The effect of early-life nasal colonization with Lactobacillus on the development of the local immune response and the later onset of recurrent wheeze, childhood asthma, and allergic rhinitis

项目总结 综合证据表明，早期上呼吸道微生物群的某些分类群起到了 守门人，以防止儿童呼吸道疾病的发作，这是发病率和 儿科人口死亡率。在这种情况下，我们之前对儿童的研究结果以及来自 多项动物研究暗示乳杆菌在婴儿期鼻腔定植具有潜在的保护作用 关于儿童哮喘和其他特应性疾病的发展。然而，这还不够。 在人类身上进行了研究。乳杆菌在婴儿期鼻腔定植的机制可能是 保护性的也在很大程度上是未知的。此外，目前还没有可用的干预措施来修改 有上呼吸道生物失调风险的婴儿，如剖宫产婴儿的鼻部微生物群。至 为了解决这些知识上的差距，我们提出了以下具体目标：目标1：检查早期- 乳杆菌在鼻腔内的终身定植与一种独特的局部免疫机制的建立有关 反应和后来发展为反复喘息、过敏性鼻炎和儿童哮喘。目标2：实现 确定一项随机对照试验(RCT)的可行性，以评估经阴道播种的有效性 修改剖宫产婴儿的早期鼻部微生物群。为了实现目标1，我们将 在一组健康的婴儿中进行嵌套队列研究，这些婴儿登记在正在进行的大规模人群中- 出生队列(n=749)。为了实现目标2，我们将进行单中心、平行臂、盲目、虚假- 健康剖宫产婴儿随机对照试验(n=40)。 NIH K23-所需的独立临床试验(PA-18-374)提案的目的是让候选人 发展关于如何研究早期上呼吸道微生物群对儿童呼吸影响的专业知识 疾病，以及如何将发现转化为临床试验的实施，这样他最终可以成为 一位独立的、以患者为中心的儿童哮喘一级预防研究者。要完成 为此，他将通过实现拟议的具体目标和通过组合 专家指导，高级教学课程，临床和微生物组研究的实践经验， 以及其他有重点的职业发展活动。他将与一个由多学科导师组成的团队密切合作 在儿童哮喘流行病学、微生物组研究、微生物学和 免疫学，以及临床试验的设计和实施。这个团队也有丰富的经验来促进 早期调查人员的发展，这--除了对 候选人的研究生涯和卓越的学术环境--无疑将确保他 继续取得成功。

PROJECT SUMMARY The aggregated evidence suggests that certain taxa of the early-life upper airway microbiome act as gatekeepers to prevent the onset of childhood respiratory diseases, which are a leading cause of morbidity and mortality in the pediatric population. In this context, the results from our prior studies in children and those from multiple animal studies allude to a potential protective effect of nasal colonization with Lactobacillus in infancy on the development of childhood asthma and other atopic diseases. However, this has not been adequately studied in humans. The mechanisms through which nasal colonization with Lactobacillus in infancy could be protective are also largely unknown. Furthermore, there are currently no available interventions to modify the nasal microbiome in infants at risk of upper airway dysbiosis, such as those born by cesarean section. To address these gaps in knowledge, we propose the following specific aims: Aim 1: To examine whether early- life nasal colonization with Lactobacillus is associated with the establishment of a distinct local immune response and the later development of recurrent wheeze, allergic rhinitis, and childhood asthma. Aim 2: To determine the feasibility of a randomized controlled trial (RCT) assessing the utility of vaginal seeding in modifying the early-life nasal microbiome of infants born by cesarean section. To achieve Aim 1, we will conduct a nested cohort study among a group of healthy infants enrolled in an ongoing large, population- based, birth cohort (n=749). To achieve Aim 2, we will conduct a single-center, parallel-arm, blinded, sham- controlled, feasibility RCT in healthy cesarean-born infants (n=40). The purpose of this NIH K23 – Independent Clinical Trial Required (PA-18-374) proposal is for the candidate to develop expertise in how to study the impact of the early-life upper airway microbiome on childhood respiratory diseases and how to translate findings to the implementation of clinical trials, so he can ultimately emerge as an independent patient-oriented investigator in the primary prevention of childhood asthma. To accomplish this, he will augment his research skills by achieving the proposed specific aims and through a combination of expert mentorship, advanced didactic coursework, hands-on experience in clinical and microbiome research, and other focused career development activities. He will work closely with a multidisciplinary team of mentors with collective expertise in pediatric asthma epidemiology, microbiome research, microbiology and immunology, and the design and conduct of clinical trials. This team also has extensive experience in fostering the development of early-stage investigators, which —in addition to a strong institutional commitment to the candidate’s research career and an exceptional academic environment— will undoubtedly ensure his continued success.