Regulation of immune response to virus and aeroallergen by infant gut microbial products: mechanistic studies

About This Grant

Our group recently identified a real-life model that uniquely illustrates the impact of the environment on asthma risk. Two populations of comparable Mexican ancestry living only 70 miles apart in Tucson, AZ, USA and Nogales, Mexico (MX) differ strikingly in their rates of childhood asthma, which are 4-fold lower in MX. The Binational Early Asthma and Microbiome Study (BEAMS-1, P01AI148104) was launched to test the hypothesis that MX or US residence impacts microbiome composition and metabolic capacity in pregnant mothers and their children, thereby shaping microbiome and immune responses and the child’s asthma risk. Initial findings from BEAMS-1 have supported this hypothesis. Asthma-predictive symptom (S) scores at 6-9 months (mo) were significantly higher in US than MX infants and were significantly associated with infant fecal microbiome composition and metabolome. Dietary lipids were the largest class of S-score-associated stool metabolites. Oleic, palmitic & linoleic acid metabolites were enriched in high S-score infants, while poly- unsaturated fatty acids were enriched in low S-score infants. These data linked dietary lipid stool metabolites to S-scores and infant asthma risk, but the underlying mechanisms remained unknown. Because asthma risk is associated with both early allergic sensitization and early respiratory viral infections, we now propose to define the mechanisms through which stool metabolites from BEAMS children with distinct S-scores differentially affect immune responses to airway viral infection and aeroallergens, and airway barrier integrity. Our plan stems from a rich set of preliminary data. Sterile fecal extracts (SFEs) from 1-mo-old infants with distinct S-scores 1) differed in their ability to reduce viral load and promote anti-viral responses in mice infected with human rhinovirus (RV), and 2) differentially affected aeroallergen-driven lung inflammation, in part through a novel B cell/IL17/neutrophil pro-inflammatory axis. 3) SFEs from 1-mo old MX infants more effectively promoted human airway epithelial barrier integrity compared to SFEs from their US counterparts. 4) Specific stool metabolites enriched in asthma-protected farm children protected mice from allergic inflammation and enhanced human airway barrier integrity. Therefore, we hypothesize that increased infant S-scores reflect the production of pathogenic microbial metabolites that dysregulate immune responses to respiratory viruses and aeroallergens, and impair airway barrier integrity, thus licensing the initiation of the asthma trajectory. Relying on extant BEAMS samples, we propose to expose mice to SFEs from 1- and 24-mo children with distinct S-scores and characterize the immune mechanisms and microbial metabolites that dysregulate responses to RV infection (Aim 1) and aeroallergen (Aim 2). (Aim 3) will characterize the transcriptional mechanisms that regulate human airway barrier responses to 1- and 24-mo SFEs from children with distinct S- scores, and their relation to SFEs metabolites. Our data will reveal mechanisms that connect gut microbial metabolites to asthma-predictive symptoms and inform approaches that target microbial metabolic dysfunction.