype. Other bacterial groups that have been associated with an increased asthma phenotype are members of the Clostridium genus.22 Interestingly, our studies also suggest that there may be a ‘window of opportunity’ during which shifts of the intestinal microbiota can lead to disease. In the murine asthma model, vancomycin only results in increased asthma when given to neonate mice shortly after birth and before weaning. This and other studies suggest that it is during early life that the intestinal microbiota may play a role in asthma pathogenesis and that later shifts may not cause disease.23 Animal models of asthma have also provided with possible immune mechanisms that drives pathogenesis from the intestinal tract into the lung. Vancomycin-treated mice showed a decrease in regulatory T cells (Tregs) in the gut and an increase in IgE.20 Tregs have been shown to expand in the colon of mice upon exposure with clostridial strains, preventing colitis.22 Invariant natural killer T (iNKT) cells may also play a role in microbiota-driven asthma. These cells accumulate in the colonic lamina propria and the lung of germ-free mice with an exacerbated asthma phenotype. Upon bacterial colonization, there is a marked reduction of iNKT cell accumulation in the gut and lung mucosae, as well as a reduction in expression of the chemokine ligand CXCL16, a known recruiter of iNKT cells. Remarkably, the microbiota induces a reduction of hypermethylation of the gene for CXCL16, suggesting that the microbiota regulates the immune response via epigenetic mechanisms.23 In another study, animals treated with a strong cocktail of antibiotics showed an obliteration of the resident intestinal microbiota and increased lung inflammation associated with high IgE titers and elevated numbers of circulating basophils.17 The authors suggest that members of the microbiota downregulate the expression of IgE via MyD88 signalling in B cells, and that the significant reduction of microbial signals increase IgE production, which drives basophilopoeisis in the bone marrow. These studies are only a partial snapshot of the many cellular events that transfer immunological information from the intestinal mucosa to the other mucosal sites and
Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
Intestinal microbiota and allergic asthma
3
considerable effort is still needed to fully comprehend the series of events that lead to asthma development. 10.
Future directions Epidemiological and animal studies have provided important data that support the hygiene hypothesis. However, while the hygiene hypothesis may explain the origin of these disorders, little is known to date on what constitutes a healthy intestinal microbiome and more importantly, which microbial groups are essential for immune homeostasis. Manipulation of the microbiota with specific microbial groups, microbial products, or dietary components that favour the growth of particular bacteria will likely begin to be tested as therapeutical strategies to prevent allergic disease. The challenge for future research will be to determine whether microbiota manipulation is an effective way to treat disease, since most of the animal studies point to microbial modulation of the immune system as a very early event in the life of the host.
11.
12.
13.
14.
Conflict of interest 15.
The authors have no conflict of interest to report.
Acknowledgements The authors thank Dr. Yanet Valdez for her critical review of this manuscript. The authors are funded by a Team Grant from the Canadian Institutes of Health Research (CIHR), 108029.
16.
17.
References 1. Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet 2002 Oct 26;360(9342):1313e22. PubMed PMID: 12414223. 2. Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001e2010. NCHS Data Brief 2012 May;94:1e8. PubMed PMID: 22617340. 3. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N. Engl J Med 2006 Nov 23;355(21):2226e35. PubMed PMID: 17124020. 4. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989 Nov 18;299(6710):1259e60. PubMed PMID: 2513902. Pubmed Central PMCID: 1838109. Epub 1989/11/18. eng. 5. Martinez FD, Vercelli D. Asthma. Lancet 2013 Oct 19; 382(9901):1360e72. PubMed PMID: 24041942. 6. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C, et al. Exposure to environmental microorganisms and childhood asthma. N. Engl J Med 2011 Feb 24; 364(8):701e9. PubMed PMID: 21345099. 7. Wlasiuk G, Vercelli D. The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease. Curr Opin Allergy Clin Immunol 2012 Oct;12(5):461e6. PubMed PMID: 22892709. 8. Custovic A, Rothers J, Stern D, Simpson A, Woodcock A, Wright AL, et al. Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J Allergy Clin Immunol 2011 Feb;127(2). 390e397.e1ee9. PubMed PMID: 21281869. Pubmed Central PMCID: 3075116. 9. Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature 2012 Jun 14;
18.
19.
20.
21.
22.
23.
