Investigating the physiological systems that regulate food intake and metabolic processes in the treatment of Obesity and other metabolic diseases

克罗恩病和溃疡性结肠炎是慢性、不可治愈的炎症性肠病。饮食、环境因素、生活方式、药物、微生物群和遗传因素都在推动不可预测和失效期的“闪光”方面发挥关键作用，这些“闪光”对肠道具有累积的损害作用。目前治疗IBD等胃肠道疾病的策略被认为不能解决宿主-微生物相互作用的主要功能障碍，而宿主-微生物相互作用可能在疾病的病理生理中发挥关键作用。此外，直到最近，还很难理解随着人类胃肠道中食物的摄入，分子环境如何随着时间的推移而变化。我们已经获得了伦理许可，可以在整个胃肠道使用试管取样技术。这导致了一项从胃、十二指肠、回肠和上升结肠取样的项目的启动。我们已经成功地从回肠和上升结肠中提取了样本下面是三种饮食之间回肠核磁共振代谢组学差异的初步汇总表，在这三种饮食中，饮食1被高度精炼和处理，饮食2在最低限度地处理，其中食物结构是完整的，饮食3与饮食2相同，但细胞结构被破坏。这突出了潜在的新分子(S)，可能是代谢活性的，如棉籽糖3。我们还进行了分析，探索回肠代谢物与GLP-2释放之间的关系。我们证明了回肠乳酸与GLP-2释放有关。目的目前的研究方案概述了一项为期两年的研究方案，重点是在特定的患者群体(S，健康志愿者和炎症性肠病)中识别GPCRs和微生物衍生配体之间的新的相互作用。其目的是：1.了解健康人和IBD患者胃肠道中的饮食分子环境如何影响GPCR信号系统，以调节肠道中的关键功能(修复/再生、紧密连接形成和胃肠激素释放，如GLP-2)2.建立多饮食配体信号分子和GPCRs的计算系统生物学相互作用的GPCR途径

Crohn's disease and ulcerative colitis are chronic, incurable inflammatory bowel diseases. Diet, environmental factors, lifestyle, drugs, the microbiome and genetics all play a key role in driving unpredictable and disabling periods of 'flare' that have a cumulative damaging effect on the bowel. Current strategies for treating gastrointestinal conditions such as IBD are not believed to address the primary dysfunction of the host-microbial interactions that are likely to play a critical role in the disease pathophysiology. Furthermore until recently access to understanding how the molecular environment changes over time following the consumption of food in the human GIT has been difficult.Work to date1. We have obtained ethical permission to use the tube sampling techniques throughout the gastrointestinal tract. This has resulted in the initiation of a project that is sampling from stomach,duodenum, ileum and ascending colon.2. We have successfully taken samples from the ileum and ascending colonBelow is a initial summary table of NMR metabolomic differences in the ileum across three diets are shown below where diet 1 is highly refined and processed, diet 2 in minimally processedwhere the food structures are intact and diet 3 is identical to diet 2 but with the cell structure disrupted. This bring highlights potential new molecule(s) that may be metabolically active suchas raffinose3. We have also run analysis exploring the relationship exploring the relationship between the metabolite profile in the ileum an GLP-2 release. We demonstrate the ileum lactate relates to GLP-2 release.ObjectivesThe current proposal outlines a 2 year research proposal focused on the identification of novel interactions between GPCRs and microbiome derived ligands in a defined patient population(s) healthy volunteer and inflammatory bowel disease). The objectives are:1. to understand how the dietary molecular environment in the human GIT in healthy and IBD patients influences GPCR signalling systems to mediate key functions in the gut(repair/regeneration, tight junction formation and gut hormone release e.g. GLP-2)2. To develop a computational systems biology interactome GPCR pathway for multipledietary ligand signalling molecules and GPCRs