Altered infant human gut microbiome composition and metabolic activity are implicated in childhood atopy and asthma1. We hypothesized that compositionally distinct neonatal human gut microbiota exist and are differentially related to relative–risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1–11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age 35 days) were divisible into three microbiota–composition states (NGM1–3). Each incurred significantly different RR for multi–sensitized atopy at age–two years and doctor–diagnosed asthma at age–four years. The highest risk group, NGM3, showed lower relative abundance of certain bacteria (e.g. Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula), and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of adult human peripheral T–cells with sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin–4 and reduced the relative abundance of Foxp3+CD25+CD4+ cells. 12,13 DiHOME which discriminated NGM3 from lower–risk NGMs, recapitulated the effect of NGM3 fecal water on Foxp3+CD25+CD4+ cell relative abundance. These findings suggest that neonatal gut microbiome dysbiosis drives CD4+ T–cell dysfunction associated with childhood atopy.

Background Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. Objective We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. Methods A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined. Results Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; % CI, 0.25–.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33–1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02–0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002–0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01–0.88). Adverse events were rare and similar among arms. Conclusions Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.

Significance Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii , which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response.

Capsule Summary Pet-ownership, which has been shown to be protective against allergic disease development, is associated with increased house dust bacterial diversity and fewer fungal species, suggesting a potentially microbial-based mechanism for this protective effect.

Author contributions S.R.L. designed the study, performed immune assays, animal models, metagenomic analysis, biochemical assays, mass spectrometry and statistical analyses, and developed the manuscript. K.A.S. assisted with animal models, performed all microscopy analysis and contributed to the manuscript. D.L.L. assisted with animal models and human immune assays. A.R.P. assisted with animal models and manuscript editing. K.E.F. and K.M. assisted with metagenomic and statistical analysis. E.F. assisted with microscopy. D.R.O., E.M.Z. and C.C.J. provided WHEALS cohort samples and data. M.M. and M.D.C. provided TIPS cohort samples and data. H.A.B. contributed to manuscript development. S.V.L. designed and supervised the study and developed the manuscript. Competing interests S.V.L. is co-founder of Siolta Therapeutics Inc., and serves as both a consultant and a member of its Board of Directors. Furthermore, the Regents of the University of California, UCSF have filed a provisional patent application (Application number 62/637,175) on behalf of S.V.L. and S.R.L. relating to the methods and compositions of EH genes.