Project 4 Alteration of Mouse Maternal Gut Microbiota Alters Metabolic Profiles and Immune Phenotype in Offspring

在我们最初的P01中，我们发现口服了有狗的家中的灰尘的老鼠对

In our initial P01, we found that mice orally supplemented with dust from homes with dogs were resistant to induction of allergic lung inflammation compared to mice supplemented with dust from homes without pets. Examination of ceca from mice supplemented dog-home dust identified a keystone species, Lactobacillus johnsonii. Oral supplementation of mice with viable but not killed L. johnsonii reduced susceptibility to induction of both allergic and respiratory syncytial virus (RSV) induced lung inflammation. These reductions in lung inflammation appear to be related to alterations in the functional activity of bone marrow-derived dendritic cells (DC). Preliminary data suggests that microbial metabolites in the circulation of supplemented animals differ from those of un-supplemented animals. Limited data suggests that the differences in circulating metabolites are responsible for the alterations in DC function. Our rationale for including studies of RSV are epidemiologic studies showing that RSV infections in human infants increase the risk of subsequent asthma. Our mouse models mirror this relationship since neonatal infection with RSV leads to greater pathology when the mice are sensitized to allergen 4 weeks later. Interestingly our preliminary studies have shown that supplementation of female mice with L. johnsonii prior to mating reduces responses to allergen and RSV challenges in offspring to a level similar to that observed in directly supplemented mice. Among the questions raised by this observation was whether the effects of maternal supplementation on offspring occurred during in utero development or post-partum from components of breast milk. This question led to cross-fostering experiments. In these experiments offspring of supplemented or un-supplemented mice were nursed by either supplemented or un- supplemented mothers revealing that breast feeding can partially protect pups of un-supplemented mothers from RSV. Based on our findings we propose studies in this Project based on the hypothesis that the maternal microbiota shapes the developing neonatal immune homeostatic mechanisms through alteration of the offspring gut microbiota and related microbial metabolites which lead to differences in immune responsiveness and the risk of pathogenic allergic responses. Our studies will continue to examine the mechanisms though which microbial changes affect pathologic responses to allergens and RSV. These studies will include further studies to differentiate in utero effects and breast milk effects on offspring. Finally, we will examine the effects of supplementation with consortia of bacteria selected in Project 3 on the response of offspring to allergen and RSV challenges. These studies will provide greater insight into the findings from the human studies in Projects 1 & 2, especially questions concerning when effective interventions might be most safely instituted.