486(7402):207e14. PubMed PMID: 22699609. Pubmed Central PMCID: 3564958. Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, et al. Disordered microbial communities in asthmatic airways. PloS One 2010;5(1):e8578. PubMed PMID: 20052417. Pubmed Central PMCID: 2798952. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011 Feb;127(2). 372e381.e1ee3. PubMed PMID: 21194740. Pubmed Central PMCID: 3037020. Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001 Oct;108(4):516e20. PubMed PMID: 11590374. Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001 Jan;107(1):129e34. PubMed PMID: 11150002. van Nimwegen FA, Penders J, Stobberingh EE, Postma DS, Koppelman GH, Kerkhof M, et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J Allergy Clin Immunol 2011 Nov;128(5). 948e955.e1ee3. PubMed PMID: 21872915. Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, et al. Childhood asthma after bacterial colonization of the airway in neonates. N. Engl J Med 2007 Oct 11; 357(15):1487e95. PubMed PMID: 17928596. Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K, Cahenzli J, et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Critical Care Med 2011 Jul 15;184(2):198e205. PubMed PMID: 21471101. Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 2012 Apr;18(4): 538e46. PubMed PMID: 22447074. Pubmed Central PMCID: 3321082. Hunt JR, Martinelli R, Adams VC, Rook GA, Brunet LR. Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model. Clinical and experimental allergy. J Br Soc Allergy Clin Immunol 2005 May;35(5):685e90. PubMed PMID: 15898994. Arnold IC, 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 Aug;121(8):3088e93. PubMed PMID: 21737881. Pubmed Central PMCID: 3148731. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Reports 2012 May;13(5):440e7. PubMed PMID: 22422004. Pubmed Central PMCID: 3343350. Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM, Finlay BB. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 2013 MareApr;4(2):158e64. PubMed PMID: 23333861. Pubmed Central PMCID: 3595077. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011 Jan 21; 331(6015):337e41. PubMed PMID: 21205640. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012 Apr 27;336(6080): 489e93. PubMed PMID: 22442383. Pubmed Central PMCID: 3437652.
Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
www.elsevierhealth.com/journals/jinf
The intestinal microbiota and allergic asthma Marie-Claire Arrieta a, Brett Finlay a,b,* Michael Smith Laboratories, 301 e 2185 East Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z4 b Department of Microbiology and Immunology, 2350 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z4 a
Accepted 18 July 2014 Available online - - -
KEYWORDS Asthma; Microbiota; Hygiene hypothesis; Regulatory T cells
Summary There is increasing evidence that environmental changes are involved in the sharp increase in asthma incidence, as well as with other immune-mediated diseases. This increase matches the introduction of modern life advances such as antibiotics and caesarean sections. Several epidemiological studies provide convincing evidence that a lack of exposure to microbes early in life is associated with later development of allergic asthma. In addition, animal studies have shown that early life modulation of the intestinal microbiota with antibiotics has profound effects in the immune cellular mechanisms that lead to asthma. By describing some of the most relevant human and animal studies in this field, we explore the concept that significant perturbations of the intestinal and perhaps the lung microbiota are a cause of allergic asthma. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Asthma and the hygiene hypothesis Asthma is a multifactorial immune-mediated disease consisting of bronchial hyper-responsiveness and chronic airway inflammation. The symptoms of asthma range from mild episodes of airway obstruction to very severe and recurrent symptoms kindred to chronic obstructive pulmonary disease (COPD) that are difficult and costly to treat.1
Asthma affects 5e16% of people worldwide2 and its incidence has steadily increased since the mid 1900s.3 There are several other immune-mediated and autoimmune disorders that, like asthma, have increased in prevalence since the post WWII era. This common feature is one of the main factors that led to the generation of the hygiene hypothesis. This hypothesis, introduced for the first time 25 years ago,4 describes the sharp increase in these disorders
* Corresponding author. 301 e 2185 East Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4. Tel.: þ1 604 822 2210; fax: þ1 604 822 9830. E-mail address: [email protected] (B. Finlay). http://dx.doi.org/10.1016/j.jinf.2014.07.015 0163-4453/ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
2 as a result of modern life advances, such as antibiotics, vaccinations, caesarean sections, increased sanitation, etc. These societal and medical changes have shifted the ecology of our mucosal microbial communities, reduced early childhood infections and led to an imbalanced development of our immune system. The pathogenesis of asthma has genetic and environmental components. Gene wide association studies (GWAS) have reported many gene loci associated with the disease, however, most loci do not explain the largest proportion of the heritability of asthma.5 The genetic component in asthma is considered to be polygenetic, which may explain the heterogeneity of asthma phenotypes in humans.5 Studies regarding the environmental exposures of asthma patients have yielded significant information about the role of the environment in asthma. Children raised in farms within developed countries are significantly less likely to develop asthma than children raised in non-farm rural areas, or in cities.6,7 Young children that attend day care facilities are also less likely to develop asthma during school years.8 These studies are part of an ever-expanding group of research reports that associate early life events that alter the mucosal microbiota (pre and perinatal antibiotics, formula feeding, caesarean sections, perinatal stress, etc.) with an increased risk of atopy or asthma.
