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.