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

围产期微生物组对哮喘表型的影响：与生命早期免疫特征的关联

• 批准号: 10455581
• 负责人: Yishin Chang
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455581
• 关键词: 1 year old; Address; Allergic; Allergic Disease; Asthma; Birth; Cells; Child; Data; Development; Disease; Environment; Enzymes; Epigenetic Process; Exhibits; Feces; Genes; Goals; HDAC4 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Human Milk; Immune; Immune response; Immune system; Infant; Innate Immune System; Intervention; Investigation; Knowledge; Life; Light; Mononuclear; Mothers; Neonatal; Outcome; Pathway interactions; Pattern recognition receptor; Perinatal; Peripheral Blood Mononuclear Cell; Phenotype; Physicians; Predisposition; Sampling; Scientist; Source; Structure; T-Lymphocyte; Taxonomy; Therapeutic; Training; Umbilical Cord Blood; Wheezing; asthmatic; atopy; base; clinically relevant; cytokine; follow-up; gut microbiome; gut microbiota; microbial; microbiome; microbiome analysis; microbiome composition; microbiota; multiple omics; novel; peripheral blood; predictive modeling; respiratory microbiome; response; transcription factor; transcriptomics

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.

项目摘要