Abstract
Background: Although
atopic dermatitis (AD) is associated with certain gene variants, the
rapidly increasing incidence of AD suggests that environmental factors
contribute to disease development. In this study, we investigated the
association of AD incidence and phenotype with antibiotic exposure
within 6 months of age, considering the dose administered and genetic
risk.
Methods: This study included 1,637 children from the COCOA
birth cohort. Pediatric allergists assessed the presence of AD at each
visit and obtained information about antibiotic exposure for more than 3
days. IL-13 (rs20541) polymorphism was genotyped by the TaqMan
method. We stratified the AD phenotypes into 4 groups and used
multinomial logistic regression models for analysis.
Results: Antibiotic exposure within 6 months of age was found
to increase the risk of AD within 3 years of life (aOR=1.40, 95%, CI
1.09–1.81) in dose-dependent manner. Antibiotic exposure more than
twice increased the risk of the early-persistent AD phenotype (aOR=2.50,
95% CI 1.35–4.63). There was a weak interaction between genetic
polymorphisms and environmental factors on the development of AD (p for
interaction=0.06). Children with the IL-13 (rs20541) GA+ AA
genotype have a higher risk of the early-persistent AD phenotype when
exposed to antibiotics more than twice than those with the IL-13
(rs20541) GG genotype and without exposure to antibiotics (aOR=4.73,
2.01–11.14).
Conclusion: Antibiotic exposure within 6 months was related to
the incidence of early-persistent AD and a dose-dependent increase in
the incidence of AD in childhood, whose effect was modified by theIL-13 (rs20541) genotype.
Key words: dermatitis, atopic; phenotype; anti-bacterial
agents; IL-13 ; polymorphism
Introduction
Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease
characterized by itching eczematous lesions, and it is the leading cause
of health burden due to non-fatal skin-related disease globally.(1) The
prevalence rate of childhood AD ranges from 15% to 20%(2) and varies
widely from one country to another globally. In Korea, primary surveys
of children and adolescents demonstrated increasing trends in the
prevalence of AD symptoms within the last 12 months.(3)
To identify the cause of AD and to effectively prevent and manage it,
many epidemiological studies have been conducted on hygiene hypothesis.
This hypothesis states that the Western lifestyle not only limits
infection and microbial exposure but also alters the colonization of the
gut microbiome, thereby disrupting the development of the immune system
and leading to allergic disease. As part of this concept, there is
growing evidence that the increased prevalence of allergic diseases can
be attributed to increased exposure to antibiotics.(4) In particular,
the antibiotic prescription rate for all pediatric patients increased
from 34.8% in 2010 to 70.4% in 2014 in Korea.(5) Therefore, it is
necessary to investigate the relationship between increasing exposure to
antibiotics and the development of AD. Previous studies have
demonstrated that the composition and function of the gut microbiome at
6 months of age could affect the course of AD in early childhood (6) and
antibiotic administration aggravates clinical signs in a mouse model of
AD (7). No other studies have analyzed the severity and natural course
of AD according to the frequency of early-life antibiotic exposure.
Thus, considering these factors, we hypothesized that antibiotic
exposure within the first 6 months of life affects not only the severity
of AD but also the natural course of AD through changes in the
microbiome. In this prospective birth cohort study, we focused on the
relationship between the development of AD and antibiotic exposure
within 6 months, a critical period in the development of the microbiome
and the immune system, and further examined whether the frequency of
antibiotic exposure is differently associated with the severity and
phenotypes of AD.
AD was considered a TH2 disease characterized by
interleukin (IL)-4 and 13 signaling. IL‐13 has a significant
impact on the alteration of the skin microbiome, causing the
deterioration in barrier function of the skin, and it may be a more
important mediator for the TH2 response in the skin thanIL‐4. (8) Previous studies have identified that polymorphisms in
the IL-13 promoters are associated with the development of AD,(9,
10) and among them, many studies have focused on rs20541, especially in
terms of its relationship with AD, in the existing Asian
population.(11-13) Following on from the above considerations, we
hypothesized that antibiotic exposure influences the AD phenotype and
this relationship can be modified by IL-13 polymorphism. In this
study, we explored the association of the occurrence and phenotype of AD
with antibiotic exposure within 6 months of age, considering the dose
administered and IL-13 (rs20541) polymorphism.