Timing of Gluten Intake In Infant Nutrition and Risk of Celiac Disease Autoimmuni

婴儿营养中麸质摄入的时机和乳糜泻自身免疫性疾病的风险

• 批准号: 7612761
• 负责人: Alessio Fasano
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612761
• 关键词: Address; Affect; Age; Age-Months; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Barley; Binding; Biology; Biometry; CXCR3 gene; Celiac Disease; Cell physiology; Cereals; Child; Childhood; Consensus; Coupled; Data; Development; Diagnosis; Diet; Dietary Intervention; Disease; Double-Blind Method; Enrollment; Environment; Environmental Risk Factor; Epidemiology; Epithelial; Event; Exposure to; Feasibility Studies; Feeding Patterns; First Degree Relative; Functional disorder; Gastroenterology; Genetic; Gliadin; Gluten; Goals; Human Genetics; Immune; Immune response; Immune system; Immunity; Immunology; In Vitro; Incidence; Indium; Individual; Infant; Inflammation; Inflammatory disease of the intestine; Ingestion; Intake; Intervention Studies; Intestines; Lead; Life; Literature; Maryland; Modeling; Molecular; Molecular and Cellular Biology; Natural Immunity; Nutritional; Onset of illness; Outcome Study; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Permeability; Population; Prevention Research; Primary Prevention; Proteins; Randomized; Recommendation; Research; Resources; Retrospective Studies; Risk; Role; Rye cereal; Serum; Symptoms; Time; Tissues; Transglutaminases; United States National Institutes of Health; Universities; Up-Regulation; Wheat; Work; base; chemokine receptor; cost; design; evidence base; genetic association; human leukocyte antigen gene; infant nutrition; innovation; insight; medical schools; prevent; prospective; public health relevance; response; symposium; zonulin

DESCRIPTION (provided by applicant): Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten containing grains (i.e.; wheat, barley, and rye) in genetically susceptible individuals. Given the undisputable role of gliadin in causing inflammation and autoimmunity, CD represents a unique model of autoimmune disorder for which, in contrast to most other autoimmune diseases, the triggering environmental factor (gliadin), a close genetic association with HLA genes (DQ2 or DQ8), and a highly specific humoral autoimmune response (auto-antibodies to tissue transglutaminase) are known. However, despite the significant progress made in understanding the adaptive immunological aspects of CD pathogenesis, the early steps following intestinal mucosal exposure to gliadin leading to the loss of tolerance and the development of the autoimmune process are still largely unknown. Increasing evidence in literature seem to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of the disease. Recent retrospective studies also suggest that this dysfunctional cross talk is influenced by the timing of gluten introduction in the diet of subjects genetically susceptible to CD. Therefore, we propose to investigate this aspect of CD pathogenesis in a blend of basic and applied studies, which will yield fundamental insights into the role of timing of gluten introduction in early steps involved in the onset of the disease. Our overall hypothesis is that the timing of introduction of gluten-containing cereals into the diet of infants genetically at risk for CD may influence the loss of tolerance to the protein and subsequent activation of the adaptive immune system causing the intestinal and extra-intestinal inflammation typical of the disease. We will take full advantage of a very conducive environment (that includes the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland) thematically relevant to this proposal. Our long-term objective is to capitalize on the unique features of CD as an autoimmune disorder to gain insights on the role of the timing of gluten exposure in dictating loss of intestinal tolerance to the protein and possibly to other non-self antigens leading to CD and other autoimmune disorders associated with CD. PUBLIC HEALTH RELEVANCE Increasing evidence in literature seems to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of celiac disease (CD). Several retrospective studies have suggested that the time of gluten introduction in the diet of infants at risk for CD may affect the incidence of the disease. However, the data supporting this hypothesis are circumstantial, limited by their retrospective design, and often criticized by alternative interpretations suggesting that the delay in gluten exposure merely postpones the onset of symptoms rather than preventing the disease. In order to address this issue in a more rigorous manner, with this application we propose to perform a prospective, randomised, double-blind dietary intervention study to establish the relationship between age of gluten introduction and development of CD autoimmunity in at-risk infants. By investigating the role of infant nutrition (early vs late exposure to dietary gluten) this project will contribute to clarify the early pathophysiological changes that may lead to CD development. The consequent implementation of strategies of primary prevention of CD in the general pediatric population could significantly reduce the costs associated with the diagnosis and treatment of this life-long disorder.

