Microbiome Influences on Asthma-Related Outcomes in Early Life

点击翻译按钮获取中文摘要

BEAMS ABSTRACT: Project 1 Observations by our group and others indicate that risk for asthma originates very early in life. Some of the implicated early childhood environmental exposures, such as to farms and pets, can inform establishment and development of the gut microbiome in the neonate. This in turn may affect asthma risk through influencing both the child’s immune development and response to respiratory infections such as those due to rhinovirus. Maternal prenatal factors, including immunological phenotype and microbiota, similarly may influence development of the child’s microbiota and asthma risk. We recently showed that Mexican-American schoolchildren living in Tucson, AZ, have a fourfold higher rate of asthma than those living in nearby Nogales, Mexico (MX). We also showed that infants born in Tucson and Nogales, MX, who are ancestrally related, are exposed to dramatically different home environments and have differential gut microbiota characteristics at 1 month of age. We postulate that exposure to specific microbial taxa in Nogales, MX may account for the relative protection against asthma as compared to Tucson, and that this protection is mediated by differential seeding of the infant’s gut microbiota in Tucson as compared to Nogales, MX. Project 1 of BEAMS will identify divergent early-life microbial and immune developmental trajectories associated with asthma protection in Nogales, MX compared with Tucson, AZ, and the microbiota exposures that promote them. Aim 1 will identify maternal factors related to asthma protection, including characteristics of maternal (gut, vagina) and environmental (dust, water) sources of differentially present microbiota, as well as immunologic characteristics which may relate to these exposures. We will extensively phenotype these PBMCs using multiplexed cytokine panels and CyTOF, to identify cellular phenotypes and characteristics that relate to exposures, location, and asthma outcomes in the child. Finally, we will identify differential DNA methylation patterns from cord blood collected during delivery that relate to the transborder differential microbiota and immune outcomes. Aim 2 will identify infant gut microbiota, environmental and maternal factors, and infant immune cellular characteristics and phenotypes related to asthma protection, in early life and longitudinally, using as an early asthma-related outcome the presence of wheezing with type 2 inflammation (T2 Wheezing, T2W) at age 2. Further, we will use single-cell analyses to identify differential cellular transcription and development related to location and in response to ex-vivo stimulation with rhinovirus. Aim 3 will identify the specific microbial exposures that may modulate the association between polymorphisms in the asthma risk locus at chromosome 17q and wheezing lower respiratory illnesses at each location. This innovative project utilizes a longitudinal, multiple-omics approach to identify potential microbiological and immunological pathways by which exposure to dramatically different urban environments, prenatally through early-life, may be associated with asthma protection or risk.