Early-life gut microbiota from asthma-prone infants reduces pulmonary peripheral T regulatory cells and alters lung physiology in recipient mice 3005

Abstract Description Our earlier studies within the prospective Danish cohort (COPSAC2010) investigating early-life determinants of asthma revealed a strong association between gut microbiota composition at 1 year and asthma status at 5 years. To explore this further, we developed a mouse model to compare the effects of fecal microbiota from 1-year-old infants with asthma and an at-risk microbiota, versus controls without asthma or an at-risk microbiota, on lung immunity. Fecal microbiota transfer was optimized by inoculating germ-free breeders and studying their progeny. Compared to gavaged breeders, progeny exhibited more stable T cell differentiation and immunoglobulin levels. Human microbiota successfully engrafted in the progeny, closely mirroring the profiles of the infant donors. The at-risk fecal microbiota of asthmatic children increased serum IgE levels, heightened airway resistance to methacholine, and reduced pulmonary T regulatory (Treg) cells compared to the control microbiota. Following sensitization and challenge with house dust mite (HDM) antigen, the mice with the at-risk microbiota displayed increased pulmonary infiltration of polymorphonuclear leukocytes and lower numbers of peripheral Tregs compared to both the HDM-challenged control mice and PBS-challenged control groups. These findings provide evidence that the early life gut microbiota compositions influence susceptibility to lung inflammation (‘immunological tone’) that could predispose a host to allergic responses. Funding Sources National Institutes of Health (U01AI22285, TL1TR001447, T32AI007180) and the Bernard Levine Immunology Fellowship, the Fondation Leducq TransAtlantic Network and Emch and Sergei Zlinkoff foundations Topic Categories Mucosal and Regional Immunology (MUC)