Maternal β-Glucosylceramides Alter Neonate Hematopoiesis and Lung Microbiota

Abstract

Asthma affects over 25 million Americans and is the most common chronic pulmonary disease in children in the United States. Currently approximately 1 in 14 children are afflicted with asthma in the United States. Between 2008 and 2013, the estimated economic burden of asthma in the United States was $81.9 billion. The prevalence of asthma has steadily increased over the last 40 years, and the 20-year projected economic impact of uncontrolled asthma alone is projected to be about $300 billion from year 2019 to 2038. Offspring born to allergic mothers are three times more likely to develop allergies than offspring born to mothers without allergies. Lipids such as αTocopherol, γ-Tocopherol, and β-Glucosylceramides are known to influence allergen hyperresponsiveness. Elevated β-Glucosylceramides alter dendritic cell populations in neonates, and β-Glucosylceramides are known to signal through a C-type lectin receptor called Mincle. In addition, lung microbial dysbiosis is associated with development of allergic asthma in children. Here we show that maternal β-Glucosylceramides alter hematopoiesis in the neonate by signaling through Mincle in hematopoietic precursors. This causes the expansion of IRF4+ dendritic cells, which are known to induce allergy. Furthermore, we show that the lung microbiota is altered in mouse pups born to allergic mothers and that this dysbiotic microbiota is sufficient to induce allergen hyperresponsiveness in neonates. Β-Glucosylceramides altered lung microbial relative abundance compared to vehicle-treated controls and enhanced biofilm formation in bacteria isolated from mouse lungs. In silico analysis revealed predictions of microbes and metabolites that are important for microbial response to β-Glucosylceramides. This new knowledge is important for our understanding of not only allergy development, as well as immune development in neonates overall. Understanding the mechanism of action of elevated β-Glucosylceramides provides an opportunity to counteract their harmful effects, for instance by dietary α-Tocopherol supplementation during pregnancy and nursing.