Perinatal Dysbiosis, Lung Development and Asthma

环境暴露改变哮喘风险(剖腹产、母乳喂养)也会影响微生物定植。 生物失调以不同的方式调节粘膜IL-17A和IL-22水平，减少IL-22的产生，同时促进 IL-17A产生细胞的募集。白介素22介导粘膜表面的动态平衡，白介素17A 产生与更严重的哮喘表型相关，这表明失调诱导哮喘的调节。 发病机制可能与IL-22/IL-17A平衡失调有关。我们的初步数据 结果表明：(1)围产期生物失调导致肺结构改变，基础气道高反应性增加 (AHR)和夸大的屋尘螨(HDM)诱导的哮喘表型(更严重的AHR，升高 趋化因子的产生，促进产生IL-17A的细胞的招募)；(2)来自生物失调的有机物- 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阻断消除围产期生物失调增强的HDM诱导的AHR；(4) 围产期IL-22阻断概括了围产期生物失调的一些特征(增加的呼吸道反应和 (5)IL-22Ra1的表达受发育调控。 肺间充质细胞；和(6)补充醋酸盐可逆转围产期诱导的生物失调 肺泡通透性。因此，我们假设围产期生物失调导致新生儿间充质减少。 IL-22信号驱动肺发育改变，增加过敏原驱动的IL-17A产生细胞的募集 以及更严重的哮喘，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：定义推动增长的机制 变应原诱导的IL-17A产生细胞募集及IL-17A分泌细胞鉴定 围产期生物失调后的哮喘，我们将确定围产期生物失调是否会影响免疫细胞 对趋化信号的反应性，确定与趋化因子增加有关的肺结构细胞 生产，并确定哪些产生IL-17A的ILC是必要的，并且足以推动结构和 围产期生物失调后的哮喘表型观察。目的2：确定围产期IL-22信号是否在 间充质细胞影响肺发育、基线AHR和过敏原的严重程度。 在AHR的驱动下，我们将针对危重新生儿期间间充质细胞中IL-22激活的信号通路 对照小鼠的窗口，并补充暴露于围产期生物失调的动物产生rIL-22或IL-22 细胞，并评估对失调诱导的表型的影响，目标3：确定失调是否诱导 补充细菌可以逆转肺部发育或哮喘严重程度的变化 代谢物，我们将测试预防性和治疗性给予细菌代谢物的能力。 逆转生物失调诱导的表型。总而言之，这些研究将阐明 围产期生物失调影响哮喘的发展。

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.