Irritable bowel syndrome-diarrhea: the role of gluten intolerance and HLA-DQ2

描述（由申请人提供）：本申请涉及广泛的挑战领域临床研究和特定的挑战主题04-DK-103：开发了解和治疗功能性疾病的新方法。在本申请中，我们计划确定饮食在功能性GI和动力障碍的发展中的作用，以及基因型如何有助于功能性GI和动力障碍的发展。感兴趣的基因型是混合组织相容性复合体，HLA。有流行病学证据表明肠易激综合征（IBS）和功能性慢性腹泻之间存在显著重叠[FD（Locke et al 2005）]。乳糜泻和IBS的关系很复杂;虽然指南建议对FD或IBS伴腹泻（IBS-D）患者进行乳糜泻筛查，但缺乏证据支持这一建议。在奥姆斯特德公司，MN，组织转氨酶血清学阳性的总体患病率为4%，乳糜泻不能解释IBS或消化不良的存在（Locke et al 2004）。在成本效益分析中，当患病率> 8%，乳糜泻检测的特异性> 98%，或IBS治疗成本超过130美元/月时，乳糜泻检测成为主要策略（Spiegel BM，et al 2004）。事实上，当患病率降至1%以下时，乳糜泻检测的增量成本超过50，000美元。社区研究表明，乳糜泻影响美国0.5%至1.0%的人。另一方面，越来越多的人认识到对IBS-D或FD患者麸质不耐受的潜在作用。无乳糜泻的麸质不耐受在1981年首次作为临床实体推广（库珀BT等1981）。然而，直到最近，对麸质不耐受作为导致IBS-D或FD的因素的作用的研究非常有限。Wahnschaffe et al证明，在IBS-D或FD患者中，腹泻对GFD的应答受HLA类型和IgG组织转氨酶抗体的影响：对于HLA DQ 2 +ve、IgG TGA +ve，62%的患者发生了对麸质戒断的应答;相反，在DQ 2 -ve和IgG TGA -ve患者中，12%的患者发生了应答（Wahnschaffe et al 2007）。这表明在没有乳糜泻的IBS-D或FD患者中存在对麸质不耐受的免疫遗传易感性。IBS患者对麸质不耐受的机制尚不清楚。在对谷蛋白致敏的HLA-D8转基因小鼠中，麦胶蛋白暴露（与阴性和阳性对照相比）导致绒毛的CD 3、CD 4淋巴细胞和巨噬细胞浸润，以及平滑肌对电场刺激和卡巴胆碱的收缩反应增加（Verdu et al 2008）。这种收缩活动可能是腹泻发生的一种机制。谷蛋白或麦醇溶蛋白与炎症之间的联系可能是肠道通透性增加，这在乳糜泻中得到了充分证实，并涉及与趋化因子受体CXCR 3结合，导致MyD 88依赖性连蛋白释放（Lammers et al 2008）。目前还不清楚在没有乳糜泻的情况下，麸质是否会改变渗透性。另一方面，有报告称IBS（非感染性和感染后类型）的粘膜渗透性增加，这通常会导致IBS-D（Dunlop et al 2006）。我们的总体假设是，麸质摄入增加了易感患者的肠道通透性，并导致胃肠道功能的改变，表现为IBS-D或慢性腹泻。我们的总体目标是了解症状提示IBS-D或FD患者中谷蛋白诱导症状的机制，并优化这些患者的治疗。我们建议测试以下内容：具体假设：1。HLA-DQ 2阳性的IBS-D或FD患者的小肠和结肠通透性高于HLA-DQ 2阴性患者。2.在HLA-DQ 2阳性的IBS-D或FD患者中，补充麸质四周可增加小肠通透性并加速结肠运输。具体目标：1.比较HLA-DQ 2阳性或阴性的IBS-D或FD患者的小肠和结肠通透性。2.在一项平行组、随机、对照试验中，比较富含谷蛋白与无谷蛋白饮食对HLA-DQ 2阳性和HLA-DQ 2阴性IBS-D或FD患者小肠和结肠通透性、小肠和结肠粘膜形态以及胃肠道和结肠转运的影响。 公共卫生相关性：本申请涉及消化系统疾病临床研究的挑战领域，以及了解和治疗功能性GI和动力障碍的新方法的开发。该应用程序特别关注麸质（面粉中的一种蛋白质）饮食和患者的遗传组成在慢性腹泻和肠易激综合征（IBS）腹泻发展中的作用，以及无麸质饮食如何使肠道功能和排便正常化。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area CLINICAL RESEARCH and specific Challenge Topic, 04-DK-103: Develop Novel Approaches to Understand and Treat Functional Disorders. In this application, we plan to determine the role of diet in the development of functional GI and motility disorders and how genotype contributes to the development of functional GI and motility disorders. The genotype of interest is the mixed histocompatibility complex, HLA. There is epidemiological evidence of significant overlap between irritable bowel syndrome (IBS) and functional chronic diarrhea [FD (Locke et al 2005)]. The relationship of celiac disease and IBS is complex; while guidelines suggest screening for celiac disease in patients with FD or IBS with diarrhea (IBS-D), there is a paucity of evidence to support that recommendation. In Olmsted Co., MN, overall prevalence of positive tissue transglutaminase serology was 4%, and celiac disease did not explain the presence of either IBS or dyspepsia (Locke et al 2004). In a cost effectiveness analysis, testing for celiac disease became the dominant strategy when prevalence was >8%, specificity of the test for celiac disease was >98%, or the cost of IBS treatment exceeded $130/month (Spiegel BM, et al 2004). In fact, the incremental cost of testing for celiac disease exceeded $50,000 when the prevalence fell below 1%. Community studies suggest that celiac disease affects 0.5 to 1.0% of people in the USA. On the other hand, there is increasing recognition of a potential role of intolerance to gluten in patients with IBS-D or FD. Gluten intolerance without celiac disease was first popularized as a