153 Microbiome modulation by antibiotics in patients with asthma the baseline of the antibiotic group (controls: median SI 3.9, IQR 3.6-4.1; antibiotic group before treatment: SI 3.8, IQR 3.6-4.0; Wilcoxon P=.76). On a genus level, patients in the antibiotics group had a similar composition at baseline as controls. However, after antibiotics their composition profoundly changed, with overgrowth of Streptococcus spp. and a decrease in anaerobic taxa, such as Bacteroides spp. (Figure 1C). Intrabronchial HDM/LPS instillation induced an increase in eosinophil, neutrophil and lymphocyte numbers in BALF when compared with saline, while the number of alveolar macrophages was not altered (Figure 1D). There was no difference in the primary outcome between groups: eosinophil and neutrophil counts were similar in patients in the antibiotics group and the control group upon local HDM/LPS challenge (Figure 1D). Likewise, lymphocyte and alveolar macrophage numbers did not differ between groups. To obtain further insight into the effect of antibiotic-induced gut microbiome disruption on inflammatory responses after HDM/LPS challenge, we measured a broad spectrum of mediators relevant for allergic lung inflammation in BALF. HDM/LPS instillation, when compared with saline, induced increases in neutrophil chemoattractants, such as interleukin (IL)-1ß, IL-8 and tumor necrosis factor (TNF)-α, the eosinophil attractant RANTES and other mediators of inflammation. None of these responses were influenced by antibiotic-induced distortion of the gut microbiome (Supplementary Table 2). Discussion In this proof-of-concept study, we report no effect of short-term antibiotic-mediated gut microbiome disruption on pulmonary inflammation in patients with allergic asthma. An increasing body of animal data support the hypothesis of the gut-lungaxis in asthma, as local microbiota of the gut influence pulmonary immune responses through a shared mucosal immune system [4-6]. In humans, an extensive populationbased cohort analysis, showed that a decrease in antibiotic use at infancy was associated with a decrease in asthma incidence in children [1]. In this cohort microbiome diversity was a significant mediator between antibiotic exposure and asthma diagnosis [1]. Our study has limitations. First, results obtained from patients with mild allergic asthma cannot be extrapolated directly to severe asthma and this trial did not distinguish between different endotypes of asthma. Second, the trial design was aimed at direct effects of short-term gut microbiome modulation on subsequent airway inflammation in adult asthmatics. Results of this trial cannot be compared with data on the role of early-life antibiotics on the onset of asthma. Third, the timing of BALF collection, seven hours after provocation, could preclude effects that are expected at later timepoints. Fourth, even though our focus was on the influx of eosinophils and neutrophils into the bronchoalveolar space, a more in-depth analysis of other immune cells such as type-2 innate lymphoid cells was not performed and could be of interest in future studies. Last, due to the combination of antibiotics used, we cannot distinguish effects of single antibiotics or bacterial strains. We opted for this broad-spectrum antibiotic regimen arguing that, if an effect of microbiome modulation on allergic asthma were to be expected, it would be so after profound gut microbiome distortion [7]. 7
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