Title: Association between the intestinal microbiota and allergic sensitization, eczema, and asthma: A systematic review
Abstract: The intestinal microbiota plays an important role in development of the immune system and regulation of immune responses. This review summarizes the association between the intestinal microbiota and the development of allergic sensitization, eczema, and asthma in neonates and children. Overall, a greater relative abundance of Bacteroidaceae, Clostridiaceae, and Enterobacteriaceae and a lower relative abundance of Bifidobacteriaceae and Lactobacillaceae is associated with the development of allergic sensitization, eczema, or asthma. Reduced bacterial diversity can be associated with the development of allergic disease. The association between the composition of the intestinal microbiota and the development of allergic disease or asthma is less consistent in older children than in neonates, suggesting that early-life microbial exposure plays a more important role. Inconsistencies in the results reported from different studies might partly be explained by heterogeneity in design, study populations, diagnostic criteria, microbiota analysis methods, and reporting on different taxonomic levels. Larger studies that better account for antenatal and postnatal factors will further help determine specific microbial intestinal signatures associated with increased risk of allergy and asthma. This will enable the early identification of infants at high risk and facilitate novel strategies and interventions to prevent and treat these conditions, including modifying the intestinal microbiota early in life. The intestinal microbiota plays an important role in development of the immune system and regulation of immune responses. This review summarizes the association between the intestinal microbiota and the development of allergic sensitization, eczema, and asthma in neonates and children. Overall, a greater relative abundance of Bacteroidaceae, Clostridiaceae, and Enterobacteriaceae and a lower relative abundance of Bifidobacteriaceae and Lactobacillaceae is associated with the development of allergic sensitization, eczema, or asthma. Reduced bacterial diversity can be associated with the development of allergic disease. The association between the composition of the intestinal microbiota and the development of allergic disease or asthma is less consistent in older children than in neonates, suggesting that early-life microbial exposure plays a more important role. Inconsistencies in the results reported from different studies might partly be explained by heterogeneity in design, study populations, diagnostic criteria, microbiota analysis methods, and reporting on different taxonomic levels. Larger studies that better account for antenatal and postnatal factors will further help determine specific microbial intestinal signatures associated with increased risk of allergy and asthma. This will enable the early identification of infants at high risk and facilitate novel strategies and interventions to prevent and treat these conditions, including modifying the intestinal microbiota early in life. It is now clear that early-life determinants influence the development of allergic disease and asthma in genetically predisposed subjects. The intestinal microbiota plays a central role in development and regulation of the immune system, and its composition is associated with the development of many immune-mediated and non–immune-mediated diseases.1Marchesi J.R. Adams D.H. Fava F. Hermes G.D. Hirschfield G.M. Hold G. et al.The gut microbiota and host health: a new clinical frontier.Gut. 2016; 65: 330-339Crossref PubMed Scopus (1334) Google Scholar, 2Zeevi D. Korem T. Segal E. Talking about cross-talk: the immune system and the microbiome.Genome Biol. 2016; 17: 50Crossref PubMed Scopus (18) Google Scholar For example, a decrease in species diversity is associated with the development of neonatal sepsis,3Madan J.C. Salari R.C. Saxena D. Davidson L. O'Toole G.A. Moore J.H. et al.Gut microbial colonisation in premature neonates predicts neonatal sepsis.Arch Dis Child Fetal Neonatal Ed. 2012; 97: F456-F462Crossref PubMed Scopus (238) Google Scholar chronic inflammatory bowel disease,4Manichanh C. Rigottier-Gois L. Bonnaud E. Gloux K. Pelletier E. Frangeul L. et al.Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach.Gut. 2006; 55: 205-211Crossref PubMed Scopus (1616) Google Scholar and diabetes mellitus,5Knip M. Siljander H. The role of the intestinal microbiota in type 1 diabetes mellitus.Nat Rev Endocrinol. 