Open Collections

The effect of the microbiome and short-chain fatty acid metabolites on early life immune development with long term consequences for atopy and asthma

University of British Columbia

Asthma is the most common childhood medical condition and it accounts for nearly two million hospital visits and thousands of deaths per year. Despite its immense societal burden, there is no cure, there are very few treatment options, and no prevention strategies. In fact, the etiology of asthma remains elusive. There is an emerging understanding that an association exists between the gut microbiome and asthma. Herein, we provide evidence that the microbiome impacts early-life immune development with consequences for asthma via the production of short chain fatty acid (SCFA) metabolites. We found that mice treated with vancomycin have an altered microbiome and metabolite profile, exhibit exacerbated Th2 responses, and are more susceptible to allergic lung inflammation. Here we show that dietary supplementation of SCFAs ameliorates this enhanced asthma susceptibility by modulating the activity of T cells and dendritic cells. Informed by this animal model, we sought to determine whether alterations in microbiome carbohydrate fermentation pathways could also be identified in human infants prior to developing atopic disease using shotgun metagenomic sequencing of the gut microbiome. We found that the microbiome of infants that went on to develop asthma later in childhood lacked genes encoding key functional enzymes for carbohydrate breakdown and butyrate production. To better understand the imprint of SCFAs on immune development, we successfully transferred the phenotypes of both heightened and dampened Th2 skewing via bone marrow transplants to irradiated recipient mice. Consistent with the hypothesis that the transferred phenotype is encoded within the epigenome, we found unique regulatory states, as defined by DNA acetylation, within the genomes of purified hematopoietic stem and progenitor cells of recipient mice that received BM transplants from dysbiotic mice. Altogether, this research highlights the role of microbially-derived metabolites, SCFAs, in the development of asthma and atopy. We present a new understanding of the intricate relationship between the microbiome, microbial metabolites and asthma. Knowledge of this process will have potential practical applications in the prevention and treatment of disease.

Text

2019-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66414

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/