What constitutes a healthy microbiota? Although a logical and critically important question to ask, there is very little consensus in terms of the taxonomic composition of the microbiota in the healthy human body. The microbiota e known as the collection of bacteria, archaea, fungi, protozoa and viruses e inhabits our skin surface and mucosae. The human gastrointestinal tract is heavily colonized by 104e1013 cells/ml, with the colon harbouring the majority of cells and the most biodiverse microbial ecosystem.9 There is great intra and inter-individual microbial taxonomic variability, however, metabolomics analysis revealed that the microbial metabolic pathways remain highly conserved between individuals, suggesting that different microbiotas serve similar functions.9 Previously considered a sterile organ, high-throughput sequencing methods have also shown the presence of a resident lung microbiota.10,11 However, the studies that aim to characterize the lung microbiome are scarce and they vary greatly in the methodology used and data obtained, making it very early yet to understand the compositional and functional aspects of the lung microbiome. Until then, it remains speculative e although logical e to consider that the resident lung microbiota may also play an important role in the lung immune development and the pathogenesis of asthma. While it remains very complicated to answer whether a healthy microbiome can be described taxonomically, it may be more likely that the general microbial composition is less important than the balance between certain microbial groups that confer immune homeostasis. In human asthma studies there is evidence of microbial dysbiosis in the intestine12e14 and the lung, even in patients not under corticosteroid treatment.10,11,15 A common observation in these studies is the reduction in intestinal
M.-C. Arrieta, B. Finlay bacterial diversity, as well as the an alteration of the Firmicutes:Bacteroides ratios, two of the most important phyla in the human intestinal microbiota. However, dysbiosis can be a product of the inflammatory response in asthma, and it is through animal studies that a causal relationship between the microbiota and asthma is being explored.
Microbial dysbiosis as a cause of asthma Germ-free animal models of asthma exhibit an exacerbated phenotype16,17 which can be ameliorated upon bacterial colonization.18,19 Studies from our laboratory have shown that treatment with vancomycin, but not streptomycin lead to an increase in asthma severity.20,21 Analysis of the intestinal microbiota of the vancomycin-treated mice revealed a marked increase in Lactobacillaceae family members and a reduction in Bacteroides, suggesting that perhaps the increase in the former group and/or an underrepresentation of the latter group is involved in directing the immune response towards an allergic phenotype. Other bacterial groups that have been associated with an increased asthma phenotype are members of the Clostridium genus.22 Interestingly, our studies also suggest that there may be a ‘window of opportunity’ during which shifts of the intestinal microbiota can lead to disease. In the murine asthma model, vancomycin only results in increased asthma when given to neonate mice shortly after birth and before weaning. This and other studies suggest that it is during early life that the intestinal microbiota may play a role in asthma pathogenesis and that later shifts may not cause disease.23 Animal models of asthma have also provided with possible immune mechanisms that drives pathogenesis from the intestinal tract into the lung. Vancomycin-treated mice showed a decrease in regulatory T cells (Tregs) in the gut and an increase in IgE.20 Tregs have been shown to expand in the colon of mice upon exposure with clostridial strains, preventing colitis.22 Invariant natural killer T (iNKT) cells may also play a role in microbiota-driven asthma. These cells accumulate in the colonic lamina propria and the lung of germ-free mice with an exacerbated asthma phenotype. Upon bacterial colonization, there is a marked reduction of iNKT cell accumulation in the gut and lung mucosae, as well as a reduction in expression of the chemokine ligand CXCL16, a known recruiter of iNKT cells. Remarkably, the microbiota induces a reduction of hypermethylation of the gene for CXCL16, suggesting that the microbiota regulates the immune response via epigenetic mechanisms.23 In another study, animals treated with a strong cocktail of antibiotics showed an obliteration of the resident intestinal microbiota and increased lung inflammation associated with high IgE titers and elevated numbers of circulating basophils.17 The authors suggest that members of the microbiota downregulate the expression of IgE via MyD88 signalling in B cells, and that the significant reduction of microbial signals increase IgE production, which drives basophilopoeisis in the bone marrow. These studies are only a partial snapshot of the many cellular events that transfer immunological information from the intestinal mucosa to the other mucosal sites and
Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
Intestinal microbiota and allergic asthma
3
considerable effort is still needed to fully comprehend the series of events that lead to asthma development. 10.
