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

肠易激综合征-腹泻：麸质不耐受和 HLA-DQ2 的作用

基本信息

批准号：
7943984
负责人：
MICHAEL L. CAMILLERI
金额：
$ 50万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943984
关键词：
Address Affect Antibodies Area Binding CD3 Antigens CD4 Positive T Lymphocytes CXCR3 gene Carbachol Celiac Disease Chronic Clinical Clinical Research Communities Complex Cost Effectiveness Analysis Defecation Development Diarrhea Diet Digestive System Disorders Dyspepsia Epidemiology Flour Functional disorder Genetic Genotype Gliadin Gluten Guidelines Hand Human Immunogenetics Immunoglobulin G Infiltration Inflammation Intake Intestines Investigation Irritable Bowel Syndrome Link Major Histocompatibility Complex Morphology Patients Permeability Predisposition Prevalence Proteins Randomized Controlled Trials Recommendation Reporting Role Screening procedure Serologic tests Small Intestines Smooth Muscle Specificity Supplementation Symptoms Testing Tissues Transgenic Mice Transglutaminases Villus Withdrawal chemokine receptor cost falls gastrointestinal gastrointestinal function interest macrophage motility disorder novel strategies public health relevance response zonulin

项目摘要

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.

描述（由申请人提供）：此申请涉及广泛的挑战领域临床研究和特定挑战主题，04-DK-103：开发新颖的方法来理解和治疗功能障碍。在此应用中，我们计划确定饮食在功能性GI和运动障碍发展中的作用，以及基因型如何促进功能性GI和运动障碍的发展。感兴趣的基因型是混合的组织相容性复合物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着重叠[FD（Locke等，2005）]。乳糜泻和IBS的关系很复杂。虽然指南表明在FD或IBS患有腹泻（IBS-D）患者中筛查乳糜泻（IBS-D），但很少有证据支持该建议。在明尼苏达州奥尔姆斯特德公司（Olmsted Co.在成本效率分析中，当患病率> 8％时，对乳糜泻的测试成为主要策略，乳糜泻的测试特异性> 98％，或IBS治疗的成本超过130美元/月（Spiegel BM等人，2004年）。实际上，当患病率降至1％以下时，乳糜泻的测试成本超过50,000美元。社区研究表明，乳糜泻影响0.5至1.0％的美国。另一方面，对IBS-D或FD患者的面筋的潜在作用的认识越来越高。未经腹腔疾病的麸质不耐症首先在1981年被普及为临床实体（Cooper BT等，1981）。但是，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等人证明，在IBS-D或FD患者中，腹泻对GFD的反应受HLA类型的影响，并且IgG组织转凝胺酶抗体的存在：HLA DQ 2 +VE，IgG TGA +，IgG TGA +VE，对Gluten的反应，响应于62％的62％；相反，在那些DQ 2 -VE和IgG TGA -VE中，有12％的回应（Wahnschaffe等，2007）。这表明在没有腹腔疾病的情况下，IBS-D或FD患者的面筋不耐受存在免疫原性的易感性。 IBS人类中这种面筋不耐受性的机制尚不清楚。在对面筋敏化的HLA-D8转基因小鼠中，麦醇麦二丁蛋白暴露（与阴性和阳性对照相反）会导致CD3，CD4淋巴细胞和绒毛的巨噬细胞浸润，并增加平滑肌对电场刺激和卡巴乔尔的收缩反应（Verdu等人2008）。这种收缩活动可能是腹泻发展的机制。麸质或麦醇溶蛋白和炎症之间的联系可能是肠道通透性的增加，肠道渗透性在乳糜泻中已建立，并涉及与趋化因子受体CXCR3结合，从而导致MyD88依赖性的Zonulin释放（Lammers等人2008）。目前尚不清楚面筋是否在没有腹腔疾病的情况下会改变渗透性。另一方面，有报道称非感染和感染后品种的IBS中粘膜渗透性增加，通常会引起IBS-D（Dunlop等人，2006年）。我们的总体假设是，麸质摄入量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。我们的总体目的是了解麸质诱导的症状的机制，表现为IBS-D或FD，并优化对这些患者的治疗。我们建议测试以下内容：特定假设：1。HLA-DQ2阳性的IBS-D或FD患者的肠道和结肠通透性小于HLA-DQ2阴性患者。 2。补充四周的麸质增加了小肠通透性，并加速了HLA-DQ2阳性的IBS-D或FD患者的结肠传输。具体目的：1。比较IBS-D或FD患者阳性或阴性HLA-DQ2患者的小肠道和结肠通透性。 2。要在平行组，随机，对照试验中进行比较，无麸质与无麸质饮食对小肠和结肠通透性的影响，小肠和结肠粘膜形态以及HLA-DQ2阳性和HLA-DQ2阳性和HLA-DQ2阴性患者的胃肠道和结肠传播。公共卫生相关性：该申请涉及消化疾病中临床研究的挑战领域，以及发展和治疗功能性GI和运动障碍的新颖方法的发展。该应用专门针对麸质（蛋白质在面粉中）的作用和患者的遗传构成在慢性腹泻和肠易激综合征（IBS）的发展中的作用，以及无麸质饮食如何使肠功能和肠子运动归一化。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea.

DOI：
10.1016/j.cgh.2012.05.006
发表时间：
2012-09
期刊：
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
12.6
作者：
Wong, Banny S.;Camilleri, Michael;Carlson, Paula;McKinzie, Sanna;Busciglio, Irene;Bondar, Olga;Dyer, Roy B.;Lamsam, Jesse;Zinsmeister, Alan R.
通讯作者：
Zinsmeister, Alan R.

Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea.

HLA-DQ 基因与腹泻性肠易激综合征的肠道运输、屏障功能和炎症的关联。

DOI：
10.1152/ajpgi.00294.2012
发表时间：
2012
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
0
作者：
Vazquez-Roque,MariaI;Camilleri,Michael;Smyrk,Thomas;Murray,JosephA;O'Neill,Jessica;Carlson,Paula;Lamsam,Jesse;Eckert,Deborah;Janzow,Denise;Burton,Duane;Ryks,Michael;Rhoten,Deborah;Zinsmeister,AlanR
通讯作者：
Zinsmeister,AlanR

LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin.