The early-life microbiome has a fundamental role in human immunity. Indigenous microbiota provides crucial signals for maturation and modulation of the immune system (1, 2). In contrast, dysbiosis in infancy might cause stunting and dysregulation of immunity (3, 4). The composition of gut microbiota also correlates with vaccine immunogenicity (5). Evidence has suggested the association between early-life microbial colonization and sustainable vaccine-specific memory T-cells and antibody responses (6).

Exposure to medications, particularly antibiotics, is a common cause of dysbiosis (7, 8). Even short-term or low-dose antibiotics can disturb the delicate ecosystem of the infant microbiome (9, 10). Early-life antibiotic exposure has been linked to a higher risk of various conditions, including inflammatory bowel disease, type 2 diabetes, and atopic disorders (11–13). However, little is known about the effect of infantile antibiotic exposure on susceptibility to later-life infections. In addition, although antibiotic-driven dysbiosis has been found to impair vaccine responses (10, 14, 15), limitations are that most studies were conducted with a small sample size and in animal models or adults. Whether early-life antibiotic exposures decrease vaccine efficacy or increase the risk of breakthrough infections in the pediatric population remains to be elucidated.

Varicella was once associated with a significant impact on public health in Taiwan (16). Since the implementation of universal varicella vaccination (UVV) in 2003, disease transmission has been successfully controlled (17). However, varicella outbreaks among schoolchildren still occurred occasionally (18), and breakthrough infections continue to be reported despite high rates of national vaccination coverage (19). The present study was aimed to investigate the effect of early-life antibiotic exposure on childhood varicella risk and breakthrough infections.

This nationwide cohort study suggests that antibiotic exposure early in life is an independent risk factor for childhood varicella. Even though herd immunity has been reached in the vaccination era, a significantly higher incidence of breakthrough varicella is observed in children exposed to antibiotics in early life. The present study adds to the mounting evidence that antibiotic-driven dysbiosis during infancy may cause sequelae linked with immune dysfunction, including increased susceptibility to infections.

Commensal-pathogen interactions involve the direct microbiota-related colonization resistance and the indirect microbiome-mediated immune modulation (29). Commensal microbiota can limit colonization of the invading pathogen through upregulating epithelial barrier function, competition for specific resources, and bactericidal or bacteriostatic effects (29, 30). Eubiotic microbiota also supports healthy immune development, shaping optimal innate and acquired immune responses against infective challenges (1, 2).

Evidence has demonstrated that a decrease in bacterial taxa, vacant nutrient niches, and metabolic environment changes after antibiotic administration predispose individuals to certain infections (31, 32), whereas the commensals may progressively return to baseline following antibiotic cessation (33). On the other hand, antibiotic-driven dysbiosis, especially in early life, might result in enduring immune alterations and long-lasting health impacts (3, 4). Animal studies have demonstrated that infant mice exposed to antibiotics had reduced and dysfunctional interferon-γ-producing CD8 T cells, resulting in subsequent increased mortality from vaccinia virus infection (34). In humans, children exposed to early-life antibiotics have been found to exhibit lower infection-induced cytokines, including interleukin 1β, interferon α, interferon γ, tumor necrosis factor α, and IP10 protein (35). Our results align with these immunological findings and support the microbiome-immune-infection axis theory. Early-life antibiotic exposure is associated with dysbiosis and impaired anti-infectious immunity and increases susceptibility to future varicella infections.

The role of the microbiome in the modulation of vaccine immunogenicity has recently been addressed (5). Several observational studies have documented the correlation between microbiota composition, such as the abundance of Bifidobacterium and Bacteroides species, and vaccine responses (6, 36, 37). Immunomodulatory molecules derived from microbiota, such as flagellin, peptidoglycan, and lipopolysaccharides, regulate T cell priming and immunoglobulin production in response to antigenic stimulation (36, 38, 39). Increasing data also suggests that epitopes encoded by the microbiota can cross-reactive with pathogen-encoded epitopes, presumably with vaccine-encoded epitopes (40, 41).

Despite the association between microbiome and vaccine responses, controversy exists over the influence of microbial perturbation on immunization. Antibiotic-driven dysbiosis impairs vaccine immunogenicity in infant mice but not in adult mice (14). From human research, adults with low pre-existing immunity have been found to present markedly reduced post-vaccination antibody titers after experiencing antibiotic treatment (10). Nevertheless, antibiotic exposure in early life has not significantly affected immunogenicity induced by routine infant vaccines, while sample sizes of these studies were modest (42, 43). Additionally, effects of prebiotics or probiotics on vaccine response are variable, depending on the antigens, probiotic strains, and population (44–46). To date, none of these microbiota-targeted interventions have been transferred from research into clinical practice. Our study assessed incidence of breakthrough varicella among children exposed to early-life antibiotics. Although the UVV program has provided robust protection, infantile antibiotic exposure was still an independent risk factor for childhood breakthrough varicella. Such risk might result from increased varicella pathogenicity following antibiotic exposure overwhelming the vaccine protective efficacy or alteration of vaccine responses induced by antibiotic-driven dysbiosis. Further studies are needed to clarify the effects of early-life antibiotic exposure on immunization and vaccine efficacy.