2016; 12: 154-167Crossref PubMed Scopus (259) Google Scholar whereas an increase in bacterial diversity is associated with better vaccine responses.6Eloe-Fadrosh E.A. McArthur M.A. Seekatz A.M. Drabek E.F. Rasko D.A. Sztein M.B. et al.Impact of oral typhoid vaccination on the human gut microbiota and correlations with S. typhi-specific immunological responses.PLoS One. 2013; 8: e62026Crossref PubMed Scopus (74) Google Scholar Several lines of evidence suggest that the features and composition of the intestinal microbiota also play a significant role in the “inappropriate” immune responses that lead to allergic disease and asthma. In this article we systematically review studies that have investigated the association between the composition of the intestinal microbiota and the development of allergic sensitization, eczema, and asthma in children and conclude that early-life microbial exposure plays an important role in patients with these conditions. A systematic search of MEDLINE was done in April 2018 using the OVID interface from 1946 to present the following search terms: (eczema OR dermatitis, atopic OR asthma OR hypersensitivity OR immunoglobulin) AND (microbio* OR biodiversity OR DNA, bacterial OR 16S rRNA OR metagenom* OR Lactobacillus OR Bacteroid* OR Bifidobacter* OR feces OR faeces OR meconium OR intestin* OR stool OR gut). These terms were used without language limitations. This identified 1747 studies, of which 42 were original controlled studies investigating the association between the composition of the intestinal microbiota and allergic sensitization, eczema, or asthma in neonates and children. Studies in which no healthy control subjects were included or studies in which probiotics or bacterial lysate were given as an intervention were excluded from this review. Three more recent publications were identified through PubMed. References were hand searched for additional publications, and 2 more articles were identified. Our review resulted in a total of 47 studies reporting results from 11,954 stool samples from 3,071 children with allergic sensitization, eczema, or asthma and from 3,606 control subjects (Table I).7Arrieta M.C. Stiemsma L.T. Dimitriu P.A. Thorson L. Russell S. Yurist-Doutsch S. et al.Early infancy microbial and metabolic alterations affect risk of childhood asthma.Sci Transl Med. 2015; 7: 307ra152Crossref PubMed Scopus (958) Google Scholar, 8van Nimwegen F.A. Penders J. Stobberingh E.E. Postma D.S. Koppelman G.H. Kerkhof M. et al.Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.J Allergy Clin Immunol. 2011; 128 (e1-3): 948-955Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 9Bisgaard H. Li N. Bonnelykke K. Chawes B.L. Skov T. Paludan-Muller G. et al.Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age.J Allergy Clin Immunol. 2011; 128 (e1-5): 646-652Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 10Penders J. Thijs C. Mommers M. Stobberingh E.E. Dompeling E. Reijmerink N.E. et al.Intestinal lactobacilli and the DC-SIGN gene for their recognition by dendritic cells play a role in the aetiology of allergic manifestations.Microbiology. 2010; 156: 3298-3305Crossref PubMed Scopus (27) Google Scholar, 11Adlerberth I. Strachan D.P. Matricardi P.M. Ahrne S. Orfei L. Aberg N. et al.Gut microbiota and development of atopic eczema in 3 European birth cohorts.J Allergy Clin Immunol. 2007; 120: 343-350Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 12Penders J. Thijs C. van den Brandt P.A. Kummeling I. Snijders B. Stelma F. et al.Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.Gut. 2007; 56: 661-667Crossref PubMed Scopus (585) Google Scholar, 13Azad M.B. Konya T. Guttman D.S. Field C.J. Sears M.R. HayGlass K.T. et al.Infant gut microbiota and food sensitization: associations in the first year of life.Clin Exp Allergy. 2015; 45: 632-643Crossref PubMed Scopus (272) Google Scholar, 14Gosalbes M.J. Llop S. Valles Y. Moya A. Ballester F. Francino M.P. Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants.Clin Exp Allergy. 2013; 43: 198-211Crossref PubMed Scopus (256) Google Scholar, 15Ismail I.H. Oppedisano F. Joseph S.J. Boyle R.J. Licciardi P.V. Robins-Browne R.M. et al.Reduced gut microbial diversity in early life is associated with later development of eczema but not atopy in high-risk infants.Pediatr Allergy Immunol. 2012; 23: 674-681Crossref PubMed Scopus (135) Google Scholar, 16Abrahamsson T.R. Jakobsson H.E. Andersson A.F. Bjorksten B. Engstrand L. Jenmalm M.C. Low diversity of the gut microbiota in infants with atopic eczema.J Allergy Clin Immunol. 