From bench to bedside; using patient-based assays that model the gut microbiome-host interface to aid diagnosis and inform treatment of immune dysregu

免疫调节失调和肠粘膜屏障功能受损是两种儿科炎症性肠道疾病的密切联系的特征，即移植物抗宿主病(GVHD)和坏死性小肠结肠炎(NEC)。越来越多的证据表明肠道微生物和免疫群体之间存在相互作用。缺乏肠道细菌多样性和特定的厌氧菌菌株与疾病结局有关，然而，因果关系的方向仍不确定。事实上，更好地了解肠道上皮、肠道微生物和免疫细胞之间的复杂相互作用将对未来的治疗进展至关重要。这个项目的首要目标是检验免疫细胞功能可以通过微生物“治疗”来调节的假设。因此，该项目具有直接的翻译后果，有可能帮助诊断和治疗炎症性肠道疾病。目的1.建立儿科健康和疾病时外周血和肠腔的免疫图谱，以辅助诊断和发现。2.为了研究肠道上皮、微生物和免疫细胞之间的复杂相互作用，使用原代肠道上皮的体外模型，学生将开发一种新的与生理相关的肠道上皮单层模型，该模型将严格结合肠道上皮两侧的厌氧“共生”细菌(顶端表面)和免疫细胞(基侧表面)。“迷你肠道”模型是一种尖端技术和无价工具，用于研究人类系统中肠道细菌和免疫细胞之间的相互作用，并具有开发以患者为基础的分析的令人兴奋的潜力。

Immune dysregulation and impaired gut mucosal barrier function are intimately linked features of two paediatric inflammatory gut disorders; namely graft-versus-host disease (GVHD) and necrotizing enterocolitis (NEC). There is growing evidence of the cross-talk between gut microbes and immune populations. Lack of gut bacterial diversity and specific anaerobic bacterial strains have been implicated in disease outcome, however, the direction of causality remains undetermined. Indeed, a better understanding of the complex interplay between gut epithelium, gut microbes and immune cells will be critical for future therapeutic advance. The overarching aim of this project is to test the hypothesis that immune cell function can be modulated by microbial "therapy". As such, this project has direct translational consequences with the potential to aid diagnosis and treatment of inflammatory gut disorders. Objectives 1. To develop an immune atlas of the paediatric peripheral blood and gut compartments, in health and disease, as an aid to diagnosis and discovery. 2. To investigate the complex interplay between gut epithelium, microbes and immune cells, using an ex vivo model of primary gut epithelium The student will develop a novel physiologically relevant model of the gut epithelial monolayer that will incorporate both strictly anaerobic "commensal" bacteria (apical surface) and immune cells (basolateral surface) on either side of the gut epithelium. The "mini gut" model is a cutting-edge technique and an invaluable tool for investigating the documented interplay between gut bacteria and immune cells in a human-based system and holds exciting potential to develop patient-based assays.