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

项目 4 小鼠母体肠道微生物群的改变会改变后代的代谢特征和免疫表型

• 批准号: 10480058
• 负责人: Nicholas W Lukacs
• 金额: $ 115.23万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480058
• 关键词: 10 year old; Address; Affect; Allergens; Allergic; Allergic Disease; Animal Model; Animals; Asthma; Bacteria; Blood Circulation; Bone Marrow; Breast Feeding; Breeding; Canis familiaris; Cell physiology; Cells; Child; Childhood; Clinical Research; Data; Dendritic Cells; Development; Disease; Dust; Environment; Extrinsic asthma; Female; Fostering; Health; Home; Homeostasis; House Dust; Human; Human Milk; Hypersensitivity; Immune; Immune response; Infant; Institutes; Intestines; Knowledge; Lactobacillus; Lead; Life; Lipids; Lung immune response; Metabolic; Mothers; Mus; Neonatal; Omega-3 Fatty Acids; Partner in relationship; Pathogenicity; Pathologic; Pathology; Phenotype; Population; Postpartum Period; Predisposition; Pregnancy; Pulmonary Inflammation; Resistance; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Shapes; Stimulus; Supplementation; System; Testing; Weaning; allergic response; attenuation; base; effective intervention; epidemiology study; experimental study; gut microbiota; high risk; in utero; individualized prevention; insight; long-term sequelae; maternal microbiome; maternal microbiota; metabolic profile; metabolome; microbial; microbiome; microbiota; mouse model; neonatal infection; neonatal mice; neonate; offspring; oral supplementation; pet animal; preclinical study; pup; response

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.

在我们最初的 P01 中，我们发现口服补充有狗的家中的灰尘的小鼠能够抵抗 与补充来自没有宠物的家中的灰尘的小鼠相比，诱导过敏性肺部炎症。 对添加了狗舍灰尘的小鼠盲肠进行检查，发现了一个关键物种——乳酸菌 约翰逊。给小鼠口服补充活的但未杀死的约氏乳杆菌可降低诱导敏感性 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 炎症似乎与骨髓源性树突状细胞功能活性的改变有关 （直流）。初步数据表明，补充补充剂的动物循环中的微生物代谢物有所不同 来自未补充的动物。有限的数据表明循环代谢物的差异 负责 DC 功能的改变。我们纳入 RSV 研究的理由是流行病学 研究表明，人类婴儿 RSV 感染会增加随后患哮喘的风险。我们的鼠标 模型反映了这种关系，因为当小鼠感染 RSV 时，新生儿感染会导致更大的病理变化。 4周后对过敏原过敏。有趣的是，我们的初步研究表明，补充 交配前接种约氏乳杆菌的雌性小鼠可降低后代对过敏原和 RSV 挑战的反应 与直接补充的小鼠中观察到的水平相似。这一观察提出的问题中 母亲补充对后代的影响是否发生在子宫发育期间或 产后来自母乳的成分。这个问题引发了交叉培养实验。在这些 实验中，补充或未补充小鼠的后代分别由补充或未补充的小鼠喂养。 补充补充剂的母亲揭示母乳喂养可以部分保护未补充补充剂的母亲的幼崽 来自RSV。根据我们的发现，我们在这个项目中提出的研究基于以下假设： 微生物群通过改变新生儿免疫稳态机制来塑造发育中的免疫稳态机制。 后代肠道微生物群和相关微生物代谢物导致免疫反应差异 以及致病性过敏反应的风险。我们的研究将继续检验其机制 哪些微生物变化会影响对过敏原和 RSV 的病理反应。这些研究将包括进一步 研究区分子宫效应和母乳对后代的影响。最后我们来看看效果 补充项目 3 中选择的细菌群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，特别是有关何时最安全地采取有效干预措施的问题。