Intestinal microbiota and its effect on the immune system — A nested case-cohort study on prevention of atopy among small children in Trondheim: The IMPACT study☆

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Abstract

Background

In the past 20–30 years, the prevalence of atopic diseases, particularly among children in the Western world, has increased. It has been suggested that Western lifestyle may have reduced the overall exposure to microbial stimulation early in life. The role of the gut flora in this connection has been studied, but prospective studies are in demand.

Within the frame of a comprehensive controlled prospective primary prevention study of atopy and allergic diseases with the aim to reduce the incidence of atopy and allergic diseases among children from birth to six years, a nested case-cohort study is established, “The IMPACT study”.

Aim

The aim of “The IMPACT study” is to study the impact of gut microbiota composition on cytokine profile development, and on development of atopic disease.

Design

Information on risk factors and on disease, together with biological specimens, will be collected prospectively, and analysed in a nested case-cohort design.

Method

720 pregnant women are recruited from the control-cohort in the PACT study.

The composition of the infant gut microbiota is analysed in stool samples from all children with atopic disease, and randomly selected children sensitized and not sensitized at age 2, at 4, 7, 10 days after birth, and at age 4, 12 and 24 months. 16S rDNA hybridisation technique will be used to specify and quantify the microbial composition in faeces. Cord blood from the same children and venous blood at age 10 days, 4, 12 and 24 months are collected to study the cytokine profile at different ages, in relation to microbial stimulation. Peripheral blood mononuclear cells (PBMC) are stored in liquid nitrogen, and faeces are stored at − 80 °C. Atopic children will be identified by questionnaire, and the diagnosis confirmed by paediatric examination at age 2 years.

Introduction

Internationally, it is generally recognised that there is an increasing incidence of asthma, AAD and AEDS, and that this increase does not only depend on new criteria for diagnosis and improved diagnostic methods [1]. Environmental factors have impact on incidence changes in individuals with different predisposition for allergic disease [2]. The morbidity is also dependent on the age of the individual, when the exposure takes place [3]. Age when exposure takes place, and the variation in expression of disease, has lead to increased focus on how the immunity in newborns and infants develops, and how the interaction between exposure and immunological development may influence the occurrence of asthma, AAD and AEDS [4], [5].

Studying the association between exposure to certain environmental factors, and immunological development, and its impact on the outcome of asthma, AAD and AEDS is the forthcoming challenge.

Section snippets

Background

There are differences in the incidence of allergic diseases across cultures and communities with different living conditions, environmental influences and dietary habits. Ecological studies have shown that the incidences of allergic diseases among children are lower in Eastern European countries than in the Scandinavian countries [6].

Since the way of life in Eastern Europe today in many ways is similar to that of Scandinavia 30 years ago, the question is which of these lifestyle factors had a

Hypothesis

There is a strong and consistent association between the development of the composition of the intestinal microbiota in newborn, the maturation of the immune system and atopic sensitization and disease. This association is modified by genetic and environmental factors.

Aims

The aims are to:

  • •

    Study the development of the children's intestinal microbiota from birth until the age of two years and analyse how environmental factors as the mother's intestinal microbiota, perinatal routines, breastfeeding, diet, infections, use of antibiotics, and indoor climate, including passive smoking, influence the gut flora composition.

  • •

    Study the impact of the intestinal microbiota on the development of the immune system.

  • •

    Study the interactions between the composition of microbes in

Design

The Prevention of Allergy among Children in Trondheim (PACT) is a comprehensive controlled intervention study on the efficacy of systematic and structured intervention on reduced tobacco exposure, improved indoor-climate by reducing housing dampness and increased intake of omega-3-fatty acids on some 3000 pregnant women and their offspring. The control-cohort, from which 720 pregnant women in the IMPACT study is recruited at random, consists of some 14,000 children and pregnant women. Both the

Approvals and ethics

The protocol was approved by the Regional Ethics Committee (REK). The Norwegian Data Inspectorate licensed the establishment of research register. The ethical questions are mainly related to taking blood specimens from healthy children and performing other diagnostic examinations such as skin prick tests. It is not within the scope of this project to perform diagnoses beyond what is common in relation to the afflictions in question. A paediatrician will perform the diagnostic procedures. Blood

Schedule

The inclusion will start at the initiation of the control-cohort for the main study “Prevention of Atopy among Children in Trondheim” in June 2000. 720 pregnant women are to be included during the first 12 months, and the children will be given a follow-up until they are 2 years old.

Publication

The results will be published in acknowledged international journals in 2006 and 2007.

Funding

Funding for this study was obtained from the University of Trondheim, NTNU, GlaxoSmithKline Norway AS and the Norwegian Asthma and Allergy Association (NAAF).

Discussion

The main purpose with the IMPACT-study is to explore the association between the gut microbiota composition, immunological differentiation and asthma, AAD and AEDS in a prospective design. Cross-sectional studies have indicated a relationship between intestinal microbiota and allergic disease. There are few prospective studies in this field, and the published studies are conducted on selected populations, i.e. families with an increased risk of atopic disease [30], [32]. In the IMPACT-study

Acknowledgement

Funding for the IMPACT study was obtained from GlaxoSmithKline AS, Norway. The Norwegian Department of Health and Social affairs funded the Prevention of Atopy among Children in Trondheim study from 1997–2003. A university scholarship from NTNU funded the research fellows.

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    ☆

    Design and research protocol of a nested case-cohort study, on the impact of the intestinal microbiota on the immune system, asthma, and atopic sensitization as Allergic Airways Disease (AAD) and Atopic Eczema/Dermatitis Syndrome (AEDS).

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