Grant: Operating Grant: Impact Grant : CEEHRC Phase II

Asthma has become the most common childhood disease in developed countries, with major social and economic consequences. The causes of asthma are complex and poorly understood. We and others have recently shown an association between the gut microbiome and asthma. Subsequently, in mouse experiments, we found that butyrate, a fermentation product of the gut microbiome, dampens TH2 skewing of the immune system. Mice lacking exposure to butyrate early in life, due to gut microbiome dysbiosis, have a pro-inflammatory immune phenotype with heightened TH2 response in a model of asthma. In a preliminary experiment, we successfully transferred the phenotypes of both heightened and dampened TH2 skewing via bone marrow (BM) transplants to irradiated recipient mice. Epigenetic analysis strongly suggests an epigenetic mechanism is involved in these immune phenotypes. The main objective of the proposed project is to conclusively determine if and how the epigenome functions in regulation of the immune system in response to exposure or lack of exposure to butyrate. In transfer experiments, we will determine whether hematopoietic stem and progenitor cells (HSPC), or other cell types, can confer the immune phenotypes. We will conduct comprehensive epigenetic analyses of HSPC, or other cells that confer the immune phenotypes, in transfer recipients. Bioinformatic analyses of epigenetic profiles will predict immune function. We will more comprehensively characterize the immune phenotypes of the recipient mice, focusing on predicted functions. The results will be validated by exposing mouse and human HSPC to low concentrations of butyrate and subsequently determining their epigenetic profiles and the phenotypes the cells confer to recipient mice. This project will provide understanding of a novel epigenetic process linking the microbiome and the immune system, which will have potential practical applications in the prevention and treatment of asthma.