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的临床研究和特定的挑战主题，04-DK-103：开发新的方法来理解和治疗功能障碍。在这项应用中，我们计划确定饮食在功能性胃肠道和运动性疾病发展中的作用，以及基因如何在功能性胃肠道和运动性疾病的发展中起作用。感兴趣的基因是混合组织相容性复合体，即人类白细胞抗原。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等人，2005年)]。乳糜泻与肠易激综合征的关系是复杂的；尽管指南建议对FD或IBS伴腹泻(IBS-D)患者进行乳糜泻筛查，但支持这一建议的证据很少。在Olmsted Co.，MN，组织转谷氨酰胺酶血清学阳性的总体流行率为4%，乳糜泻不能解释IBS或消化不良的存在(Locke等人，2004年)。在成本效果分析中，当患病率为8%，乳糜泻检测的特异度为98%，或IBS治疗费用超过130美元/月时，乳糜泻检测成为主要策略(Spiegel BM，等人，2004年)。事实上，当患病率降至1%以下时，检测乳糜泻的增量成本超过了50,000美元。社区研究表明，乳糜泻在美国影响0.5%到1.0%的人。另一方面，人们越来越多地认识到面筋不耐受在IBS-D或FD患者中的潜在作用。没有乳糜泻的面筋不耐受在1981年首次作为临床实体被普及(Cooper，BT等，1981)。然而，直到最近，对于面筋不耐受作为导致IBS-D或FD的一个因素的作用的研究非常有限。Wahnschaffe等人证实，在IBS-D或FD患者中，腹泻对GFD的反应受HLA型和存在组织转谷氨酰胺酶抗体的影响：对于HLADQ2+ve、Ig GTGA+Ve，对停面筋的反应发生在62%；相反，在DQ2-Ve和Ig TGA-Ve的患者中，12%有反应(Wahnschaffe Et Al 2007)。这表明在没有乳糜泻的IBS-D或FD患者中存在面筋不耐受的免疫遗传易感性。患有IBS的人类对面筋不耐受的机制尚不清楚。在对面筋致敏的HLA-D8转基因小鼠中，醇溶蛋白暴露(与阴性和阳性对照相比)导致CD3、CD4淋巴细胞和巨噬细胞渗入绒毛，并增加了平滑肌对电场刺激和氨基甲胆碱的收缩反应(Verdu等人，2008年)。这种收缩活动可能是腹泻发生的机制之一。面筋或醇溶蛋白与炎症之间的联系可能是肠道通透性的增加，这在乳糜泻中得到了很好的证实，并涉及到与趋化因子受体CXCR3的结合，导致依赖MyD88的zonrin释放(Lammers等人2008)。目前还不清楚在没有乳糜泻的情况下，面筋是否会改变通透性。另一方面，有报告称IBS的粘膜通透性增加，包括非传染性和感染后的品种，这通常会导致IBS-D(Dunlop等人，2006年)。我们的总体假设是，摄入面筋会增加易感患者的肠道通透性，并导致胃肠功能的改变，表现为IBS-D或慢性腹泻。我们的总体目标是了解具有IBS-D或FD症状的患者面筋诱导症状的机制，并优化这些患者的治疗。具体假设如下：1.HLADQ2阳性的IBS-D或FD患者的小肠和结肠通透性高于HLADQ2阴性患者。2.补充面筋蛋白4周可增加HLADQ2阳性IBS-D或FD患者的小肠通透性，加速结肠转运。具体目的：1.比较HLADQ2阳性或阴性IBS-D或FD患者的小肠和结肠通透性。2.通过一项平行、随机、对照试验，比较高面筋饮食与无面筋饮食对IBS-D或FD患者的小肠和结肠通透性、小肠和结肠粘膜形态、胃肠道和结肠转运的影响。 公共卫生相关性：这项应用解决了消化疾病临床研究的挑战领域，以及了解和治疗功能性胃肠道和动力障碍的新方法的开发。该应用特别关注面筋(面粉中的一种蛋白质)饮食和患者的基因构成在慢性腹泻和肠易激综合征(IBS)腹泻发展中的作用，以及无谷蛋白饮食如何使肠道功能和肠道运动正常化。

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.