Manganese in Inflammatory Bowel Disease

锰在炎症性肠病中的作用

基本信息

批准号：
10057437
负责人：
Young Ah Seo
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10057437
关键词：
Acute Adherent Culture Affect American Animals CRISPR/Cas technology Ceramidase Chronic Consumption Crohn&apos s disease Data Dependence Development Diet Dietary Fiber Dietary Manganese Digestive System Disorders Disease Disease model Disease susceptibility Dose Environmental Risk Factor Enzymes Epithelial Cells Etiology Exhibits Family Fatty acid glycerol esters Food Future Genes Genetic Genetic Models Grain Health Homeostasis Human In Vitro Incidence Individual Inflammatory Inflammatory Bowel Diseases Intake Intestinal permeability Intestines Investigation Ions Iron Knock-in Mouse Knockout Mice Lead Lipids Manganese Meat Mediating Metals Micronutrients Minor Mitochondria Mus Mutant Strains Mice Mutation Normal Range Nutrient Nutritional Nuts Organoids Patients Plants Play Positioning Attribute Predisposition Production Reactive Oxygen Species Recommendation Research Resources Rice Role Single Nucleotide Polymorphism Sodium Dextran Sulfate Source Testing Ulcerative Colitis Variant Vegetables Zinc alkalinity base dextran sulfate sodium induced colitis divalent metal epidemiology study genome wide association study high risk inflammatory disease of the intestine inhibitor/antagonist insight intestinal epithelium manganese deficiency mouse model novel therapeutic target transcriptomics western diet

项目摘要

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic inflammatory disorders of the gastrointestinal tract that affect over 3 million Americans. While genetic background clearly plays a role, environmental factors, especially dietary nutrients, have been suspected as triggers to contribute to the disease development. Identifying the direct causal mechanisms by which genetics and dietary nutrients coordinately influence IBD susceptibility may provide direct utility in uncovering both how the disease develops and how it may be treated in the future. Although genetic factors appear to play relatively minor roles in IBD, there is one particular association of single nucleotide polymorphism (SNP) with IBD that showed up at the top of a recent genome-wide association screen in IBD: a common variant in the manganese transporter SLC39A8 (p.Ala391Thr). We and others have shown that this transporter is critical for the incorporation of manganese (Mn), a micronutrient required for many enzymatic activities. The SLC39A8 A391T variant was shown in vitro to have reduced Mn incorporating function, and we made similar observations independently. These revelations hint toward alterations in Mn levels caused by diet or genetics, as contributing factors for IBD. Yet, Mn deficiency has traditionally been rare in humans due to its various dietary sources. Mn is abundant in plant-based foods, including whole grains, rice, nuts, and leafy vegetables, whereas animal-based foods lack this nutrient. Recent epidemiological studies have revealed >40% reduction in dietary Mn consumption in the past 15 years due to a Western diet characterized by high intakes of red meats, high fat foods, and refined grains. This data is congruent with the increasing incidence of IBD, and it supports an inverse relationship between nutritional Mn levels and IBD patients. However, we still have not established if there is a causal role of Mn in IBD and the mechanism by which Mn contributes to IBD. This project will define functional insight into the roles of dietary Mn and SLC39A8 that maintain intestinal health, thereby advancing research into the etiology of IBD. Our findings will pave the way for future research in individuals at high risk of IBD to provide dietary recommendations and therapeutic targets.

炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是胃肠道的慢性炎症性疾病家族，影响超过300万美国人。虽然遗传背景显然起着作用，但环境因素，尤其是饮食营养素，被怀疑是为疾病发展做出贡献的触发因素。确定遗传学和饮食营养素协同影响IBD易感性的直接因果机制可能会提供直接的效用，以揭示疾病的发展方式以及将来如何治疗疾病。尽管遗传因素在IBD中似乎起着相对较小的作用，但单核苷酸多态性（SNP）与IBD有一种特殊的关联，它显示在IBD中最近全基因组关联屏幕的顶部：锰型型Transporter SLC39A8中的一种常见变体（P.Ala391thr）（P.Ala391thr）。我们和其他人表明，这种转运蛋白对于掺入锰（MN）至关重要，锰（MN）是许多酶活性所需的微量营养素。在体外显示了SLC39A8 A391T变体，以降低MN的合并功能，我们独立进行了类似的观察结果。这些启示暗示，饮食或遗传学引起的MN水平改变是IBD的促成因素。然而，由于其各种饮食来源，MN缺乏症在人类中一直很少见。 MN在植物性食品中丰富，包括全谷物，大米，坚果和多叶蔬菜，而基于动物的食物则缺乏这种营养。最近的流行病学研究表明，由于西方饮食的特征是，饮食中的MN消耗量降低了40％，其特征是高摄入红肉，高脂食品和精制谷物。这些数据与IBD的发生率的增加是一致的，并且支持营养MN水平与IBD患者之间的反比关系。但是，如果MN在IBD中具有因果关系以及MN对IBD的贡献的机制，我们仍然没有确定。该项目将定义对维持肠道健康的饮食中MN和SLC39A8作用的功能洞察力，从而提高了对IBD病因的研究。我们的发现将为IBD高风险的个人的未来研究铺平道路，以提供饮食建议和治疗目标。