Elsevier

The Lancet

Volume 357, Issue 9262, 7 April 2001, Pages 1076-1079
The Lancet

Articles
Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(00)04259-8Get rights and content

Summary

Background

Reversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in Western societies. In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life. Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora. We assessed the effect on atopic disease of Lactobacillus GG (which is safe at an early age and effective in treatment of allergic inflammation and food allergy).

Methods

In a double-blind, randomised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for 6 months to their infants. Chronic recurring atopic eczema, which is the main sign of atopic disease in the first years of life, was the primary endpoint.

Findings

Atopic eczema was diagnosed in 46 of 132 (35%) children aged 2 years. Asthma was diagnosed in six of these children and allergic rhinitis in one. The frequency of atopic eczema in the probiotic group was half that of the placebo group (15/64 [23%] vs 31/68 [46%]; relative risk 0·51 [95% Cl 0·32–0·84]). The number needed to treat was 4·5 (95% Cl 2·6–15·6).

Interpretations

Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. Thus, gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics, for prevention of atopic disease.

Introduction

Allergy, in the form of atopic diseases such as atopic eczema, allergic rhinitis, and asthma, is a chronic disorder of increasing importance in economically more-developed countries.1 The International Study of Asthma and Allergies in Childhood2, 3 included 11 607 Finnish children aged 13–14 years; 10–20% of the children had symptoms of asthma, 15–23% allergic rhinitis, and 15–19% atopic eczema. Proof of an inverse association between infections early in life and atopy has led to renewed interest in the hygiene hypothesis devised by Strachan4 a decade ago. The recent rapid rise in atopy might be a result of improved hygiene and reduced family size. Recent epidemiological studies have yielded results both for,5, 6, 7 and against,8 such a hypothesis.

We propose that specific microbes in the commensal gut microflora are more important than sporadic infections in atopic disease prevention. Gastrointestinal microflora promote potentially antiallergenic processes: (1) T-helper-1-type immunity;9 (2) generation of transforming growth factor β, 10, 11 which has an essential role in suppression of T-helper-2-induced allergic inflammation12 and induction of oral tolerance;13 and (3) IgA production,14 an essential component of mucosal immune defence. The gut microflora might therefore be a major postnatal counter-regulator of the universal T-helper-2-skewed immune system in fetuses and neonates. Confrontation between microbes and their antigens in the gastrointestinal tract begins instantly after birth, and the viable cells of fully established gut microflora outnumber those of the human host by a factor of ten.15 Consequently, commensal gastrointestinal microbes are the earliest and biggest stimulus for development of gut-associated lymphoid tissue.

Probiotics are cultures of potentially beneficial bacteria of healthy gut microflora15 and one such strain, Lactobacillus rhamnosus (Lactobacillus GG, American Type Culture Collection 53103), has proved safe at an early age and effective in treatment of allergic inflammation11 and food allergy.16 In a double-blind randomised placebo-controlled trial of prevention of atopic disease, we gave Lactobacillus GG prenatally to mothers and postnatally for 6 months to their infants at high risk of these diseases.

Section snippets

Participants and study design

The only inclusion criterion was a family history of atopic disease—ie, one or more family members (mother, father, or older sibling) with atopic eczema, allergic rhinitis, or asthma. Families were recruited in antenatal clinics in Turku, Finland (population 170 000) between February, 1997, and January, 1998 to avoid the effect of birth month on atopic sensitisation. On the basis of our sample-size calculation before the study, 159 mothers were randomly assigned by computer to receive two

Baseline characteristics and participants

Baseline characteristics were similar in the placebo and Lactobacillus GG groups (table 1). The mean (95% CI) start of treatment was 26 (24–28) days before delivery. 132 of 159 (83%) participants completed the 2-year study. The only reason for discontinuation was non-compliance—ie, the family did not arrive for the study visit–and rates were similar in both groups (figure 1). None of the drop-outs had shown signs of atopic disease before discontinuation. The mean (95% CI) times of exclusive and

Discussion

We have shown prospectively that a specific microbe can prevent atopic disease. Our new insight might provide an opportunity to devise strategies against allergy, the pandemic that affects almost half the population in more-developed countries.1

The notion of probiotics use in primary prevention of atopic disease was based on their ability to reverse increased intestinal permeability24—characteristic of children with atopic eczema and food allergy.25 Probiotics also enhance gut-specific IgA

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