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Infant airway microbiota and topical immune perturbations in the origins of childhood asthma.

ABSTRACT: Asthma is believed to arise through early life aberrant immune development in response to environmental exposures that may influence the airway microbiota. Here, we examine the airway microbiota during the first three months of life by 16S rRNA gene amplicon sequencing in the population-based Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort consisting of 700 children monitored for the development of asthma since birth. Microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at age one month are associated with asthma by age 6 years, both individually and with additional taxa in a multivariable model. Higher relative abundance of these bacteria is furthermore associated with an airway immune profile dominated by reduced TNF-? and IL-1? and increased CCL2 and CCL17, which itself is an independent predictor for asthma. These findings suggest a mechanism of microbiota-immune interactions in early infancy that predisposes to childhood asthma.

SUBMITTER: Thorsen J

PROVIDER: S-EPMC6825176 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Infant airway microbiota and topical immune perturbations in the origins of childhood asthma.

Thorsen Jonathan J Rasmussen Morten A MA Waage Johannes J Mortensen Martin M Brejnrod Asker A Bønnelykke Klaus K Chawes Bo L BL Brix Susanne S Sørensen Søren J SJ Stokholm Jakob J Bisgaard Hans H

Nature communications 20191101 1

Asthma is believed to arise through early life aberrant immune development in response to environmental exposures that may influence the airway microbiota. Here, we examine the airway microbiota during the first three months of life by 16S rRNA gene amplicon sequencing in the population-based Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC<sub>2010</sub>) cohort consisting of 700 children monitored for the development of asthma since birth. Microbial diversity and the relative ...[more]

PMID: 31676759

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Project description:BackgroundAsthma and obesity are both complex conditions characterized by chronic inflammation, and obesity-related severe asthma has been associated with differences in the microbiome. However, whether the airway microbiome and microbiota-immune response relationships differ between obese persons with or without nonsevere asthma is unestablished.ObjectiveWe compared the airway microbiome and microbiota-immune mediator relationships between obese and nonobese subjects, with and without mild-moderate asthma.MethodsWe performed cross-sectional analyses of the airway (induced sputum) microbiome and cytokine profiles from blood and sputum using 16S ribosomal RNA gene and internal transcribed spacer region sequencing to profile bacteria and fungi, and multiplex immunoassays. Analysis tools included QIIME 2, linear discriminant analysis effect size (aka LEfSe), Piphillin, and Sparse inverse covariance estimation for ecological association inference (aka SPIEC-EASI).ResultsObesity, irrespective of asthma status, was associated with significant differences in sputum bacterial community structure and composition (unweighted UniFrac permutational analysis of variance, P = .02), including a higher relative abundance of Prevotella, Gemella, and Streptococcus species. Among subjects with asthma, additional differences in sputum bacterial composition and fungal richness were identified between obese and nonobese individuals. Correlation network analyses demonstrated differences between obese and nonobese asthma in relationships between cytokine mediators, and these together with specific airway bacteria involving blood PAI-1, sputum IL-1β, GM-CSF, IL-8, TNF-α, and several Prevotella species.ConclusionObesity itself is associated with an altered sputum microbiome, which further differs in those with mild-moderate asthma. The distinct differences in airway microbiota and immune marker relationships in obese asthma suggest potential involvement of airway microbes that may affect mechanisms or outcomes of obese asthma.

Project description:BackgroundPrenatal and infant acetaminophen exposure has been associated with an increased risk of childhood asthma phenotypes. Demonstration of biologically plausible interactions between these exposures and maternal and child antioxidant gene polymorphisms would strengthen causal inference.ObjectiveTo explore potential interactions between prenatal and infant acetaminophen exposure and antioxidant genotypes on childhood asthma.MethodsIn the Avon Longitudinal Study of Parents and Children, we typed a functional nuclear erythroid 2 p45-related factor 2 (Nrf2) polymorphism and glutathione S-transferase (GST) M1, T1, and P1 polymorphisms. Effects of prenatal and infant acetaminophen exposure on asthma phenotypes at 7 years were stratified by genotype in >4000 mothers and >5000 children.ResultsRisk of asthma and wheezing associated with early gestation acetaminophen exposure was increased when maternal copies of the minor T allele of Nrf2 were present (P interactions, .02 and .04, respectively). Risk of asthma associated with late gestation exposure was higher when maternal GSTT1 genotype was present rather than absent (P interaction, .006), and risk of wheezing was increased when maternal GSTM1 was present (P interaction, .04). Although acetaminophen use in infancy was associated with an increased risk of atopy, child antioxidant genotype did not modify associations between infant acetaminophen use and asthma phenotypes. However, the increased risk of asthma and wheezing associated with late gestation acetaminophen exposure in the presence of maternal GSTM1 was further enhanced when GSTM1 was also present in the child.ConclusionMaternal antioxidant gene polymorphisms may modify the relation between prenatal acetaminophen exposure and childhood asthma, strengthening evidence for a causal association. In contrast, relations between infant acetaminophen use and asthma and atopy were not modified by child genotype and may be confounded by pre-existing wheeze or allergy.

Project description:BACKGROUND:Differences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids. OBJECTIVE:To assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics. METHODS:A cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13) were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6) and to themselves after six weeks of treatment with fluticasone propionate (FP). Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing. RESULTS:Unsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP), termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1? and TNF-? and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1? and TNF-? was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls. CONCLUSION:The underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to microbiota.

Dataset Information

Infant airway microbiota and topical immune perturbations in the origins of childhood asthma.

Publications

Infant airway microbiota and topical immune perturbations in the origins of childhood asthma.

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