Impact of Parabacteroides presence, timing and function on preterm infant health

项目摘要 我们的首要目标是了解微生物组在早产儿发育中的作用，并确定 优化微生物组以改善早产儿健康的方法。早产儿微生物组的研究 迄今为止，主要是微生物组多样性和分类模式与特定 临床因素。微生物组功能及其影响早产儿的机制 发展仍然是知识方面的一个重大差距。代谢产物的产生可能影响生长 或直接影响宿主是微生物组功能的关键机制。我们的研究从 早产儿队列和用早产儿微生物群落进行动物区系转移的小鼠模型均 将Distasonis副拟杆菌（Parabacteroides distasonis，Pd）确定为与早产儿健康相关的关键微生物 （减少炎症，改善生长，增强肠道发育）。我们现在有一个重要的工具 来解读哪些微生物群功能和输出是早产儿健康的关键。根据这项建议，我们将 研究从早产儿中分离的Pd对微生物群落功能的影响，特别是 代谢组学输出，并检验Pd可用于理解微生物组功能的假设 早产儿的健康和发展。我们将使用培养和生物反应器模型来研究 微生物/微生物相互作用，并确定添加Pd产生了哪些代谢物。我们还将 使用带有或不带有Pd的早产儿微生物群落的小鼠模型进行研究 微生物组/宿主告知代谢物和细胞水平上的相互作用，这在人类中是不可能的 婴儿患者将对Pd的反应与对嗜酸乳杆菌的反应进行比较， 双歧杆菌（La/Bi），作为已用于早产儿的益生菌组合的一个例子 新生儿坏死性小肠结肠炎的临床试验，以确定是否存在Pd与 其他益生菌然后，我们将使用从这些模型中获得的功能信息来询问我们的 从具有已知临床症状的早产儿纵向收集的粪便样品的现有生物储存库 结果，以确认哪些代谢产物，由微生物产生，并与特定的分子效应， 与实际婴儿的健康结果有关，以及在哪个时间段内。微生物群落 改变，功能结果（炎症，生长，肠道发育）和代谢组学特征都将 接受检查。这项研究将开始揭示哪些基于微生物群的功能对早产儿最关键。 婴儿健康以及哪些时间窗口对微生物组优化最重要。这种知识是 这对于为这种脆弱的患者开发合理的基于微生物组的治疗方案是必要的 人口

PROJECT SUMMARY Our overarching goal is to understand the role of the microbiome in preterm infant development, and to identify means of optimizing the microbiome to improve preterm infant health. Studies of the preterm infant microbiome to date have primarily been correlation studies of microbiome diversity and taxonomy patterns with specific clinical factors. Microbiome function and the mechanisms by which the microbiome impacts preterm infant development remains a significant gap in knowledge. Production of metabolites that can influence the growth of other organisms or directly impact the host is a key mechanism of microbiome function. Our studies from both a preterm infant cohort and mouse models transfaunated with preterm infant microbial communities have identified Parabacteroides distasonis (Pd) as a critical organism associated with preterm infant health (decreased inflammation, improved growth, enhanced intestinal development). We now have an important tool to decipher what microbiome functions and outputs are key for preterm infant health. With this proposal, we will investigate the effect of Pd isolated from a preterm infant on microbial community function, specifically metabonomics output, and test the hypothesis that Pd can be used to understand microbiome functions critical to preterm infant health and development. We will use cultivation and bioreactor models to study microbe/microbe interactions and identify what metabolites are produced by the addition of Pd. We will also use mouse models transfaunated with preterm infant microbial communities with or without Pd for investigation of microbiome/host informed metabolites and interactions at the cellular level that are not possible in human infant patients. Responses to Pd will be compared to responses to Lactobacillus acidophilus and Bifidobacterium infantis (La/Bi), as an example of a combination of probiotics already used in preterm infant clinical trials for neonatal necrotizing enterocolitis, to determine if there are functions specific to Pd versus other probiotics. We will then use the functional information obtained from these models to interrogate our existing biorepository of longitudinally collected fecal samples from preterm infants with known clinical outcomes to confirm which metabolites, produced by microbes and associated with specific molecular effects, are associated with health outcomes in actual infants, and during which window of time. Microbial community alteration, functional outcomes (inflammation, growth, intestinal development) and metabonomic profiles will all be examined. This study will begin to reveal which microbiome-based functions are most critical for preterm infant health and which windows of time are most important for microbiome optimization. This knowledge is necessary for the development of rational microbiome-based therapeutic options for this vulnerable patient population.