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

小于32周出生的早产儿在生理、解剖和免疫上都是不成熟的。大约10%的人会发展为坏死性小肠结肠炎（NEC），这是一种炎症介导的肠道疾病，20%的人会发展为迟发性败血症。异常的肠道微生物组发育和饮食是这两种疾病发病机制的组成部分。 母乳含有一系列可以调节微生物组发育的成分，包括丰富的人乳低聚糖（HMO），可以作为益生菌的生长基质。 该项目将基于早产儿的健康和疾病，但在这一领域内，学生可以专注于什么，这可以随着项目的进展进行修改的灵活性。一些关键目标可能包括：1）研究母乳或供体母乳对早产肠道微生物组的影响以及发生NEC和/或迟发性脓毒症的风险2）实验性地测试母乳、供体人母乳、和早产配方影响宿主功能，使用组织衍生的类器官模型，其重现早产肠上皮3）确定新的治疗方法是否可以调节早产儿肠道微生物组和宿主功能，使其达到与健康相关的状态学生将与学术和临床主管密切合作，并将获得大北新生儿生物库，其中包含> 10，000母乳和> 30，000个早产儿粪便样本。他们将进行宏基因组测序，以纵向分析这些重要样本中的微生物组，同时直接进行细菌分离株的微生物培养。学生还将建立早产组织衍生的类器官（即，肠），并使用这些来测试不同的饮食成分如何在生理相关的氧梯度下影响上皮表面处的宿主功能。这将包括供体乳汁、配方奶粉和母乳的共培养，以及特定成分，包括HMO和先前分离的细菌物种。 临床重点工作包括发现和转化两个方面。在这个跨学科项目的过程中，学生将获得广泛的湿实验室技术相关经验，如微生物学，分子生物学，组织培养，转录组学（主机），元转录组学（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.