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Казахский национальный медицинский университет им. С.Д. Асфендиярова
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In consideration of past reports, the influence of antibiotics on allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis in Japan seems to be similar to that in western countries.

Because our study design was not based on basic science research, we could not show how exposures to antibiotics played a role in the later development of allergic diseases compared with other studies. A birth cohort study in Finland found that taking antibiotics altered and led to less diversity in the gut microbiota.[21], [22] In addition, the study found it took a long time for microbiota to recover from exposure to antibiotics.21 In mice, the gut microbiota regulates the immune system of several types of T cells.[23], [24] Cahenzli et al25 indicated that appropriate gut microbiota was important for protecting against immunoglobulin E induction. Microbiota altered by antibiotic exposure can compromise the immune system, leading to the development of allergic diseases. In a mouse model, mice treated with kanamycin during infancy showed a decrease in the production of interleukin (IL)-12, which regulates the maturation of T-helper type (TH) TH1 cells, and led to TH2-polarized immune deviation.26 Similarly, adding moxifloxacin to human monocytes decreased IL-8, IL-1β, and tumor necrosis factor-α secretion,27 suggesting that suppressing the TH1 response could polarize the immune system toward a TH2 response.

A Danish cohort study showed that antibiotic use increased the risk of inflammatory bowel diseases.28 Exposure to antibiotics in the first 6 months of life has been shown to raise the risk of increasing late-life body mass or obesity.[29], [30] Antibiotic exposure also can influence other health conditions, such as inflammatory bowel diseases and obesity.[28], [29], [30] Because the microbial community could play an important role in health and various diseases,31 further studies are needed to investigate how various health outcomes regarding gut microbiota are affected by antibiotic exposure.

This study has several limitations. First, exposure and outcome measurements were assessed by questionnaire and we did not confirm the diagnosis of allergic diseases directly with physicians or obtain information about the number of times antibiotics were used. We used validated questionnaires to evaluate outcomes in the same way as other cohort studies. In addition, we could not evaluate the dose-response analysis because we did not obtain details of antibiotic doses or courses. Hoskin-Parr et al32 observed a dose-dependent relation between antibiotic exposure and asthma development before 7.5 years of age. Ong et al33 also found a dose-dependent influence of antibiotic exposure on the onset of asthma before 3 years of age. A dose-dependent association between exposure to antibiotics and the development of allergic disorders such as asthma are apparent in the results of these past studies. Most past studies evaluated the association of postnatal exposure to antibiotics within the first year of life. Although we did not confirm the exact timing and course of antibiotics in our study, we found that any antibiotic exposure in children younger than 3 years was associated with allergic diseases. We hypothesize that the wide range of timing of antibiotic exposure in infants is associated with the development of allergic diseases. Further studies are expected to examine the relation of the frequency and timing of exposure to antibiotic use and allergic diseases. Second, we could not fully take into account other possible confounders such as prebiotics and probiotics because of a lack of information, although potential confounders including maternal history of allergy, maternal age at pregnancy, maternal smoking during pregnancy, mode of delivery, gestational age at delivery, daycare attendance, number of previous live births, bronchitis, and sex of the child were included in the multivariate regression analysis to obtain the aORs. Chawes34 observed that high levels of C-reactive protein, a sensitive marker of systemic low-grade inflammation in early life, was related to a lower forced expiratory volume in 1 second and a higher prevalence of bronchial hyperresponsiveness. Low-grade infections might be another important confounder, although in the present study history of bronchitis was included as a confounder. Wang et al35 demonstrated an association of exposure to antibiotics and/or acetaminophen to allergy development and found acetaminophen exposure in particular to be an important factor. In addition, we did not collect stool samples to evaluate microbiota or DNA samples of the mother and child. A previous study showed the additive effects of unfavorable IL-13 or CD14 genotypes, prenatal antibiotic exposure, and delivery mode on the development of atopic dermatitis in infancy.36 Further studies are needed to examine how these confounders and antibiotics play a role in the development of allergic diseases. Third, our study was a single-center and small birth cohort study, and we lost some participants during follow-up. A comparison of participants analyzed in our study with those lost to follow-up showed a difference in the number of previous live births (P < .001). Background differences constituted another limitation. Lack of statistical significance for the ORs in the models used might be due to the small sample with insufficient power to demonstrate the statistical significance of the effects. Our study was not an intervention study but an observational study. However, although the evidence level in our study was lower than that of an intervention study, we could demonstrate the association between antibiotic use and allergic outcomes. In future, we would like to confirm these findings using data from a large nationwide birth cohort study in Japan.37

In conclusion, our birth cohort study in Japan suggested that exposure to antibiotics at younger than 3 years increased the risk of developing allergic diseases at 5 years. Although the use of antibiotics is unavoidable when treating bacterial infections, appropriate antibiotic use for young children is encouraged as an approach to prevent the development of allergic diseases.

Acknowledgments

We deeply thank the mothers and children who participated in the T-CHILD and all staff members who were involved in the study.

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    Disclosures: Authors have no nothing to disclose.

    Funding Sources: This study was supported in part by Health and Labour Sciences Research grant 09158522 from the Ministry of Health, Labour, and Welfare of Japan and grant 20A-1 from the National Center for Child Health and Development.

    © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc.

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