The gut metagenome harbors metabolic and antibiotic resistance signatures of moderate-to-severe asthma.

Asthma is a common allergic airway disease that has been associated with the development of the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing of 95 stool samples from a cross-sectional cohort of 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in adults and children 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways, which have been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes (ARGs) in people with asthma. Several differentially abundant ARGs in the asthma cohort encode resistance to macrolide antibiotics, which are often prescribed to patients with asthma. Lastly, we found that ARG and virulence factor (VF) richness in the microbiome were correlated in both cohorts. ARG and VF pairs co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are coselected and maintained in the fecal microbiota of people with asthma. Overall, our results show functional alterations via LCFA biosynthetic genes and increases in antibiotic resistance genes in the gut microbiota of subjects with moderate-to-severe asthma and could have implications for asthma management and treatment.

The gut microbiota of people with asthma influences lung inflammation in gnotobiotic mice.

The gut microbiota in early childhood is linked to asthma risk, but may continue to affect older patients with asthma. Here, we profile the gut microbiota of 38 children (19 asthma, median age 8) and 57 adults (17 asthma, median age 28) by 16S rRNA sequencing and find individuals with asthma harbored compositional differences from healthy controls in both adults and children. We develop a model to aid the design of mechanistic experiments in gnotobiotic mice and show enterotoxigenic Bacteroides fragilis (ETBF) is more prevalent in the gut microbiota of patients with asthma compared to healthy controls. In mice, ETBF, modulated by community context, can increase oxidative stress in the lungs during allergic airway inflammation (AAI). Our results provide evidence that ETBF affects the phenotype of airway inflammation in a subset of patients with asthma which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

The gut metagenome harbors metabolic and antibiotic resistance signatures of moderate-to-severe asthma.

Asthma is a common allergic airway disease that develops in association with the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing of 95 stool samples from 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in children and adults 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways which have been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes (ARGs) in people with asthma. One differentially abundant ARG was a macrolide resistance marker, ermF, which significantly co-occurred with the Bacteroides fragilis toxin, suggesting a possible relationship between enterotoxigenic B. fragilis, antibiotic resistance, and asthma. Lastly, we found multiple virulence factor (VF) and ARG pairs that co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are co-selected and maintained in the fecal microbiota of people with asthma. Overall, our results show functional alterations via LCFA biosynthetic genes and increases in antibiotic resistance genes in the gut microbiota of subjects with moderate-to-severe asthma and could have implications for asthma management and treatment.

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation.

Homeostatic mucosal immune responses are fine-tuned by naturally evolved interactions with native microbes, and integrating these relationships into experimental models can provide new insights into human diseases. Here, we leverage a murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Colonization with Bph induces the differentiation of interleukin-17A (IL-17A)-secreting T-helper cells that aid in controlling bacterial abundance. Bph colonization protects from AAI and is associated with increased production of secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. These findings are additionally supported by clinical data showing that higher levels of upper respiratory SLPI correlate both with greater asthma control and the presence of Haemophilus, a bacterial genus associated with AAI. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway.

Breathe Soft, What Bugs through Early Windows Break?

In this issue of Cell Host & Microbe, Teo et al. (2018) explore the development of the upper airway microbiota over the first 5 years of life and provide evidence for a "critical window" of microbial exposure that contributes to chronic wheezing, a precursor to asthma.