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

在我们最初的P01中，我们发现口服补充有狗的家庭灰尘的小鼠对 与补充有来自没有宠物的家庭的灰尘的小鼠相比，诱导过敏性肺部炎症。 对补充了狗舍灰尘的小鼠盲肠的检查确定了一个关键物种，乳酸杆菌 约翰逊氏菌。小鼠口服补充活的但未杀死的L.约翰逊氏菌对诱导的敏感性降低 过敏性和呼吸道合胞病毒（RSV）引起的肺部炎症。这些肺的减少 炎症似乎与骨髓来源的树突状细胞功能活性的改变有关 （DC）。初步数据表明，微生物代谢物在循环补充动物不同 与未补充的动物相比。有限的数据表明，循环代谢物的差异 对DC功能的改变负责。我们纳入RSV研究的理由是流行病学 研究表明人类婴儿中的RSV感染增加了随后哮喘的风险。我们的小鼠 模型反映了这种关系，因为新生儿感染RSV会导致更严重的病理学， 4周后对过敏原致敏。有趣的是，我们的初步研究表明， 雌性小鼠感染L.交配前接种约氏肺炎链球菌可降低后代对过敏原和RSV攻击的反应， 与直接补充的小鼠中观察到的水平相似。在这一观察所提出的问题中， 母体补充对后代的影响是否发生在子宫内发育期间， 从母乳中提取的成分。这个问题导致了交叉培养实验。在这些 实验补充或未补充的小鼠的后代由补充或未补充的哺乳动物喂养。 补充母乳的母亲揭示母乳喂养可以部分保护未补充母乳的母亲的幼崽 从RSV根据我们的研究结果，我们建议在本项目中进行研究，前提是产妇 微生物群通过改变新生儿的免疫系统， 后代肠道微生物群和相关的微生物代谢物，导致免疫反应性的差异 以及致病性过敏反应的风险。我们的研究将继续检查的机制，虽然 这些微生物变化影响对过敏原和RSV的病理反应。这些研究将包括进一步 研究区分子宫内影响和母乳对后代的影响。最后，我们将研究 补充项目3中选择的细菌财团对后代对过敏原的反应的影响， RSV挑战。这些研究将为项目中的人类研究结果提供更深入的见解 1和2，特别是关于何时最安全地采取有效干预措施的问题。

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.