Filling a hole in ozone research: The impacts of early life microbiome alterations on pulmonary responses to a non‐atopic asthma trigger

The predominantly commensal collection of bacteria, fungi, archaea, protozoa, and viruses that inhabit multicellular organisms constitutes the microbiota, and their DNA is referred to as the microbiome. Early-life microbiome perturbation influences the development of asthma (Russell et al., (2012)), which is a chronic lung disease that is characterized, in part, by persistent lung inflammation, cough, dyspnea, wheeze, variable expiratory flow limitation, and airway hyperresponsiveness (AHR). As a heterogeneous lung disease, asthma materializes as a diverse number of clinical phenotypes that result from exposure to either atopic or nonatopic stimuli (Wenzel, 2012). Russell et al. (2012) demonstrated that the magnitude of atopic lung inflammation induced by antigen (ovalbumin) sensitization and challenge in an animal model, which mimics features of atopic asthma in humans, is dependent upon the age when the gastrointestinal microbiota is perturbed. For example, administration of vancomycin, a glycopeptide antibiotic, to neonatal mice exacerbated antigen-induced lung inflammation that was assessed by enumerating the number of bronchoalveolar lavage (BAL) eosinophils. However, dosing adult mice with vancomycin did not exacerbate lung inflammation. Russell et al. (2012) proposed that heterogeneity in antigen-induced lung inflammation between vancomycin-treated mice of different ages was associated with differences in the composition of the gut microbiota yet did not present any extensive data to provide a mechanism for this phenomenon. The impact of early-life microbiome alterations on AHR and lung inflammation induced by exposure to ozone (O3), an air pollutant and a nonatopic asthma trigger, have not been previously addressed. In this issue, Brown, Tashiro, Kasahara, Cho, & Shore (2019) report the effects of reshaping the microbiome in male and female weaning mice on O3induced changes in lung pathology in adulthood. Specifically, the early-life microbiome was perturbed by cohousing weaning C57BL/6 mice that were purchased from two different vendors (The Jackson Laboratory and Taconic Farms), which are known to have distinct gut microbiota (Ivanov et al., 2009; Velazquez et al., 2019). Prior singleand cohousing experiments have concluded that despite highly similar genetic backgrounds, C57BL/6 mice from these two vendors have markedly dissimilar responses, including antibacterial and antifungal immunity (Ivanov et al., 2009; McAleer et al., 2016). These divergent responses were attributed, in part, to differences in the progression of a Th-17 immune response by segmented filamentous bacteria that are present in Taconic but not Jackson mice (Ivanov et al., 2009; McAleer et al., 2016). Brown et al. (2019) demonstrated that cohousing of weanling C57BL/6 mice from Jackson and Taconic largely abolished any vendor-related differences in the microbiome, which the authors attributed to coprophagy. Furthermore, increases in the number of BAL neutrophils, a hallmark feature of O3-induced lung inflammation, and O3-induced increases in airway responsiveness in cohoused male mice were significantly reduced as compared to same-housed mice. These results are in contrast to those of Russell et al. (2012) who reported that manipulating the early-life microbiome of neonatal mice with vancomycin exacerbated lung inflammation in response to antigen, an atopic asthma trigger. Although the early-life microbiome was altered in these studies via different mechanisms (antibiotic administration vs. cohousing), it is doubtful that this leads to opposing responses to atopic and nonatopic stimuli. In support of this thought, the investigators previously demonstrated that O3induced lung inflammation and AHR were also reduced in germ-free mice or mice treated with antibiotics (Cho et al., 2018). Thus, opposing responses of early-life microbiome perturbations on lung inflammation induced by atopic and nonatopic stimuli may be dependent on the branch of the immune system that drives these responses. For example, O3-induced lung inflammation is driven by the innate immune system while antigen-induced lung inflammation is initiated and perpetuated by both the innate and the adaptive immune system.