Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study

John Penders

Carel Thijs

Piet Brandt

Ischa Kummeling

C Thijs, Department of Epidemiology, Care and Public Health Research Institute (Caphri), Maastricht University, Maastricht, the Netherlands

R van Ree, Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands

F Stelma, H Adams, E E Stobberingh, Department of Medical Microbiology, University Hospital of Maastricht, Maastricht, the Netherlands

Correspondence to: John Penders
Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands; j.penders@epid.unimaas.nl

J Penders, P A van den Brandt, I Kummeling, B Snijders, Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, the NetherlandsC Thijs, Department of Epidemiology, Care and Public Health Research Institute (Caphri), Maastricht University, Maastricht, the NetherlandsR van Ree, Department of Experimental Immunology, Academic Medical Center, Amsterdam, the NetherlandsF Stelma, H Adams, E E Stobberingh, Department of Medical Microbiology, University Hospital of Maastricht, Maastricht, the NetherlandsCorrespondence to: John Penders
Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands; j.penders@epid.unimaas.nl

Revised 2006 Oct 3; Accepted 2006 Oct 5.

Abstract

Background and aims

Perturbations in intestinal microbiota composition due to lifestyle changes may be involved in the development of atopic diseases. We examined gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation.

Methods

The faeces of 957 infants aged 1 month and participating in the KOALA Birth Cohort Study were analysed using quantitative real‐time PCR. Information on atopic symptoms (eczema, wheeze) and potential confounders was acquired through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits when the infant was 2 years old. During these home visits a clinical diagnosis of atopic dermatitis was made according to the UK‐Working Party criteria.

Results

The presence of Escherichia coli was associated with a higher risk of developing eczema (OR_adj = 1.87; 95% CI 1.15 to 3.04), this risk being increased with increasing numbers of E coli (p_{for trend} = 0.016). Infants colonised with Clostridium difficile were at higher risk of developing eczema (OR_adj = 1.40; 95% CI 1.02 to 1.91), recurrent wheeze (OR_adj = 1.75; 95% CI 1.09 to 2.80) and allergic sensitisation (OR_adj = 1.54; 95% CI 1.02 to 2.31). Furthermore, the presence of C difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (OR_adj = 1.73; 95% CI 1.08 to 2.78).

Conclusion

This study demonstrates that differences in gut microbiota composition precede the development of atopy. Since E coli was only associated with eczema and C difficile was associated with all atopic outcomes, the underlying mechanisms explaining these association may be different.

Keywords: atopy, Clostridium difficile , Escherichia coli , gut microbiota, infant

Abstract

The prevalence of atopy has been increasing worldwide during the past decades, particularly in the Western world and amongst children.¹ An enhanced T helper 2 (Th2) immune response and the elaboration of cytokines such as interleukin (IL)‐4, IL‐13 and IL‐5 contribute to the induction of atopic diseases.² Although genetic susceptibility plays an important role in atopy, changes in the prevalence of these diseases have been much faster than any possible shift in genetic constitution.³ Therefore, environmental changes associated with a western lifestyles are thought to be involved in the atopic epidemic. In 1989 Strachan introduced the “hygiene hypothesis”, which states that reduced exposure to infections during childhood results in aberrant immune responses to innocuous antigens later in life.⁴⁵ However, an alternative interpretation of this hypothesis is that perturbations in the composition of gastrointestinal microbiota as a result of changed lifestyles (antibiotic use, diet) in westernised countries have disrupted the mechanisms involved in the development of immunological tolerance.⁶ Regulatory antigen presenting cells (APCreg) and regulatory T cells (Treg) play a crucial role in the development of immunological tolerance. The maturation of these cells might be hampered as a result of reduced exposure to certain microbes (“old friends”) and consequently a person may develop T helper 1 (Th1) or Th2 mediated inflammatory disorders.⁷

Differences in intestinal microbiota composition have been shown between infants in countries with high (Sweden) and low (Estonia) allergy prevalence and also between allergic and healthy infants.⁸⁹¹⁰¹¹ Most reports were based on small populations and although the majority of observational studies found an association between the gut microbiota and allergy, no protective or potentially harmful bacteria have yet been identified.¹²

Further support for the role of the gut microbiota comes from several clinical trials using probiotics in the treatment¹³¹⁴¹⁵ and prevention¹⁶¹⁷ of atopic eczema, although not all studies have shown probiotics to be effective.¹⁸¹⁹

In a large prospective birth cohort study in the Netherlands, we examined the composition of the intestinal microbiota of nearly 1000 infants aged 1 month and the subsequent development of atopic manifestations and/or sensitisation within the first 2 years of life.

Acknowledgements

We thank Chantal Delnoy, Brigitte Winants and Karen Groot for home visits, Cobie Martens and Willeke Hendrikx for assistance with data collection questionnaires, Astrid van Leeuwen (Sanquin) for IgE determination, and last but not least, all mothers and their infants participating in the KOALA study.

Acknowledgements

Abbreviations

CFU - colony forming units

Ig - immunoglobulin

IL - interleukin

OR - odds ratio

Th1 - Th2, T helper 1, 2

Treg - regulatory T cell

UK‐WP - UK‐Working Party

Abbreviations

Footnotes

Funding: This study was supported by grants from the Dutch Asthma Foundation (grant 3.2.03.48) and Royal Friesland Foods (the Netherlands).

Competing interests: None declared.

Footnotes

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