Manganese in Inflammatory Bowel Disease

炎症性肠病(IBD)，包括克罗恩病和溃疡性结肠炎，是一种慢性胃肠道炎症性疾病家族，影响超过300万美国人。虽然遗传背景显然起到了作用，但环境因素，特别是饮食营养，一直被怀疑是导致疾病发展的触发因素。确定遗传和饮食营养协调影响IBD易感性的直接原因机制，可能会在揭示疾病如何发展以及未来可能如何治疗方面提供直接有用的信息。虽然遗传因素在IBD中的作用相对较小，但有一种特殊的单核苷酸多态(SNP)与IBD的关联出现在最近的IBD全基因组关联筛查的顶部：锰转运蛋白SLC39A8(p.Ala391Thr)的一个常见变异。我们和其他人已经证明，这种转运蛋白对于锰(Mn)的结合至关重要，锰是许多酶活动所需的一种微量营养素。SLC39A8 A391T突变体在体外被证明具有降低锰的结合功能，我们独立地进行了类似的观察。这些发现暗示，饮食或遗传导致的锰水平变化是IBD的促成因素。然而，由于其饮食来源的多样性，锰缺乏症传统上在人类中很少见。锰在植物性食物中含量丰富，包括全谷物、大米、坚果和叶类蔬菜，而动物性食物缺乏这种营养。最近的流行病学研究显示，在过去的15年里，由于西方饮食的特点是大量摄入红肉、高脂肪食品和精制谷物，饮食中的锰摄入量减少了40%。这一数据与IBD发病率的增加是一致的，并支持营养锰水平与IBD患者之间的负相关关系。然而，我们仍然没有确定是否有锰在IBD中的因果作用，以及锰在IBD中的作用机制。这个项目将定义对饮食中锰和SLC39A8在维持肠道健康中的作用的功能洞察，从而推动对IBD病因学的研究。我们的发现将为未来对IBD高危人群的研究提供饮食建议和治疗目标铺平道路。

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.