Editorial: Disentangling Early‐Life Antibiotics and Infections as Risk Factors for the Development of Childhood IBD

As the global prevalence of inflammatory bowel disease (IBD) is increasing, emphasis has been placed on identifying modifiable risk factors that can aid in prevention [1]. Early-life factors, including antibiotic use and the occurrence of infections, increase the risk of developing IBD [2, 3]. This has been demonstrated in several studies, including a large-scale population-based study in Denmark, which found that antibiotic use was associated with an 84% increase in the risk of developing IBD in childhood [4]. However, most of these studies were unable to disentangle whether this increased risk was attributable to underlying infection, the use of antibiotics or, potentially, both. Marild et al. capitalised on using parent questionnaire data from two Scandinavian birth cohorts, assessing whether antibiotic exposure and/or infections in the first 3 years of life increased the risk of IBD [5]. They concluded that early-life antibiotic use, independent of infection frequency, was associated with an increased risk of developing IBD. Furthermore, there was no clear association between the number of childhood infections and the later development of IBD, although up to 20% of data were missing. This was similar to the findings by Oh et al., in which a dose-dependent association was seen between childhood antibiotic use and the development of IBD, independent of type of underlying infection [6]. Interestingly, however, Marild et al. noted differential findings when stratifying by antibiotic subtype. Penicillins (narrow and broad-spectrum) increased the risk of IBD when utilised within the first year of life; non-penicillin antibiotics increased the risk of IBD when used during the first 1–3 years of life. Although the significance of this remains uncertain, it does imply that antibiotic use may contribute to the development of IBD differently through the ages. We see evidence of this in prior studies, as individual classes of antibiotics posed differential risks for the development of IBD based on both an individual's chronological age as well as the antibiotic's potential impact on the intestinal microbiome [7, 8]. Additionally, although the link between antibiotic use and incident IBD has been uniformly demonstrated, the link between an underlying infection and the later development of IBD has not. This study, in contrast to prior data by Axelrad et al., demonstrated that frequency of infections in childhood may not be a significant risk factor for childhood IBD [9]. This may be due to the inclusion of milder infections, as these survey-based data do not rely on clinical codes which inherently exclude mild infections managed at home. To this end, when stratifying by severity of infection, Marild et al. did find that infections requiring hospitalisation were associated with a 35% increase in risk of IBD [5]. While this study centres on the first 3 years of life—a critical period for immune and microbiome development—future work must also account for exposures that continue to occur throughout life. This will deepen our understanding of long-term risk factors for developing IBD and pave the way for future preventive strategies. Katherine L. Stone: writing – original draft, writing – review and editing. Adam S. Faye: writing – original draft, writing – review and editing. Katherine L. Stone declares no conflicts of interest. Adam S. Faye reports research Support from Crohn's and Colitis Foundation, American College of Gastroenterology and the NIH. Adam S. Faye has received consultant fees from Takeda, BMS and Abbvie. This article is linked to Marild et al paper. To view this article, visit https://doi.org/10.1111/apt.18358. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.