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

免疫失调和肠道黏膜屏障功能受损是两种儿童炎症性肠道疾病密切相关的特征；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。肠道细菌多样性和特定厌氧菌菌株的缺乏与疾病结果有关，然而，因果关系的方向仍未确定。事实上，更好地了解肠道上皮、肠道微生物和免疫细胞之间复杂的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测试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结果，有可能帮助诊断和治疗炎症性肠道疾病。目标1。建立儿童外周血和肠道区室的免疫图谱，用于健康和疾病的诊断和发现。2. 为了研究肠道上皮、微生物和免疫细胞之间复杂的相互作用，使用原代肠道上皮的离体模型，学生将开发一种新的肠道上皮单层生理学相关模型，该模型将在肠道上皮的两侧结合严格厌氧“共生”细菌（顶端表面）和免疫细胞（底外侧表面）。“迷你肠道”模型是一项前沿技术，也是研究肠道细菌和免疫细胞在人体系统中相互作用的宝贵工具，在开发基于患者的检测方面具有令人兴奋的潜力。

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.