UCSF

Allergic asthma is a chronic inflammatory disease characterized by Th2 inflammation and elevated circulating immunoglobulin E (IgE) concentrations. Although risk alleles associated with atopy and asthma have been identified, the rapid increase in prevalence, particularly amongst school-aged children in industrialized nations, cannot be explained by host genetics alone. This indicates that environmental factors must play a role in disease development.Dog ownership represents an early-life environmental exposure associated with a decreased relative-risk of atopy and lower levels IgE in childhood. Alterations in the gut microbiome in early life have also been linked to development of childhood atopy and asthma, thus we hypothesized that the reduced risk of atopy associated with dog ownership may be due in part to changes in gut microbial composition and development. To determine the impact of dog exposure on the gut microbiome over the first year of life we performed 16S rRNA gene bacterial profiling focusing on the V4 region in longitudinally collected infant stool samples (1 week, and 1, 3, 6, and 18 months) from the children of mothers living with ≥1 dog in the home for ≥6 months pre-delivery or mothers living in a pet-free home. We found that prenatal and early-life indoor dog exposure associates with increased gut microbial richness (p=0.046) and diversity (p=0.036) during infancy, with the latter being most apparent between 3 and 6 months of age. Several organisms with immunomodulatory capacities including Ruminococcaceae, Lachnospiraceae, and Clostridiaceae were found to be enriched across the sampling period in dog-exposed infants. Interestingly, statistically significant effects of dog exposure on β-diversity metrics were restricted to formula-fed children suggesting that in the absence of breast milk, dogs may provide an alternative source of environmental microbes that influence development of the infant gut microbiome. Thus, the emerging data suggests that early life dog exposure enriches microbes in the gut capable of modulating responses to inflammatory stimuli. Differences in gut microbiota community composition6–8 and changes in the fecal and urinary metabolic microenvironment in early life6–8 have also been shown to precede development of childhood asthma. Additionally, cell-free fecal products from low-risk for asthma infants6 and from high-risk for asthma infants supplemented with a Lactobacillus rhamnosus GG (LGG) probiotic during the first 6 months of life8 have been shown to promote T regulatory (Treg) cell expansion ex vivo. While these studies highlight the importance of microbial metabolites in promoting early-life immune tolerance, the specific metabolites contributing to this effect remain unknown. We thus used shotgun metagenomic sequencing and metabolomics to determine gut microbiota functional features that distinguish healthy controls (HC) from high-risk for asthma (HRP) infants. We observed divergent amino acid biosynthesis and metabolism in the gut microbiomes of HC compared to HRP infants. Specifically, HC infant microbiomes were statistically significantly enriched for ornithine biosynthesis and the metabolite L-ornithine while HRP infants showed enrichment for ornithine degradation. We next sought to examine the impact of L-ornithine or the HC fecal metabolic milieu on immune cell phenotypes and gene expression respectively. These experiments remain ongoing.