Influence of the perinatal microbiome on asthmatic phenotypes: associations with early life immune profiles

项目摘要 早期生命微生物群影响包括哮喘在内的特应性疾病的发展。机械论 对这种影响的解释包括肠道微生物区系与模式识别受体的相互作用 先天免疫系统，细菌代谢产物对酶和转录因子的调节，以及 广泛的表观遗传改变。虽然一些研究已经确定了肠道微生物群对特应症的影响 随着疾病的发展，越来越明显的是，其他微生物来源也会导致特应性反应。例如，我们最近 证明脐带血微生物区系对哮喘表型有贡献，而其他人的研究 还发现了呼吸道微生物群和母乳微生物群与特应性疾病的关联。不过， 不同微生物区段的相对贡献和相互关系及其作用机制 它们是如何影响特应性启动的，目前仍不清楚。我们提出了一种数据驱动的方法：(1)确定 新生儿多区系微生物群对哮喘表型发生的影响 以及(2)描述与哮喘表型相关的免疫途径改变 微生物组特征。 在目标1中，我们将描述脐带血、肠道和母亲母乳的微生物区系，并比较 患有哮喘表型的婴儿和没有哮喘表型的婴儿之间存在这些差异。具体地说，我们将收集 出生时的脐带血、母亲的母乳以及孩子1个月后的粪便样本 微生物组分析。将比较表现出结果指标的受试者之间的微生物组图谱 在1岁时反复喘息的儿童与不重复喘息的儿童相比，结果的预测模型将是 基于分类特征创建的。这些结果将揭示以前未被检查过的关系 多个新生儿微生物区系与哮喘表型的关系。 在目标2中，我们将使用转录和细胞因子图谱来表征早期生命免疫的差异 在哮喘表型中，并阐明免疫改变是表观遗传扰动和 微生物群组成。具体地说，来自婴儿脐带血和外周血的单个核细胞将 刺激激活T细胞，然后我们将比较由此产生的转录特征和细胞因子谱 有哮喘表型的婴儿和没有哮喘表型的婴儿之间的差异。我们将进一步确定 使用组蛋白脱乙酰酶抑制剂的表观遗传扰动的影响正在研究中 治疗哮喘。最后，为了阐明HDAC抑制和 微生物暴露，我们将把被HDAC抑制改变的免疫特征与微生物群联系起来 被确定为预测哮喘表型的特征。 综上所述，我们计划阐明导致哮喘的基因和环境的相互作用。 表型。

PROJECT ABSTRACT The early life microbiome influences the development of atopic diseases, including asthma. Mechanistic explanations for this influence include interactions of the gut microbiota with pattern recognition receptors of the innate immune system, modulation of enzymes and transcription factors by bacterial metabolites, and broad epigenetic alterations. While several studies have established influences of the gut microbiome on atopic disease, it is becoming evident that other microbial sources can contribute to atopy. For example, we recently demonstrated that cord blood microbiota contributes to asthmatic phenotypes, while studies from others have also uncovered associations of the airway microbiome and the breast milk microbiota with atopic disease. Still, the relative contributions and relationships of different microbiome compartments, as well as the mechanisms by which they influence atopic priming, remain unclear. We propose a data-driven approach to: (1) determine the influence of multiple compartments of the neonatal microbiome on development of asthmatic phenotypes, and (2) characterize immune pathway alterations that prime asthmatic phenotypes and associate with microbiome features. In Aim 1, we will characterize the microbiota of cord blood, gut, and maternal breast milk, and compare these between infants who develop asthmatic phenotypes versus those who do not. Specifically, we will collect cord blood at birth, and maternal breast milk as well as the child’s fecal samples at 1-month follow-up for microbiome analyses. Microbiome profiles will be compared between subjects who exhibit the outcome metric of repetitive wheeze at 1 year of age versus those who do not, and predictive models of outcome will be created based upon taxonomic features. These results will reveal previously unexamined relationships between multiple neonatal microbiome compartments and the development of asthmatic phenotypes. In Aim 2, we will characterize early life immune differences using transcriptomics and cytokine profiles in asthmatic phenotypes, and elucidate immune alterations as a function of epigenetic perturbation and microbiome composition. Specifically, mononuclear cells from cord blood and peripheral blood of infants will be stimulated to activate T cells, and then we will compare resultant transcriptomic features and cytokine profiles between infants who develop asthmatic phenotypes versus those who do not. We will further determine the effects of epigenetic perturbation using a histone deacetylase inhibitor that is under investigation as a therapeutic for asthma. Finally, in order to elucidate common pathways altered by HDAC inhibition and microbial exposures, we will correlate immune features that are altered by HDAC inhibition with microbiome features determined to be predictive of asthmatic phenotypes. In summary, we plan to elucidate the interplay of genes and environment that prime asthmatic phenotypes.