Food sensitization (FS) develops in early infancy and is a risk factor for subsequent food allergy (FA). Recent evidence suggests relationships of gut microbiota with FS and FA. However, little is known about the role of neonatal gut microbiota in the pathobiology of these manifestations. We sought to characterize gut microbiota in children using an enterotyping approach and determine the association of gut microbiota and the enterotypes with the development of FS and FA. We combined gut microbiome and fecal short-chain fatty acid data from 2 longitudinal birth-cohort studies in Japan, clustered the microbiome data from children who were 1 week to 7 years old and their mothers and identified enterotypes. We also determined the associations of gut microbiota and enterotypes with risks of developing FS and FA across the 2 studies using multivariable regression models. Data from the 2563 microbiomes identified 6 enterotypes. More gut bacteria (eg, Bifidobacterium) in 1-month-old children showed significant relationships with the development of FS and FA than in 1-week-old children. Enterotypes at 1 month old consisted of Bacteroides-dominant, Klebsiella-dominant, and Bifidobacterium-dominant enterotypes. Bifidobacterium-dominant enterotypes with the highest fecal propionate concentration had the lowest risks of developing FS and FA, especially of hen egg white sensitization. Bifidobacterium-dominant enterotypes had lower risks at 2 years old in one study (vs Bacteroides-dominant enterotype, adjusted odds ratio [adjOR]: 0.10, 95% CI: 0.01-0.78; vs Klebsiella-dominant enterotype, adjOR: 0.10, 95% CI: 0.01-0.77) and at 9 months old in the other study (vs Bacteroides-dominant enterotype, adjOR: 0.33, 95% CI: 0.11-0.91). In these birth-cohort studies, gut microbiome clustering identified distinct neonatal enterotypes with differential risks of developing FS and FA.

Background: Infants with bronchiolitis are at increased risk of developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. However, little is known about its biologically distinct subgroups based on the integrated metagenome and asthma genetic risk signature and their longitudinal relationships with asthma development.Methods: In a multicentre prospective cohort study of infants with severe bronchiolitis (i.e.bronchiolitis requiring hospitalisation), we profiled nasopharyngeal airway metagenome and virus at hospitalisation, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome–asthma genetic risk endotypes. In addition, we examined their longitudinal association with the risk of developing asthma by the age of 6 years.Results: Out of 450 infants with bronchiolitis (median age 3 months), we identified five distinct endotypes, characterised by their nasopharyngeal metagenome, virus and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled “classic” bronchiolitis), endotype E infants (characterised by a high abundance ofHaemophilus influenzae, high proportion of rhinovirus (RV)-A and RV-C infections and high asthma genetic risk) had a significantly higher risk of developing asthma (16.7%versus35.9%; adjusted OR 2.24, 95% CI 1.02–4.97; p=0.046). The pathway analysis showed that endotype E had enriched microbial pathways (e.g.glycolysis,l-lysine, arginine metabolism) and host pathways (e.g.interferons, interleukin-6/Janus kinase/signal transducers and activators of transcription-3, fatty acids, major histocompatibility complex and immunoglobin-related) (false discovery rate (FDR)<0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR<0.05).Conclusion: In this multicentre prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks of developing asthma.

Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kU_A/L increments, 0.67 and 0.66; 95%CI, 0.41-0.93 and 0.42-0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10-2.03), and these associations were observed until the end of OIT. In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Background: Bronchiolitis is the leading cause of infant hospitalization in U.S. and is associated with increased risk for childhood asthma. Immunoglobulin E (IgE) not only plays major roles in antiviral immune responses and atopic predisposition, but also offers a potential therapeutic target.Objective: We aimed to identify phenotypes of infant bronchiolitis by using total IgE (tIgE) and virus data, to determine their association with asthma development, and examine their biological characteristics.Methods: In a multicenter prospective cohort study of 1,016 infants (age <1 year) hospitalized for bronchiolitis, we applied clustering approaches to identify phenotypes by integrating tIgE and virus (respiratory syncytial virus [RSV], rhinovirus [RV]) data at hospitalization. We examined their longitudinal association with the risk of developing asthma by age 6 years and investigated their biological characteristics by integrating the upper airway mRNA and microRNA data in a subset (n=182).Results: In infants hospitalized for bronchiolitis, we identified 4 phenotypes: 1) tIgE^lowvirus^RSV-high, 2) tIgE^lowvirus^RSV-low/RV, 3) tIgE^highvirus^RSV-high, and 4) tIgE^highvirus^RSV-low/RV phenotypes. Compared to phenotype 1 infants (resembling “classic” bronchiolitis), phenotype 4 infants (tIgE^highvirus^RSV-low/RV) had a significantly higher risk for developing asthma (19% vs. 43%; adjOR, 2.93; 95% CI, 1.02–8.43; P=.046). Phenotypes 3 and 4 (tIgE^high) had depleted type I interferon and enriched antigen presentation pathways; phenotype 4 also had depleted airway epithelium structure pathways.Conclusions: In this multicenter cohort, tIgE-virus clustering identified distinct phenotypes of infant bronchiolitis with differential risks of asthma development and unique biological characteristics.

Infants hospitalized for bronchiolitis are at high risk for asthma. Glutathione-related metabolites may antagonize oxidative stress, which induces airway injuries in respiratory infection and subsequent airway remodeling. However, little is known about the relationship of glutathione-related metabolites with bronchiolitis severity and the risk of asthma. In a multicenter prospective observational cohort study of infants hospitalized for bronchiolitis, we measured nasopharyngeal and serum glutathione-related metabolites by using liquid chromatography–tandem mass spectrometry. We then examined their association with bronchiolitis severity (defined by positive pressure ventilation (PPV) use). We also identified severity-related glutathione-related metabolite signatures and examined their association with asthma at age 6 years. In 1013 infants, we identified 12 nasopharyngeal and 10 serum glutathione-related metabolites. In the multivariable models, lower relative abundances of seven metabolites, e.g., substrates of glutathione, including cysteine (adjOR 0.21, 95%CI 0.06–0.76), glycine (adjOR 0.25, 95%CI 0.07–0.85), and glutamate (adjOR 0.25, 95%CI 0.07–0.88), were significantly associated with PPV use (all FDR < 0.05). These associations were consistent with serum glutathione-related metabolites. The nasopharyngeal glutathione-related metabolite signature was also associated with a significantly higher risk of asthma (adjOR 0.90, 95%CI 0.82–0.99, p = 0.04). In infants hospitalized for bronchiolitis, glutathione-related metabolites were associated with bronchiolitis severity and asthma risk.