Determining the influence of diet and the gut microbiome in preterm infant health and disease

怀孕32周出生的早产儿在生理、解剖学和免疫学上都是“不成熟”的。大约10%的人将发展为坏死性小肠结肠炎(NEC)，这是一种炎症性肠道疾病，20%的人将发展为迟发性败血症。肠道微生物群发育异常和饮食是这两种疾病发病机制中不可或缺的一部分。母乳含有一系列可以调节微生物组发育的成分，包括丰富的人类乳寡糖(HMOS)，它可以作为益生菌的生长底物。该项目将以早产儿健康和疾病为基础，但在这一领域内，学生可以灵活地专注于什么，可以随着项目的进展而修改。一些主要目标可能包括：1)调查母乳或捐赠母乳对早产肠道微生物群的影响以及发生NEC和/或迟发性败血症的风险2)使用组织衍生的有机模型来实验测试母亲自己的母乳、捐献母乳和早产配方奶对宿主功能的影响3)确定新的疗法是否可以调节早产肠道微生物群和宿主功能，使其达到与健康相关的状态学生将与学术和临床导师密切合作，并将有机会获得包含10,000份母乳和30,000份早产粪便样本的北方新生儿生物库。他们将进行元基因组测序，以纵向描述这些重要样本中的微生物组，同时直接进行细菌分离的微生物培养。学生还将从切除的组织中建立早产组织衍生的有机物质(即肠样物质)，并使用这些物质来测试不同的饮食成分在生理上相关的氧气梯度下如何影响上皮表面的宿主功能。这将包括将捐赠者的牛奶、配方奶和母乳以及包括HMOS和以前分离的细菌物种在内的特定成分进行共培养。这项以临床为重点的工作包含了发现和翻译两个方面。在这个跨学科项目的过程中，学生将在湿实验室技术方面获得广泛的相关经验，如微生物学、分子生物学、组织培养、转录组(宿主)、转录组(细菌)以及计算技能，包括大型多组数据集的生物信息学和统计分析。

Preterm infants born <32 weeks gestation are 'immature' physiologically, anatomically and immunologically. Around 10% will develop necrotising enterocolitis (NEC), an inflammatory mediated bowel disease and 20% will develop late onset sepsis. Abnormal gut microbiome development and diet are integral to pathogenesis of both diseases. Breast milk contains a range of components that can modulate microbiome development, including an abundance of human milk oligosaccharides (HMOs), which can act as growth substrates for probiotic bacteria. The project will be based on preterm infant health and disease, but within this area there is flexibility in what the student can focus on, which can be modified as the project progresses. Some key objectives are likely to include: 1) Investigate the influence of maternal milk or donor milk on the preterm gut microbiome and risk of developing NEC and/or late onset sepsis 2) Experimentally test how mothers own milk, donor human breast milk, and preterm formula impact host function using a tissue-derived organoid model that recapitulates the preterm gut epithelium 3) Determine if novel therapeutics can modulate the preterm gut microbiome and host function toward a state associated with health The student will work closely with academic and clinical supervisors and will have access to the Great North Neonatal Biobank, containing >10,000 breast milk and >30,000 preterm stool samples. They will perform metagenomic sequencing to longitudinally profile the microbiome in these important samples, alongside directly microbiological culture of bacterial isolates. The student will also establish preterm tissue-derived organoids (i.e., enteroids) from resected tissue, and use these to test how the different dietary components impact host function at the epithelial surface under a physiologically relevant oxygen gradient. This will include co-culture of donor milk, formula, and breast milk, as well as specific components including HMOs and bacterial species previously isolated. The clinically focused work incorporates both discovery and translational aspects. During the course of this interdisciplinary project, the student will gain a wide range of relevant experience in wet-lab techniques such as microbiology, molecular biology, tissue culture, transcriptomics (host), metatranscriptomics (bacteria), alongside computational skills including the bioinformatic and statistical analysis of large multi-omic datasets.