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Microbiome in Asthma Induced by Environmental Particle Exposure

Investigators
Oldfield, Lauren Marie; Fedulov, Alexey V
Institutions
J. Craig Venter Institute
Start date
2019
End date
2024
Objective
Asthma is triggered or worsened by environmental exposures and is associated with epigenetic changesin humans and animal models. Microbial dysbiosis in the gut and the lung is increasingly being associated withthe incidence and severity of asthma, however causality studies are lacking. We have adapted a mouse modelthat focuses on the ONSET of allergic asthma early in life after an in utero exposure to environmental particlesto study how microbiome may lead to the asthma onset. In this model, we have shown that maternal exposures(to allergen or particulate matter, e.g. concentrated urban air particles (CAP), diesel exhaust particles (DEP) andtitanium dioxide particles (TiO2), trigger increased asthma risk in several generations of the offspring. Humansare widely exposed to these particulates, especially in urban and industrial settings, where the incidence ofasthma is also higher. We found that the increased ?preparedness? for asthma in these neonates is associatedwith DNA methylation changes in key immune cells ? dendritic cells (DC) that are essential in asthma origin.Important unanswered questions are why these epigenetic changes occur, and whether there is a causative linkto the aberrant microbiome seen in asthma. We hypothesize that in utero exposures to particles alter themicrobiome of the pregnant mice and their offspring, which then signals to the immune cells in a way thatpredisposes the offspring to allergy. In Specific Aim 1, we will test what happens to the maternal microbiome (gut, lung and vaginal) after thegestational particle exposure, as it is the maternal flora that largely seeds the neonate?s microbiome. Longitudinalprofiling will employ a multifaceted approach, including 16S/ITS taxonomic profiling, metagenomic sequencingand targeted metabolomics, for the comprehensive analysis of the composition and metabolism of the microbes. In Specific Aim 2, we will examine the neonatal gut microbiome via similar longitudinal profiling, includingtheir response to allergen and establishment of the asthma phenotype. Importantly, we will perform causalityexperiments by transferring the hypothetically aberrant flora from the ?asthma-at-risk? donor pups (born to thedams treated with particles) to normal recipients, and vice versa: fecal microbiota transplant (FMT). Finally, wewill test the effect of the FMT on the recipient?s DC epigenome. In Specific Aim 3, we will similarly profile neonatal lung microbiome and will test the effect of antibiotic-based alteration of the aberrant lung microflora on asthma preparedness. Significance: Here we postulate two, potentially interconnected, mechanisms in asthma onset:epigenetics and the microbiome. Both the epigenetic alterations in immune cells and the dysbiosis in the gut andlung have been linked to asthma in humans and mouse models but causality studies are lacking. The proposedresearch addresses this gap in knowledge in a study designed to test basic mechanisms of relatively commonenvironmental exposures.
Funding Source
Nat'l. Inst. of Environmental Health Sciences
Project source
View this project
Project number
1R01ES030227-01
Accession number
30227
Categories
Microbial Genetics
Microbiological Standards and Guidelines
Bacterial Pathogens
Risk Assessment, Management, and Communication