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的、无法治愈的炎症性肠病。饮食、环境因素、生活方式、药物、微生物群和基因都在导致不可预测和致残的“发作期”中发挥着关键作用，这些“发作期”会对肠道产生累积的破坏性影响。目前治疗胃肠道疾病（如IBD）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病理生理中起关键作用。此外，直到最近，了解人类胃肠道中食物消耗后分子环境如何随时间变化一直很困难。工作到今天。我们已经获得了伦理许可，可以在整个胃肠道中使用管取样技术。这导致了一项从胃、十二指肠、回肠和升结肠取样的项目的启动。我们已经成功地从回肠和升结肠中提取了样本，下面是三种饮食中回肠的核磁共振代谢组学差异的初步汇总表，如下所示，其中饮食1经过高度精制和加工，饮食2经过最低限度加工，食物结构完整，饮食3与饮食2相同，但细胞结构被破坏。这凸显了可能具有代谢活性的潜在新分子，如棉子糖3。我们还分析了回肠中代谢物与GLP-2释放之间的关系。我们证明回肠乳酸与GLP-2释放有关。目前的提案概述了一项为期2年的研究计划，重点是在确定的患者群体（健康志愿者和炎症性肠病）中鉴定gpcr与微生物组衍生配体之间的新型相互作用。目标是：1。了解健康和IBD患者胃肠道饮食分子环境如何影响GPCR信号系统介导肠道关键功能（修复/再生、紧密连接形成和肠道激素释放，如GLP-2）2。为多种膳食配体信号分子和GPCR建立计算系统生物学相互作用组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