With the advancement of high‐throughput DNA/RNA sequencing and computational analysis techniques, commensal bacteria are now considered almost as important as pathological ones. Understanding the interaction between these bacterial microbiota, host and asthma is crucial to reveal their role in asthma pathophysiology. Several airway and/or gut microbiome studies have shown associations between certain bacterial taxa and asthma. However, challenges remain before gained knowledge from these studies can be implemented into clinical practice, such as inconsistency between studies in choosing sampling compartments and/or sequencing approaches, variability of results in asthma studies, and not taking into account medication intake and diet composition especially when investigating gut microbiome. Overcoming those challenges will help to better understand the complex asthma disease process. The therapeutic potential of using pro‐ and prebiotics to prevent or reduce risk of asthma exacerbations requires further investigation. This review will focus on methodological issues regarding setting up a microbiome study, recent developments in asthma bacterial microbiome studies, challenges and future therapeutic potential.

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12-18 months Unsupervised microbiome-driven clustering Sputum microbial signature assessment Neutrophils Commensal bacteria Pathogenic bacteria Airway obstruction Macrophages Cluster 1 Severe adult asthma patients Baseline 12-18 month follow-up 2 robust microbiome clusters with relative stability after 12-18 months Cluster 2 More severe asthma Less severe asthma

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RationaleTargeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes in the microbiome that is adapted to CF lungs may occur.ObjectivesTo investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.MethodsThis was a single-center longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample were collected before and every 3 months after starting therapy, up to 1 year.ResultsTwenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that Pseudomonas aeruginosa was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow up.ConclusionsAfter starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

4 asthma cohorts • BreathCloud • U-BIOPRED adults • U-BIOPRED pediatric patients • PACMAN2 eNose technology Measure patterns of volatile organic compounds mixtures in exhaled air Machine learning (2 training + 2 validation sets) eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy Atopic Nonatopic eNose accurately classifies atopy Offline eNose pla orm Real-me SpiroNose

There is a clinical need to identify children with poor asthma control as early as possible, to optimize treatment and/or to find therapeutic alternatives. Here, we present the “Systems Pharmacology Approach to Uncontrolled Pediatric Asthma” (SysPharmPediA) study, which aims to establish a pediatric cohort of moderate-to-severe uncontrolled and controlled patients with asthma, to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach. In this multicenter observational case–control study, moderate-to-severe asthmatic children (age; 6–17 years) were included from four European countries (Netherlands, Germany, Spain, and Slovenia). Subjects were classified based on asthma control and number of exacerbations. Demographics, current and past patient/family history, and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics, and metabolomics were evaluated from multiple samples. In all, 145 children were included in this cohort, 91 with uncontrolled (median age = 12 years, 43% females) and 54 with controlled asthma (median age = 11.7 years, 37% females). The two groups did not show statistically significant differences in age, sex, and body mass index z-score distribution. Comprehensive information and diverse noninvasive biosampling procedures for various omics analyses will provide the opportunity to delineate underlying pathophysiological mechanisms of moderate-to-severe uncontrolled pediatric asthma. This eventually might reveal novel biomarkers, which could potentially be used for noninvasive personalized diagnostics and/or treatment.

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