描述（由申请人提供）：腹腔疾病（CD）是一种自身免疫性肠病，它是由遗传易感个体中摄入含谷物的麸质（即小麦，大麦和黑麦）引起的。鉴于麦醇溶蛋白在引起炎症和自身免疫性中的无可争辩的作用，CD代表了自身免疫性疾病的独特模型，与大多数其他自身免疫性疾病相比，它与触发环境因素（Gliadin）相比，与HLA基因的遗传反应密切相关（DQ2或DQ8），并且是高度的（DQ2或DQ8），并且是高度的（DQ2或DQ8） - 效果（DQ2或DQ8） - 效果 - 转谷氨酰胺酶）是已知的。然而，尽管在理解CD发病机理的适应性免疫学方面取得了重大进展，但肠粘膜暴露于麦醇溶蛋白后的早期步骤导致耐受性丧失和自身免疫过程的发展仍然很大程度上是未知的。文献中越来越多的证据似乎表明，先天性和适应性免疫之间的交叉讲座是该疾病自身免疫过程中的关键致病元素。最近的回顾性研究还表明，这种功能失调的串联谈话受到麸质引入的时间的影响，在受试者遗传上受到CD敏感的受试者饮食中。因此，我们建议在基础研究和应用研究的融合中研究CD发病机理的这一方面，这将在疾病发作的早期步骤中对麸质时间引入时间的作用产生基本见解。我们的总体假设是，将含麸质谷物的谷物引入遗传饮食中的饮食时机可能会影响对蛋白质的耐受性的丧失，并随后激活适应性免疫系统，从而导致肠道和肠外炎症。我们将充分利用一个非常有利的环境（包括粘膜生物学研究中心和马里兰州大学的腹腔研究中心），其主题与该提案有关。我们的长期目标是利用CD作为自身免疫性疾病的独特特征，以了解面筋暴露时间在决定对蛋白质以及可能导致CD和其他与CD相关的其他自身免疫性疾病的其他非自身抗原的肠道耐受性方面的作用。公共卫生的相关性越来越多的文献证据似乎表明先天性和适应性免疫之间的跨性互动率是自身免疫性腹腔疾病过程（CD）的关键致病元素。几项回顾性研究表明，面筋饮食中有症状危险的婴儿饮食中引入的时间可能会影响疾病的发生率。但是，支持这一假设的数据是间接的，受其回顾性设计的限制，并且经常受到替代解释的批评，这表明麸质暴露的延迟只是推迟症状的发作，而不是预防疾病。为了以更严格的方式解决此问题，通过此应用，我们建议进行一项前瞻性，随机，双盲饮食干预研究，以确定麸质引入年龄与处于危险婴儿中CD自身免疫性的发展之间的关系。通过研究婴儿营养的作用（早期与晚期暴露于饮食面筋），该项目将有助于阐明可能导致CD发育的早期病理生理变化。随之而来的是普通小儿人群中CD初级预防策略的实施可以显着降低与这种终身疾病的诊断和治疗相关的成本。

项目成果

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.

• DOI: 10.1186/1741-7015-9-23
• 发表时间: 2011-03-09
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Sapone A;Lammers KM;Casolaro V;Cammarota M;Giuliano MT;De Rosa M;Stefanile R;Mazzarella G;Tolone C;Russo MI;Esposito P;Ferraraccio F;Cartenì M;Riegler G;de Magistris L;Fasano A
• 通讯作者: Fasano A