Manganese in Inflammatory Bowel Disease

炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是胃肠道慢性炎症性疾病的一个家族，影响着300多万美国人。虽然遗传背景明显起作用，但环境因素，特别是饮食营养，被怀疑是导致疾病发展的触发因素。确定遗传和膳食营养素协同影响IBD易感性的直接因果机制，可能为揭示疾病如何发展以及未来如何治疗提供直接效用。尽管遗传因素似乎在IBD中起着相对较小的作用，但在最近的IBD全基因组关联筛选中，单核苷酸多态性（SNP）与IBD有一种特殊的关联：锰转运蛋白SLC39A8的一种常见变体（p.Ala391Thr）。我们和其他人已经证明，这种转运体对锰（Mn）的结合至关重要，锰是许多酶活性所需的微量营养素。SLC39A8 A391T变体在体外被证明具有降低的Mn结合功能，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锰水平改变是IBD的促成因素。然而，由于锰的各种饮食来源，传统上在人类中锰缺乏是罕见的。植物性食物中富含锰，包括全谷物、大米、坚果和多叶蔬菜，而动物性食物则缺乏这种营养。最近的流行病学研究表明，在过去15年中，由于以大量摄入红肉、高脂肪食物和精制谷物为特征的西方饮食，膳食锰摄入量减少了40%。这一数据与IBD发病率的增加是一致的，它支持营养锰水平与IBD患者之间的反比关系。然而，我们仍然没有确定Mn在IBD中是否存在因果作用以及Mn对IBD的作用机制。该项目将明确膳食Mn和SLC39A8在维持肠道健康中的功能作用，从而推进IBD病因学的研究。我们的发现将为未来对IBD高危人群的研究铺平道路，提供饮食建议和治疗目标。

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.