Manganese in Inflammatory Bowel Disease

锰在炎症性肠病中的作用

• 批准号: 10386893
• 负责人: Young Ah Seo
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10386893
• 关键词: Acute; Adherent Culture; Affect; American; Animals; CRISPR/Cas technology; Ceramidase; Chronic; Consumption; Crohn' 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; dietary; divalent metal; epidemiology study; genome wide association study; gut inflammation; high risk; inhibitor; insight; intestinal epithelium; manganese deficiency; mouse model; novel; therapeutic target; transcriptomics; western diet

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，是胃肠道慢性炎症性疾病的家族，影响超过300万美国人。虽然遗传背景显然起作用，但环境因素，特别是饮食营养素，被怀疑是导致疾病发展的触发因素。确定遗传学和膳食营养素协调影响IBD易感性的直接因果机制，可能会在揭示疾病如何发展以及未来如何治疗方面提供直接效用。虽然遗传因素似乎在IBD中发挥相对较小的作用，但单核苷酸多态性（SNP）与IBD存在一种特殊的关联，该关联出现在IBD中最近的全基因组关联筛选的顶部：锰转运蛋白SLC39A8（p.Ala391Thr）中的常见变体。我们和其他人已经表明，这种转运蛋白对于锰（Mn）的掺入至关重要，锰是许多酶活性所需的微量营养素。SLC39A8 A391T变体在体外显示具有降低的Mn掺入功能，并且我们独立地进行了类似的观察。这些发现暗示了饮食或遗传引起的Mn水平的改变，作为IBD的促成因素。然而，由于其各种饮食来源，锰缺乏症在人类中传统上是罕见的。锰在植物性食物中含量丰富，包括全谷物，大米，坚果和叶菜，而动物性食物缺乏这种营养素。最近的流行病学研究表明，在过去的15年里，由于西方饮食的特点是大量摄入红肉、高脂肪食物和精制谷物，饮食中的锰消费量减少了40%以上。该数据与IBD发病率的增加一致，并且支持营养Mn水平与IBD患者之间的负相关关系。然而，我们仍然没有确定锰在IBD中是否存在因果关系以及锰导致IBD的机制。该项目将定义饮食Mn和SLC39A8维持肠道健康的作用的功能见解，从而推进IBD病因学的研究。我们的研究结果将为IBD高风险个体的未来研究铺平道路，以提供饮食建议和治疗目标。