Perinatal Dysbiosis, Lung Development and Asthma

围产期生态失调、肺部发育和哮喘

基本信息

批准号：
10625311
负责人：
Ian Paul Lewkowich
金额：
$ 39.86万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/10625311
关键词：
Acetates Adolescent Adult Allergens Alveolar Animal Model Animals Antibiotics Asthma Automobile Driving Biological Assay Birth Breast Feeding Cell secretion Cells Cesarean section Communities Cues Data Development Disease Elderly Endothelium Environmental Exposure Epithelial Cells Epithelium Equilibrium Exposure to Extrinsic asthma Genetic Predisposition to Disease Goals Health Status Homeostasis Human IL17 gene Immune Immune response Intervention Life Link Lung Lung immune response 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 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 lung health microbial microbial colonization microbiome novel offspring perinatal period prophylactic receptor recruit response risk mitigation

项目摘要

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。生态失调以不同方式调节粘膜 IL-17A 和 IL-22 水平，减少 IL-22 的产生，同时增强 IL-22 介导粘膜表面的稳态，IL-17A 产生细胞的募集。产生与更严重的哮喘表型相关，这表明菌群失调诱导的哮喘调节我们的初步数据表明，发病机制可能涉及未被充分认识的 IL-22/IL-17A 平衡失调。表明：（1）围产期生态失调引起肺结构变化，基线气道高反应性增加 (AHR) 和夸大的屋尘螨 (HDM) 诱发的哮喘表型（更严重的 AHR、升高的趋化因子的产生，增强产生IL-17A的细胞的募集）；（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 刺激增加趋化因子的产生；(3) IL-17A 阻断消除围产期生态失调增强的 HDM 诱导的 AHR；围产期 IL-22 阻断概括了围产期生态失调的一些特征（气道反应增加和 (5) IL-22Ra1的表达在发育过程中受调控肺间充质细胞；（6）补充醋酸盐可逆转围产期菌群失调因此，我们认为围产期生态失调引起的新生儿间充质减少。 IL-22 信号传导改变肺部发育，增加过敏原驱动的产生 IL-17A 的细胞的募集以及晚年更严重的哮喘，补充细菌代谢物将逆转这些症状该假设将在三个目标中进行检验：目标 1：定义驱动增加的机制。过敏原诱导产生 IL-17A 的细胞募集并鉴定导致严重过敏的 IL-17A 分泌细胞围产期菌群失调后出现哮喘，我们将确定围产期菌群失调是否影响免疫细胞对趋化信号的反应，识别导致趋化因子增加的肺结构细胞生产，并确定哪些产生 IL-17A 的 ILC 对于驱动结构和围产期生态失调后观察到的哮喘表型目标 2：确定围产期 IL-22 信号传导是否存在。间充质细胞影响肺部发育、基线 AHR 和过敏原的严重程度在 AHR 的驱动下，我们将在关键新生儿期间靶向间充质细胞中 IL-22 激活的信号通路对照组小鼠的窗口期，以及补充暴露于围产期生态失调的动物，产生 rIL-22 或 IL-22 细胞，并评估对生态失调诱导的表型的影响，目标 3：确定生态失调是否诱导肺部发育或哮喘严重程度的改变可以通过补充细菌来逆转代谢物，我们将测试细菌代谢物预防和治疗的能力总的来说，这些研究将阐明其机制。围产期生态失调影响哮喘的发展。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Delayed Microbial Maturation Durably Exacerbates Th17-driven Asthma in Mice.

微生物成熟延迟会持续加剧小鼠 Th17 驱动的哮喘。

DOI：
发表时间：
2023-05
期刊：
影响因子：
6.4
作者：
Wilburn, Adrienne N;McAlees, Jaclyn W;Haslam, David B;Graspeuntner, Simon;Schmudde, Inken;Laumonnier, Yves;Rupp, Jan;Chougnet, Claire A;Deshmukh, Hitesh;Zacharias, William J;König, Peter;Lewkowich, Ian P
通讯作者：
Lewkowich, Ian P

Prenatal antibiotics exposure does not influence experimental allergic asthma in mice.

产前抗生素暴露不会影响小鼠实验性过敏性哮喘。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Lingel, Imke;Wilburn, Adrienne N;Hargis, Julie;McAlees, Jaclyn W;Laumonnier, Yves;Chougnet, Claire A;Deshmukh, Hitesh;König, Peter;Lewkowich, Ian P;Schmudde, Inken
通讯作者：
Schmudde, Inken

Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease.

过敏性疾病背景下 IL-4/IL-13 细胞因子信号传导的调节。