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.