Perinatal Dysbiosis, Lung Development and Asthma

围产期生态失调、肺部发育和哮喘

• 批准号: 10187646
• 负责人: Ian Paul Lewkowich
• 金额: $ 39.85万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187646
• 关键词: Acetates; Adolescent; Adult; Allergens; Alveolar; Animal Model; Animals; Antibiotics; Asthma; Automobile Driving; Biological Assay; Birth; Breast Feeding; Cells; Cellular Structures; Cesarean section; Communities; Cues; Data; Development; Disease; Elderly; Endothelium; Environmental Exposure; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Extrinsic asthma; Genetic Predisposition to Disease; Goals; Health; Homeostasis; Human; Immune; Immune response; Interleukin-17; Intervention; Life; Link; Lung; Mediating; Mesenchymal; Mesenchyme; Mucosal Immune System; Mucous Membrane; Mus; Nature; Neonatal; Organoids; Pathogenesis; Pathogenicity; Pattern; Perinatal; Perinatal Exposure; Permeability; Phenocopy; Phenotype; Play; Predisposition; Prevalence; Production; Public Health; Pyroglyphidae; Regulation; Risk; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Site; Structural defect; Structure; Supplementation; Surface; T-Lymphocyte; Testing; Therapeutic; Work; airway hyperresponsiveness; chemokine; chronic inflammatory disease; cigarette smoke; commensal bacteria; design; dysbiosis; early life exposure; epidemiologic data; human disease; in vivo; insight; interleukin-22; knockout animal; lung development; microbial; microbial colonization; microbiome; novel; offspring; perinatal period; prophylactic; receptor; recruit; response

Environmental exposures that alter asthma risk (C-section, breast feeding) also influence microbial colonization. Dysbiosis regulates mucosal IL-17A and IL-22 levels differently, reducing IL-22 production while enhancing the recruitment of IL-17A-producing cells. As IL-22 mediates homeostasis at mucosal surfaces, and IL-17A production is associated more severe asthma phenotypes, this suggests dysbiosis-induced regulation of asthma pathogenesis may involve an underappreciated dysregulation of the IL-22/IL-17A balance. Our preliminary data show that: (1) perinatal dysbiosis induces lung structural changes, increased baseline airway hyperreactivity (AHR), and exaggerated house dust mite (HDM)-induced asthma phenotype (more severe AHR, elevated chemokine production, enhanced recruitment of IL-17A-producing cells); (2) organoids derived from dysbiosis- exposed epithelial cells demonstrate reduced colony forming efficiency and increased HDM-stimulated chemokine production; (3) IL-17A blockade abrogates perinatal dysbiosis-augmented, HDM-induced AHR; (4) perinatal IL-22 blockade recapitulates some features of perinatal dysbiosis (increased airway responses and lung permeability in HDM-naïve adolescent mice); (5) IL-22Ra1 expression is regulated developmentally on pulmonary mesenchymal cells; and (6) supplementation with acetate reverses perinatal dysbiosis-induced alveolar permeability. Thus, we hypothesize that perinatal dysbiosis-induced reduction in neonatal mesenchymal IL-22 signaling drives altered lung development, increased allergen-driven recruitment of IL-17A-producing cells and more severe asthma later in life, and that bacterial metabolite supplementation will reverse these phenotypes. This hypothesis will be tested in three Aims: Aim 1: To define mechanisms driving increased allergen-induced IL-17A-producing cell recruitment and identify the IL-17A-secreting cells driving severe asthma after perinatal dysbiosis, we will determine if perinatal dysbiosis influences immune cell responsiveness to chemotactic signaling, identify pulmonary structural cells responsible for increased chemokine production, and identify which IL-17A-producing ILCs are necessary and sufficient to drive the structural and asthma phenotypes observed after perinatal dysbiosis. Aim 2: To determine if perinatal IL-22 signaling in mesenchymal cells influences pulmonary development, baseline AHR, and the severity of allergen- driven AHR, we will target IL-22-activated signaling pathways in mesenchymal cells during critical neonatal windows in control mice, and supplement animals exposed to perinatal dysbiosis with rIL-22 or IL-22 producing cells, and assess the impact on dysbiosis-induced phenotypes, Aim 3: To determine if dysbiosis-induced alterations in lung development or asthma severity can be reversed by supplementation with bacterial metabolites, we will test the capacity of bacterial metabolites administered prophylactically and therapeutically to reverse dysbiosis-induced phenotypes. Collectively, these studies will elucidate the mechanisms by which perinatal dysbiosis influences asthma development.

改变哮喘风险的环境暴露（剖腹产，母乳喂养）也会影响微生物定植。 菌群失调以不同的方式调节粘膜IL-17 A和IL-22水平，减少IL-22的产生，同时增强粘膜细胞的增殖。 IL-17 A产生细胞的募集。由于IL-22介导粘膜表面的稳态，而IL-17 A 生产与更严重的哮喘表型相关，这表明生态失调诱导的哮喘调节 发病机制可能涉及IL-22/IL-17 A平衡的未被充分认识的失调。我们的初步数据 表明：（1）围产期生态失调引起肺结构变化，增加基线气道高反应性 (AHR)和夸大的屋尘螨（HDM）诱导的哮喘表型（更严重的AHR，升高） 趋化因子产生，IL-17 A产生细胞的增强募集）;（2）源自生态失调的类器官- 暴露的上皮细胞表现出集落形成效率降低和HDM刺激的集落形成效率增加。 （3）IL-17 A阻断消除围产期生态失调增强的HDM诱导的AHR;（4） 围产期IL-22阻断概括了围产期生态失调的一些特征（增加的气道反应和 （5）IL-22 Ra 1的表达在发育过程中受到调节， 肺间充质细胞;和（6）补充醋酸盐逆转围产期生态失调诱导的 肺泡通透性因此，我们假设围产期生态失调引起的新生儿间充质细胞减少， IL-22信号传导驱动肺发育改变，增加过敏原驱动的IL-17 A产生细胞的募集 以及在以后的生活中更严重的哮喘，而细菌代谢物补充剂将逆转这些 表型这一假设将在三个目标中得到检验：目标1： 过敏原诱导的IL-17 A产生细胞募集，并确定IL-17 A分泌细胞驱动严重的 围产期生态失调后的哮喘，我们将确定围产期生态失调是否影响免疫细胞 对趋化性信号传导的反应，确定负责增加趋化因子的肺结构细胞 生产，并确定哪些IL-17 A-生产ILC是必要的和足够的驱动结构和 围产期生态失调后观察到的哮喘表型。目的2：确定是否围产期IL-22信号转导在 间充质细胞影响肺发育、基线AHR和过敏原的严重程度- 驱动AHR，我们将在新生儿重症监护期间靶向间充质细胞中的IL-22激活的信号通路。 对照小鼠和暴露于围产期生态失调的补充动物中的rIL-22或IL-22产生 目的3：确定生态失调诱导的表型是否与细胞的生长有关，并评估对生态失调诱导的表型的影响。 肺发育或哮喘严重程度的改变可以通过补充细菌 代谢物，我们将测试细菌代谢物的能力， 来逆转生态失调引起的表型总的来说，这些研究将阐明 围产期生态失调影响哮喘的发展。