Discussion
This prospective birth cohort study revealed that most children who were at risk of developing AD, especially the early-persistent AD phenotype, had antibiotic exposure within 6 months of life, which occurred in a dose-dependent manner. Moreover, the relationship between antibiotic exposure and the development and persistency of AD can be modified byIL-13 genetic susceptibility. These findings suggest that early life antibiotic exposure to a certain extent contributes to the development of AD and phenotype, especially in susceptible infants, and this can be modified by efforts toward primary prevention.
Despite antibiotic exposure in early life being a plausible risk factor for the development of AD in children, existing epidemiological evidence is controversial. Our finding on the association of antibiotics with AD in dose-response manner was similar to those in previous reports. A systematic review reported a significant positive dose–response association and approximately 7% increase in the risk of AD due to antibiotic exposure during the first year of life.(20) Another prospective cohort study from Japan reported that an increase in the current AD risk in 5-year-old children is due to antibiotic exposure within the first 2 years of life.(21) However other studies concluded that there was no such relationship between antibiotic exposure in infancy and the development of AD.(22, 23) Differences in results could be due to differences in exposure to antibiotic dose, types of antibiotics, exposure time, definition and timing of outcome, and target sample size.
Although the basic etiology of AD is not fully known, it is thought to be attributable to complex, but interrelated biologic pathways, such as dysfunction of the skin barrier and altered innate or adaptive immune responses.(24) The recent increase in the incidence of AD seems to be due to changes in lifestyles and environmental factors. For example, there is evidence that increasing antibiotic exposure in early life contributes to increased AD susceptibility in children. Note that the exposure to at least one antibiotic between 0-6 months and 0-1 year occurred in 34.3% and 67.4% of the study population, which comprised the COCOA study population (data not shown); this rate was higher than those reported in other studies.(21, 25) Therefore, much attention should be paid to various antibiotic exposure-related factors influencing human health.
The hypothesized mechanism was supported by findings of studies showing antibiotic-induced killing of commensal bacteria is important for the normal development of immune function, which in turn, leads to gut dysbiosis of the microbial community in infants. This increases the risk of developing allergic conditions later in life. In mouse model studies, antibiotics administration exacerbated clinical signs of AD and caused gut dysbiosis such as increased levels of Th2 cytokine IL-4 with significantly suppressed short-chain fatty acid levels, which influence Treg cell induction and enhance barrier function.(7) To identify potentially relevant gut microbiome changes in the early life with regard to antibiotics use and AD outcomes in children, we additionally analyzed the fecal samples of 235 Korean infants who were enrolled in COCOA study (See “Gut microbiome analysis ” in the Online Repository). The relative abundance of Firmicutes was significantly lower and Fusobacteria composition was significantly higher in AD subjects with antibiotic exposure compared with those without antibiotic exposure (Fig. E3A, E3B), which is consistent with other studies.(26, 27) Recent evidence indicates that a disproportionate representation-such as a decrease or increase in the composition-of Firmicutes and Fusobacteria can impact the CD4 T cell function and development of immune pathology in intestine.(26, 27) Therefore, antibiotic exposure in early life may affect immune development through changes in gut microbiomes, which attribute to increase the incidence of AD.
Another pathogenetic mechanism is that gut epithelial barrier destruction through the disturbance of microbiota after antibiotic administration may lead to tissue damage and allergic sensitization.(28) The aforementioned studies suggest that gut epithelial inflammation resulting from antibiotic-induced dysbiosis may play a decisive role in the development, persistence, or aggravation of AD.
Several studies have indicated that IL-13 (rs20541) is associated with the risk of AD(9, 29) and there may be gene–environment interactions between IL-13 polymorphisms and antibiotic exposure in early life, which affects the clinical features of allergic diseases.(11) Since studies regarding the association of AD phenotypes with these factors are lacking, this study focused on the effect of the interaction between risk genes and environmental risk factors and demonstrated that while antibiotic exposure in early life itself may influence the development of AD, especially early-persistent AD, this trend was particularly notable in infants carrying the IL-13 (rs20541) variant. However, we should note that we had limited power to detect such an interaction.
Key factors of AD are defects in the skin barrier function, abnormality of the skin immunologic barrier, and dysbiosis, which may aggravate each other. Gut dysbiosis induced by antibiotics was associated with reduction in mucosal CD4+T cells expressing IFN-γ which play a role in maintaining the barrier function of the skin,(27) therefore predisposes the infants to cutaneous disease. In addition, when considering the complex nature of AD along with genetic and environmental risk factors,IL-13 genetic polymorphism increases IL-13 production, which affects the expression level of the skin barrier protein,(13) and this may have an additional role in aggravating the barrier function of the skin. Further studies regarding skin barrier disturbance, microbiome and metabolite\souts induced during early life antibiotic exposure are needed to support a plausible biological pathway.
The strength of our study is the use of a large general population-based birth cohort and the measurement of potential confounders included in the analysis. We found the results for AD to be similar to those in previous studies, suggesting that antibiotic exposure in early life was associated with the risk of childhood AD.(30, 31) Our study is also strengthened by the use of pediatric allergist’s medical report of doctor-diagnosed AD as the outcome variable. In addition, this study assessed the effects of antibiotic exposure in the first 6 months of life, focusing on not only the occurrence but also the severity and persistency of AD in childhood, raising awareness about the prescription of antibiotics that can be abuse.
This study also had some limitations. First, our cohort study could not determine the exact dose, total duration, and types of antibiotics that could influence the effect of antibiotics on immune responses. As broad-spectrum antibiotics were found to have stronger effects than the narrow-spectrum one,(23) further study by utilization of the National Health Insurance data is needed to confirm these specific effects of individual antibiotics on AD. Another limitation is the increased incidence of skin infections in children with AD, which makes it difficult to identify a genuine causal association, as children are more likely to receive antibiotics. Additional studies are needed to confirm the causality and prove the mechanism by which antibiotic exposure at a young age causes changes in the skin or gut microbiome and leads to the development of AD. Moreover, acute bronchiolitis, one of the main causes of antibiotic exposure in early life, is a long-term risk factor for asthma; hence, frequent bronchiolitis may be related to predisposition to allergy. However, there was no significant difference in the history of acute bronchiolitis within the first 6 months of life according to the diagnosis of AD. More studies are still needed on maternal antibiotic administration during pregnancy, antibiotic exposure after 6 months after birth, and confounding factors caused by maternal and child infections.
Although AD is not a life-threatening disease, more than 60% of children with AD are predisposed to develop one or more atopic comorbidities, such as food allergy, asthma, or allergic rhinitis, which is so-called “atopic march.”(32) Therefore, it is important to define the exact role of early-life antibiotic exposure to evaluate its association with the development and clinical course of AD and progression to other allergic diseases to make successful strategies in allergy prevention. Our present study suggested that children with antibiotic exposure early in life were at risk of developing early-persistent AD, and a dose–response relationship was observed in young children, particularly in infants carrying IL-13 (rs20541) genetic susceptibility alleles. Attention needs to be paid to unwarranted prescription of antibiotics, especially in susceptible children receiving primary care. This study will improve our understanding on the influence of genetic and environmental causes and their interactions on childhood AD and provide comprehensive insights into the pathogenesis and phenotype of AD and therefore enable improved prevention.