Bacterial genes to function: Determining the roles of 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%的人会患上坏死性小肠结肠炎(NEC)，这是一种致命的炎症性肠道疾病。肠道微生物群发育异常是NEC发病过程中不可或缺的因素。元基因组和16S扩增序列测定方法表明，NEC婴儿肠道微生物多样性减少，变形杆菌(革兰氏阴性)增加，双歧杆菌(革兰氏阳性)减少。然而，这些方法本身并不能描述微生物体内细菌物种的功能作用。深入研究这些功能以及不同物种如何相互作用，对于理解微生物-微生物和微生物-宿主相互作用，推动和维持NEC或健康婴儿肠道微生物区系的变化至关重要。该项目将基于早产儿健康和疾病，但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)测定从健康和NEC婴儿身上分离的细菌菌株的代谢功能能力2)调查细菌菌株之间的代谢交叉喂养，并确定竞争或协同作用3)使用强大的体外早产有机共培养模型实验测试细菌菌株在宿主肠道上皮内相互作用的功能学生将与学术和临床导师密切合作，并将有机会接触到世界上最大的早产样本生物库-北方新生儿生物库。我们已经从这个资源中分离出约250个新的细菌和真菌分离物(目前正在进行全基因组测序)。我们的团队还建立了一种新的方法来产生早产类有机物，并进行厌氧细菌和早产上皮的共培养。这个博士生项目将推进我们现有的研究组合，并建立在我们已经生成的工具和大量数据的基础上。这有望使人们对早产健康和疾病有深入的了解，并有可能开发新的生物标记物和治疗方法。这项临床重点工作包括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，包括微生物学、分子生物学、生物化学、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。这些技能是高度可移植的。我们是一个多元化、有趣和包容的研究团队，积极的研究文化是我们精神的核心。我们鼓励来自代表不足的群体和第一代学生的申请。

Preterm infants born <32 weeks gestation are 'immature' physiologically, anatomically and immunologically. Around 10% will develop necrotising enterocolitis (NEC), a deadly inflammatory mediated bowel disease. Abnormal gut microbiome development is integral to NEC pathogenesis. Metagenomic and 16S amplicon sequencing approaches have shown that NEC infants have reduced gut microbial diversity, increased Proteobacteria (gram-negative), and reduced Bifidobacterium (gram-positive). However, these approaches alone do not allow for the functional roles of bacterial species within the microbiome to be characterised. In depth study of these functions and how different species interact is critical to understanding the microbe-microbe and microbe-host interactions that drive and maintain changes in the gut microbiota of NEC or healthy infants.The project will be based on preterm infant health and disease, but 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) Determine the metabolic functional capacities of bacterial strains isolated from both healthy and NEC infants2) Investigate metabolic cross-feeding between bacterial strains and determine competition or synergism3) Experimentally test the function of bacterial strain interactions within the host intestinal epithelium using a powerful ex vivo preterm organoid co-culture modelThe student will work closely with academic and clinical supervisors and will have access to the Great North Neonatal Biobank, the largest biobank of preterm samples anywhere in the world. From this resource we have already isolated ~250 novel bacterial and fungal isolates (currently undergoing whole genome sequencing). Our group have also established a novel method for generating preterm organoids and performing co-culture of anaerobic bacteria and preterm epithelium. This PhD studentship will advance our existing research portfolio and build on the tools and extensive data we have already generated. This promises to give a deep understanding of preterm health and disease with potential for developing new biomarkers and therapeutics.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 including microbiology, molecular biology, biochemistry, tissue culture, transcriptomics (host), metatranscriptomics (bacteria), alongside computational skills including the bioinformatic and statistical analysis of large multi-omic datasets. Such skills are highly-transferable.We are a diverse, fun, and inclusive research group, with positive research culture at the heart of our ethos. We encourage applications from under-represented groups and first-generation students.