The microbiota changes related to antibiotics depend on the type of antibiotic used. Previous studies have suggested that almost all types of antibiotics affect gut microbiota. The penicillin family of antibiotics, such as amoxicillin, piperacillin, and ticarcillin, may increase the abundance of Enterococcus spp. and decrease the abundance of anaerobes (47). Cephalosporins, quinolones, and sulfonamides have been associated with abundant Enterobacteriaceae except for Escherichia coli (47). Macrolide treatment has been linked to long-term gut microbiota perturbations among pre-school children, including depletion of Actinobacteria and increases in Bacteroidetes and Proteobacteria (48). The antimicrobial spectrum also influences the impact of antibiotics on the immune response to vaccination. An adult study has demonstrated that the proportion of vaccinees with a more than 2-fold anti-rotavirus antibody titer by 7 days post-vaccination was significantly higher among subjects treated with vancomycin only than those treated with broad-spectrum antibiotics (15). In the present study, early-life exposure to penicillins, cephalosporins, macrolides, or sulfonamides were all independent risk factors for childhood varicella in the pre-vaccination era. The risk of breakthrough varicella due to exposure to these antibiotics in the vaccination era was also observed, although without statistical significance owing to the small number of cases. Relationship between the risk and antimicrobial spectrum of the administered antibiotic remains to be elucidated, since we only examined the effects of using different types of antibiotics rather than the specific antibiotic on varicella occurrence. Overall, caution is warranted in prescribing any type of antibiotic to infants despite their benefits. It should also be taken into account the effects on the human microbiome when administering antibiotic therapy.

Our study has several strengths. The population-based cohort study design enabled us to assess the association between antibiotic exposure and varicella infections. By utilizing the nationwide NHIRD, we enrolled a large sample size, which prevented selection bias, allowing us to identify relatively rare conditions such as post-vaccination infection, and provide reliability in terms of statistics with a smaller margin of error.

Despite these strengths, there are several limitations. First, as this was an observational study, we could only report an association between antibiotic exposure and subsequent varicella but could not infer causality. Second, patient-specific information such as lifestyle, contact history, seeking healthcare in private practice, and over-the-counter medication use was unavailable from the NHIRD. To minimize biases, cohorts possessed comparable characteristics after matching gender, propensity score, and non-antibiotic microbiota-altering medications. We also performed multivariable analyses to adjust for potential confounders. Third, the specific date of vaccination, the total number of varicella vaccines administered, whether concomitant vaccinations were used or not, and the interval from antibiotic exposure to vaccination were not recorded in the dataset. Therefore, it is difficult to assess the effects of antibiotic exposure on immunization. Instead, we reported the association between antibiotic therapy in infancy and varicella during childhood regardless of herd immunity. Finally, as our study focused on varicella, the generalizability of our results may be limited. Nevertheless, it provided valuable information on the microbiome-immune-infection axis theory.

In conclusion, children exposed to antibiotics in infancy are associated with varicella later in life. Antibiotic exposure is an independent risk factor for varicella occurrence, even though herd immunity has been reached. These findings suggest caution when administering antibiotics in early life to prevent increased infection susceptibility and poor vaccine efficacy.

The data analyzed in this study is subject to the following licenses/restrictions: All researchers who wish to use the NHIRD and its data subsets are required to sign a written agreement declaring that they have no intention of attempting to obtain information that could potentially violate the privacy of patients or care providers. Requests to access these datasets should be directed to Center for Biomedical Resources of NHRI, https://nhird.nhri.org.tw/en/Data_Protection.html.

The studies involving human participants were reviewed and approved by the ethical review board of Taichung Veterans General Hospital (No. CE20224B). Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Study concept and design: T-LL, Y-HF, Y-JC, C-YW. Statistical analysis: Y-LC, HH. Analysis and interpretation of data: T-LL, L-LL, Y-JC. Drafting of the manuscript: T-LL, Y-JC. Critical revision of the manuscript for important intellectual content: T-LL, C-YW, Y-JC. All authors read and approved the final manuscript.

This work is supported in part by the Ministry of Science and Technology, Taiwan (MOST 109-2327-B-010-005; 109-2410-H-110-016-MY2).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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