Grant Abstract: Manganese in Inflammatory Bowel Disease

Grant Number: 5R01DK123022-03
PI Name: Seo
Project Title: Manganese in Inflammatory Bowel Disease

Abstract: 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.

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