clinical entity in 1981 (Cooper BT et al 1981). However, until recently, there have been very limited investigations of the role of gluten intolerance as a factor contributing to IBS-D or FD. Wahnschaffe et al demonstrated that, among patients with IBS-D or FD, response of diarrhea to GFD was influenced by the HLA type and the presence of IgG tissue transglutaminase antibody: for HLA DQ 2 +ve, IgG TGA +ve, the response to gluten withdrawal occurred in 62%; conversely, in those DQ 2 -ve and IgG TGA -ve, 12% responded (Wahnschaffe et al 2007). This suggests that there is an immunogenetic predisposition to gluten intolerance among patients with IBS-D or FD in the absence of celiac disease. The mechanisms underlying this intolerance of gluten in humans with IBS are unclear. In HLA-D8 transgenic mice sensitized to gluten, gliadin exposure (in contrast to negative and positive controls) results in CD3, CD4 lymphocyte and macrophage infiltration of villi, and increased contractile responses of smooth muscle to electrical field stimulation and carbachol (Verdu et al 2008). This contractile activity may be a mechanism for the development of diarrhea. The link between gluten or gliadin and inflammation may be the increase in intestinal permeability, which is well established in celiac disease and involves binding to the chemokine receptor, CXCR3, leading to MyD88-dependent zonulin release (Lammers et al 2008). It is still unclear whether gluten alters permeability in the absence of celiac disease. On the other hand, there are reports of increased mucosal permeability in IBS, both non-infectious and post-infectious varieties, that typically causes IBS-D (Dunlop et al 2006). Our overall hypothesis is that gluten intake increases intestinal permeability in susceptible patients and leads to alterations in gastrointestinal function that manifest as IBS-D or chronic diarrhea. Our overall aim is to understand the mechanism of gluten-induced symptoms in patients with symptoms suggestive of IBS-D or FD, and optimize treatment of these patients. We propose to test the following: Specific hypotheses: 1. IBS-D or FD patients who are HLA-DQ2 positive have higher small intestinal and colonic permeability than HLA-DQ2 negative patients. 2. Gluten supplementation for four weeks increases small intestinal permeability and accelerates colonic transit in patients with IBS-D or FD who are HLA-DQ2 positive. Specific aims: 1. To compare small intestinal and colonic permeability in patients with IBS-D or FD who are positive or negative for HLA-DQ2. 2. To compare in a parallel-group, randomized, controlled trial, the effect of gluten-rich versus gluten-free diet on small intestinal and colonic permeability, small bowel and colonic mucosal morphology, and gastrointestinal and colonic transit in HLA-DQ2 positive and HLA-DQ2 negative patients with IBS-D or FD. PUBLIC HEALTH RELEVANCE: This application addresses the Challenge Area of Clinical Research in Digestive Diseases and the development of novel approaches to understand and treat functional GI and motility disorders. The application focuses specifically on the role of gluten (a protein in flour) diet and patients' genetic make-up in the development of chronic diarrhea and irritable bowel syndrome (IBS) with diarrhea, and how gluten free diet normalizes intestinal functions and bowel movements.