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

项目摘要 生命早期的微生物组影响特应性疾病的发展，包括哮喘。机械论 对这种影响的解释包括肠道微生物群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组对特应性鼻炎的影响， 疾病，越来越明显，其他微生物来源可以有助于特应性。例如我们最近 表明脐带血微生物群有助于哮喘表型，而其他研究表明， 还揭示了气道微生物组和母乳微生物群与特应性疾病的关联。不过， 不同微生物区室的相对贡献和关系，以及机制 它们是如何影响特应性启动的，目前尚不清楚。我们提出了一种数据驱动的方法：（1）确定 新生儿微生物组的多个区室对哮喘表型发展的影响， 和（2）表征引发哮喘表型的免疫途径改变， 微生物特征 在目标1中，我们将描述脐带血、肠道和母乳中的微生物群，并比较 这些是发生哮喘表型的婴儿与未发生哮喘表型的婴儿之间的差异。具体来说，我们将收集 出生时的脐带血，母亲的母乳以及1个月随访时的儿童粪便样本， 微生物组分析将在表现出结局指标的受试者之间比较微生物组特征 在1岁时反复喘息与那些没有反复喘息的人相比，结果的预测模型将是 根据生物分类学特征创造的。这些结果将揭示以前未经检验的关系 多个新生儿微生物组区室与哮喘表型的发展之间的关系。 在目标2中，我们将使用转录组学和细胞因子谱来表征生命早期的免疫差异 在哮喘表型中，并阐明免疫改变作为表观遗传扰动的函数， 微生物组组成。具体地，将从婴儿的脐带血和外周血中分离单核细胞。 刺激激活T细胞，然后我们将比较所得的转录组学特征和细胞因子谱 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 使用组蛋白去乙酰化酶抑制剂的表观遗传扰动的影响， 治疗哮喘的药物。最后，为了阐明HDAC抑制改变的共同途径， 微生物暴露，我们将HDAC抑制改变的免疫特征与微生物组相关联 确定为预测哮喘表型的特征。 总之，我们计划阐明引发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.