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

项目总结 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 优化微生物群以改善早产儿健康的手段。早产儿微生物群的研究 到目前为止，主要是微生物组多样性和分类学模式与特定物种的相关性研究 临床因素。微生物组的功能及其影响早产儿的机制 发展仍然是知识方面的一大差距。会影响生长的代谢产物的产生 对其他生物体或宿主的直接影响是微生物群发挥作用的关键机制。我们的研究来自 无论是早产儿队列还是转移早产儿微生物群落的小鼠模型都有 稻瘟副杆菌(Parabacteroidesdisasonis，PD)是早产儿健康的关键生物 (减少炎症，促进生长，促进肠道发育)。我们现在有了一个重要的工具 破译哪些微生物组的功能和产出是早产儿健康的关键。有了这项提议，我们将 研究从早产儿分离的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关键功能的假设 以促进早产婴儿的健康和发育。我们将使用培养和生物反应器模型来研究 微生物/微生物之间的相互作用，并确定添加PD会产生哪些代谢物。我们还将 用有无帕金森病的早产儿微生物群落转移的小鼠模型进行研究 微生物组/宿主信息代谢物和细胞水平上的相互作用，这在人类是不可能的 婴儿病人。对PD的反应将与对嗜酸乳杆菌的反应进行比较 婴儿双歧杆菌(La/Bi)，作为已用于早产儿的益生菌组合的例子 新生儿坏死性小肠结肠炎的临床试验，以确定PD与 其他益生菌。然后我们将使用从这些模型获得的功能信息来询问我们的 临床已知早产儿粪便样本纵向采集的现有生物库 结果以确认哪些代谢物是由微生物产生的，并与特定的分子效应有关， 与实际婴儿的健康结果相关，以及在哪个时间窗口。微生物群落 改变、功能结果(炎症、生长、肠道发育)和代谢组学特征都会 接受检查。这项研究将开始揭示哪些基于微生物组的功能对早产最关键 婴儿健康和哪些时间窗口对微生物组优化最重要。这一知识是 为这位脆弱的患者开发合理的基于微生物组的治疗方案所必需的 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.