Future directions Epidemiological and animal studies have provided important data that support the hygiene hypothesis. However, while the hygiene hypothesis may explain the origin of these disorders, little is known to date on what constitutes a healthy intestinal microbiome and more importantly, which microbial groups are essential for immune homeostasis. Manipulation of the microbiota with specific microbial groups, microbial products, or dietary components that favour the growth of particular bacteria will likely begin to be tested as therapeutical strategies to prevent allergic disease. The challenge for future research will be to determine whether microbiota manipulation is an effective way to treat disease, since most of the animal studies point to microbial modulation of the immune system as a very early event in the life of the host.
11.
12.
13.
14.
Conflict of interest 15.
The authors have no conflict of interest to report.
Acknowledgements The authors thank Dr. Yanet Valdez for her critical review of this manuscript. The authors are funded by a Team Grant from the Canadian Institutes of Health Research (CIHR), 108029.
16.
17.
References 1. Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet 2002 Oct 26;360(9342):1313e22. PubMed PMID: 12414223. 2. Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001e2010. NCHS Data Brief 2012 May;94:1e8. PubMed PMID: 22617340. 3. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N. Engl J Med 2006 Nov 23;355(21):2226e35. PubMed PMID: 17124020. 4. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989 Nov 18;299(6710):1259e60. PubMed PMID: 2513902. Pubmed Central PMCID: 1838109. Epub 1989/11/18. eng. 5. Martinez FD, Vercelli D. Asthma. Lancet 2013 Oct 19; 382(9901):1360e72. PubMed PMID: 24041942. 6. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C, et al. Exposure to environmental microorganisms and childhood asthma. N. Engl J Med 2011 Feb 24; 364(8):701e9. PubMed PMID: 21345099. 7. Wlasiuk G, Vercelli D. The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease. Curr Opin Allergy Clin Immunol 2012 Oct;12(5):461e6. PubMed PMID: 22892709. 8. Custovic A, Rothers J, Stern D, Simpson A, Woodcock A, Wright AL, et al. Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J Allergy Clin Immunol 2011 Feb;127(2). 390e397.e1ee9. PubMed PMID: 21281869. Pubmed Central PMCID: 3075116. 9. Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature 2012 Jun 14;
18.
19.
20.
21.
22.
23.
486(7402):207e14. PubMed PMID: 22699609. Pubmed Central PMCID: 3564958. Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, et al. Disordered microbial communities in asthmatic airways. PloS One 2010;5(1):e8578. PubMed PMID: 20052417. Pubmed Central PMCID: 2798952. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011 Feb;127(2). 372e381.e1ee3. PubMed PMID: 21194740. Pubmed Central PMCID: 3037020. Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001 Oct;108(4):516e20. PubMed PMID: 11590374. Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001 Jan;107(1):129e34. PubMed PMID: 11150002. van Nimwegen FA, Penders J, Stobberingh EE, Postma DS, Koppelman GH, Kerkhof M, et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J Allergy Clin Immunol 2011 Nov;128(5). 948e955.e1ee3. PubMed PMID: 21872915. Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, et al. Childhood asthma after bacterial colonization of the airway in neonates. N. Engl J Med 2007 Oct 11; 357(15):1487e95. PubMed PMID: 17928596. Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K, Cahenzli J, et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Critical Care Med 2011 Jul 15;184(2):198e205. PubMed PMID: 21471101. Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 2012 Apr;18(4): 538e46. PubMed PMID: 22447074. Pubmed Central PMCID: 3321082. Hunt JR, Martinelli R, Adams VC, Rook GA, Brunet LR. Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model. Clinical and experimental allergy. J Br Soc Allergy Clin Immunol 2005 May;35(5):685e90. PubMed PMID: 15898994. Arnold IC, 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 Aug;121(8):3088e93. PubMed PMID: 21737881. Pubmed Central PMCID: 3148731. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Reports 2012 May;13(5):440e7. PubMed PMID: 22422004. Pubmed Central PMCID: 3343350. Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM, Finlay BB. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 2013 MareApr;4(2):158e64. PubMed PMID: 23333861. Pubmed Central PMCID: 3595077. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011 Jan 21; 331(6015):337e41. PubMed PMID: 21205640. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012 Apr 27;336(6080): 489e93. PubMed PMID: 22442383. Pubmed Central PMCID: 3437652.
Please cite this article in press as: Arrieta M-C, Finlay B, The intestinal microbiota and allergic asthma, J Infect (2014), http://dx.doi.org/ 10.1016/j.jinf.2014.07.015
