Mechanisms of allergy and clinical immunology
Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age

https://doi.org/10.1016/j.jaci.2011.04.060Get rights and content

Background

Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy.

Objectives

We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development.

Methods

We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life.

Results

We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils (P = .034), and allergic rhinitis (P = .007). There was no association with the development of asthma or atopic dermatitis.

Conclusions

Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease.

Section snippets

Methods

The study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for reporting observational epidemiologic studies.9

Results

Four hundred eleven infants were enrolled at 1 month of age. Cultures from fecal samples were successful in 346 neonates at 1 month and 325 infants at 12 months. DGGE PCR was completed in 300 children at 1 month and 301 children at 12 months, and 253 were completed at both time points. Baseline characteristics for the main cohort, the 253-member subgroup with complete data on DGGE PCR data, and the excluded population are compared in Table E1 (available in this article's Online Repository at //www.jacionline.org

Principal findings

Reduced bacterial diversity in the infant's intestinal flora increased the risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia but was not associated with the risk of asthma or atopic dermatitis during the first 6 years of life. Although the causal direction of these associations between the bacterial diversity of the intestinal flora and the development of atopic disease cannot be determined, the findings support the general hypothesis that imbalance of the

References (45)

  • P.V. Kirjavainen et al.

    Characterizing the composition of intestinal microflora as a prospective treatment target in infant allergic disease

    FEMS Immunol Med Microbiol

    (2001)
  • C. Gore et al.

    Bifidobacterium pseudocatenulatum is associated with atopic eczema: a nested case-control study investigating the fecal microbiota of infants

    J Allergy Clin Immunol

    (2008)
  • S. Watanabe et al.

    Differences in fecal microflora between patients with atopic dermatitis and healthy control subjects

    J Allergy Clin Immunol

    (2003)
  • C. Manichanh et al.

    Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach

    Gut

    (2006)
  • P.J. Turnbaugh et al.

    A core gut microbiome in obese and lean twins

    Nature

    (2009)
  • A. Vrieze et al.

    The environment within: how gut microbiota may influence metabolism and body composition

    Diabetologia

    (2010)
  • J. Vaahtovuo et al.

    Fecal microbiota in early rheumatoid arthritis

    J Rheumatol

    (2008)
  • D.P. Strachan

    Family size, infection and atopy: the first decade of the “hygiene hypothesis.”

    Thorax

    (2000)
  • E.E. von et al.

    The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies

    PLoS Med

    (2007)
  • H. Bisgaard et al.

    Intermittent inhaled corticosteroids in infants with episodic wheezing

    N Engl J Med

    (2006)
  • H. Bisgaard et al.

    Childhood asthma after bacterial colonization of the airway in neonates

    N Engl J Med

    (2007)
  • R. Paganelli et al.

    Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics

    Allergy

    (1998)
  • Cited by (586)

    • Correlating the Gut Microbiome to Health and Disease

      2024, The Gut-Brain Axis, Second Edition
    • Childhood respiratory viral infections and the microbiome

      2023, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus

    N. L. was supported by a scholarship kindly given by the Chinese State. Copenhagen Prospective Study on Asthma in Childhood (COPSAC) is funded by private and public research funds, all listed on www.copsac.com. The Lundbeck Foundation, the Pharmacy Foundation of 1991, the Augustinus Foundation, the Danish Medical Research Council, and the Danish Pediatric Asthma Centre provide core support for COPSAC.

    Disclosure of potential conflict of interest: H. Bisgaard has been a lecturer for AstraZeneca and Merck; has consultant arrangements with Merck and Chiesi; and has provided legal consultation/expert witness testimony for the European Medicines Agency in cases related to the guidelines on pediatric studies for documenting asthma drugs. The rest of the authors have declared that they have no conflict of interest.

    View full text