2012; 129 (e1-2): 434-440Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 17Storro O. Oien T. Langsrud O. Rudi K. Dotterud C. Johnsen R. Temporal variations in early gut microbial colonization are associated with allergen-specific immunoglobulin E but not atopic eczema at 2 years of age.Clin Exp Allergy. 2011; 41: 1545-1554Crossref PubMed Scopus (37) Google Scholar, 18Vael C. Vanheirstraeten L. Desager K.N. Goossens H. Denaturing gradient gel electrophoresis of neonatal intestinal microbiota in relation to the development of asthma.BMC Microbiol. 2011; 11: 68Crossref PubMed Scopus (74) Google Scholar, 19Sjogren Y.M. Jenmalm M.C. Bottcher M.F. Bjorksten B. Sverremark-Ekstrom E. Altered early infant gut microbiota in children developing allergy up to 5 years of age.Clin Exp Allergy. 2009; 39: 518-526Crossref PubMed Scopus (277) Google Scholar, 20Suzuki S. Shimojo N. Tajiri Y. Kumemura M. Kohno Y. A quantitative and relative increase in intestinal Bacteroides in allergic infants in rural Japan.Asian Pac J Allergy Immunol. 2008; 26: 113-119PubMed Google Scholar, 21Forno E. Onderdonk A.B. McCracken J. Litonjua A.A. Laskey D. Delaney M.L. et al.Diversity of the gut microbiota and eczema in early life.Clin Mol Allergy. 2008; 6: 11Crossref PubMed Scopus (94) Google Scholar, 22Wang M. Karlsson C. Olsson C. Adlerberth I. Wold A.E. Strachan D.P. et al.Reduced diversity in the early fecal microbiota of infants with atopic eczema.J Allergy Clin Immunol. 2008; 121: 129-134Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 23Verhulst S.L. Vael C. Beunckens C. Nelen V. Goossens H. Desager K. A longitudinal analysis on the association between antibiotic use, intestinal microflora, and wheezing during the first year of life.J Asthma. 2008; 45: 828-832Crossref PubMed Scopus (53) Google Scholar, 24Vael C. Nelen V. Verhulst S.L. Goossens H. Desager K.N. Early intestinal Bacteroides fragilis colonisation and development of asthma.BMC Pulm Med. 2008; 8: 19Crossref PubMed Scopus (79) Google Scholar, 25Suzuki S. Shimojo N. Tajiri Y. Kumemura M. Kohno Y. Differences in the composition of intestinal Bifidobacterium species and the development of allergic diseases in infants in rural Japan.Clin Exp Allergy. 2007; 37: 506-511Crossref PubMed Scopus (58) Google Scholar, 26Penders J. Stobberingh E.E. Thijs C. Adams H. Vink C. van Ree R. et al.Molecular fingerprinting of the intestinal microbiota of infants in whom atopic eczema was or was not developing.Clin Exp Allergy. 2006; 36: 1602-1608Crossref PubMed Scopus (99) Google Scholar, 27Murray C.S. Tannock G.W. Simon M.A. Harmsen H.J. Welling G.W. Custovic A. et al.Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: a nested case-control study.Clin Exp Allergy. 2005; 35: 741-745Crossref PubMed Scopus (87) Google Scholar, 28Sepp E. Julge K. Mikelsaar M. Bjorksten B. Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children.Clin Exp Allergy. 2005; 35: 1141-1146Crossref PubMed Scopus (105) Google Scholar, 29Bjorksten B. Sepp E. Julge K. 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Yurist-Doutsch S. et al.Early infancy microbial and metabolic alterations affect risk of childhood asthma.Sci Transl Med. 2015; 7: 307ra152Crossref PubMed Scopus (958) Google Scholar, 8van Nimwegen F.A. Penders J. Stobberingh E.E. Postma D.S. Koppelman G.H. Kerkhof M. et al.Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.J Allergy Clin Immunol. 2011; 128 (e1-3): 948-955Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 9Bisgaard H. Li N. Bonnelykke K. Chawes B.L. Skov T. Paludan-Muller G. et al.Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age.J Allergy Clin Immunol. 2011; 128 (e1-5): 646-652Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 10Penders J. Thijs C. Mommers M. Stobberingh E.E. Dompeling E. 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Yurist-Doutsch S. et al.Early infancy microbial and metabolic alterations affect risk of childhood asthma.Sci Transl Med. 2015; 7: 307ra152Crossref PubMed Scopus (958) Google Scholar, 8van Nimwegen F.A. Penders J. Stobberingh E.E. Postma D.S. Koppelman G.H. Kerkhof M. et al.Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.J Allergy Clin Immunol. 2011; 128 (e1-3): 948-955Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 9Bisgaard H. Li N. Bonnelykke K. Chawes B.L. Skov T. Paludan-Muller G. et al.Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age.J Allergy Clin Immunol. 