Manganese in inflammatory bowel disease

Project Summary Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a group of major chronic inflammatory disorders of the gastrointestinal tract that affect over 3 million Americans. While genetics clearly plays a role, environmental factors, especially dietary nutrients, have been suspected of triggering disease development. Identifying the direct causal mechanisms by which genetics and dietary nutrients combine to 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) that emerged at the top of a recent genome-wide association screen in IBD: a common variant in the divalent metal ion 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. These revelations hint toward alterations in Mn levels caused by diet, genetics, or a combination thereof as contributing factors for IBD. During the prior award cycle, research by our team has helped to understand how Mn, altered by diet or genetics, contributes to IBD. We provided the first evidence that dietary Mn deficiency exacerbates intestinal injury in a mouse model of IBD. We also demonstrated that SLC39A8 is not only essential for dietary Mn absorption, but also for epithelial integrity, thereby offering protection against IBD. In exploring the mechanistic drivers of Mn-induced IBD, two pivotal questions have emerged: During which developmental time stages does Mn dysregulation lead to IBD susceptibility? What are the cellular and molecular mechanisms by which low Mn levels confer a higher IBD risk with the SLC39A8 variant? This project will provide functional insight into the developmental time windows for the roles of dietary Mn and SLC39A8 gene in maintaining intestinal health, thereby advancing research into the etiology of IBD. Our findings will pave the way for future research to provide precise dietary recommendations and therapeutic interventions aimed at mitigating IBD risk across the lifespan.