2011; 128 (e1-5): 646-652Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 10Penders J. Thijs C. Mommers M. Stobberingh E.E. Dompeling E. Reijmerink N.E. et al.Intestinal lactobacilli and the DC-SIGN gene for their recognition by dendritic cells play a role in the aetiology of allergic manifestations.Microbiology. 2010; 156: 3298-3305Crossref PubMed Scopus (27) Google Scholar, 11Adlerberth I. Strachan D.P. Matricardi P.M. Ahrne S. Orfei L. Aberg N. et al.Gut microbiota and development of atopic eczema in 3 European birth cohorts.J Allergy Clin Immunol. 2007; 120: 343-350Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 12Penders J. Thijs C. van den Brandt P.A. Kummeling I. Snijders B. Stelma F. et al.Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.Gut. 2007; 56: 661-667Crossref PubMed Scopus (585) Google Scholar, 13Azad M.B. Konya T. Guttman D.S. Field C.J. Sears M.R. HayGlass K.T. et al.Infant gut microbiota and food sensitization: associations in the first year of life.Clin Exp Allergy. 2015; 45: 632-643Crossref PubMed Scopus (272) Google Scholar, 14Gosalbes M.J. Llop S. Valles Y. Moya A. Ballester F. Francino M.P. Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants.Clin Exp Allergy. 2013; 43: 198-211Crossref PubMed Scopus (256) Google Scholar, 15Ismail I.H. Oppedisano F. Joseph S.J. Boyle R.J. Licciardi P.V. Robins-Browne R.M. et al.Reduced gut microbial diversity in early life is associated with later development of eczema but not atopy in high-risk infants.Pediatr Allergy Immunol. 2012; 23: 674-681Crossref PubMed Scopus (135) Google Scholar, 16Abrahamsson T.R. Jakobsson H.E. Andersson A.F. Bjorksten B. Engstrand L. Jenmalm M.C. Low diversity of the gut microbiota in infants with atopic eczema.J Allergy Clin Immunol. 2012; 129 (e1-2): 434-440Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 17Storro O. Oien T. Langsrud O. Rudi K. Dotterud C. Johnsen R. Temporal variations in early gut microbial colonization are associated with allergen-specific immunoglobulin E but not atopic eczema at 2 years of age.Clin Exp Allergy. 2011; 41: 1545-1554Crossref PubMed Scopus (37) Google Scholar, 18Vael C. Vanheirstraeten L. Desager K.N. Goossens H. Denaturing gradient gel electrophoresis of neonatal intestinal microbiota in relation to the development of asthma.BMC Microbiol. 2011; 11: 68Crossref PubMed Scopus (74) Google Scholar, 19Sjogren Y.M. Jenmalm M.C. Bottcher M.F. Bjorksten B. Sverremark-Ekstrom E. Altered early infant gut microbiota in children developing allergy up to 5 years of age.Clin Exp Allergy. 2009; 39: 518-526Crossref PubMed Scopus (277) Google Scholar, 20Suzuki S. Shimojo N. Tajiri Y. Kumemura M. Kohno Y. A quantitative and relative increase in intestinal Bacteroides in allergic infants in rural Japan.Asian Pac J Allergy Immunol. 2008; 26: 113-119PubMed Google Scholar, 21Forno E. Onderdonk A.B. McCracken J. Litonjua A.A. Laskey D. Delaney M.L. et al.Diversity of the gut microbiota and eczema in early life.Clin Mol Allergy. 2008; 6: 11Crossref PubMed Scopus (94) Google Scholar, 22Wang M. Karlsson C. Olsson C. Adlerberth I. Wold A.E. Strachan D.P. et al.Reduced diversity in the early fecal microbiota of infants with atopic eczema.J Allergy Clin Immunol. 2008; 121: 129-134Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 23Verhulst S.L. Vael C. Beunckens C. Nelen V. Goossens H. Desager K. A longitudinal analysis on the association between antibiotic use, intestinal microflora, and wheezing during the first year of life.J Asthma. 2008; 45: 828-832Crossref PubMed Scopus (53) Google Scholar, 24Vael C. Nelen V. Verhulst S.L. Goossens H. Desager K.N. Early intestinal Bacteroides fragilis colonisation and development of asthma.BMC Pulm Med. 2008; 8: 19Crossref PubMed Scopus (79) Google Scholar, 25Suzuki S. Shimojo N. Tajiri Y. Kumemura M. Kohno Y. Differences in the composition of intestinal Bifidobacterium species and the development of allergic diseases in infants in rural Japan.Clin Exp Allergy. 2007; 37: 506-511Crossref PubMed Scopus (58) Google Scholar, 26Penders J. Stobberingh E.E. Thijs C. Adams H. Vink C. van Ree R. et al.Molecular fingerprinting of the intestinal microbiota of infants in whom atopic eczema was or was not developing.Clin Exp Allergy. 2006; 36: 1602-1608Crossref PubMed Scopus (99) Google Scholar, 27Murray C.S. Tannock G.W. Simon M.A. Harmsen H.J. Welling G.W. Custovic A. et al.Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: a nested case-control study.Clin Exp Allergy. 2005; 35: 741-745Crossref PubMed Scopus (87) Google Scholar, 28Sepp E. Julge K. Mikelsaar M. Bjorksten B. 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