Gastroenterologists have more treatments at their disposal today than ever before, particularly in the last decade. “We have had tremendous advances in many areas of understanding contributors to disease,” said Dr. Melia, an assistant professor of medicine at Johns Hopkins Medicine in Baltimore who specializes in inflammatory bowel disease (IBD). But the hurdle is in translating the science to clinical care that is individualized to each patient based on condition and stage of the condition.
Dr. Joanna Melia
“That still remains a bit of a dream,” she said. Much of her career has been devoted to chasing down a particular genetic variant that contributes to IBD, with the goal of reaching more precise treatments for patients.
In an interview, she shared how she entered this line of work, and what her research has revealed about Crohn’s disease, manganese, and a common genetic variant known as ZIP8.
Q: Your expertise is in inflammatory bowel disease and manganese deficiency. Why did you choose these two areas as your focus in GI?
Dr. Melia: In talking to many patients with IBD, I was always struck by the questions around nutritional factors related to disease. As a fellow, I was embedded in a lab that focused on genetics of IBD. A micronutrient transporter, ZIP8, has a mutation in it that increases the risk of Crohn’s disease.
I’ve dedicated the last 8 years to understanding how this mutation can increase risk. It initially started out as a project focused on zinc, because that’s what the transporter was thought to regulate. However, it’s evolved as we’ve learned more about it, underscoring the importance of manganese, another micronutrient that we derive from food.
We have established that having this mutation changes how the body handles manganese and affects downstream processes that involve manganese. What I’m doing now is trying to connect those dots on why those processes are important in Crohn’s disease and whether we can target them for treatment.
Q: How does manganese deficiency lead to chronic IBD?
Dr. Melia: In individuals with this mutation, their blood manganese levels are lower than people who don’t have this mutation. When we talk about manganese deficiency or insufficiency, what we’re really talking about is lower blood levels. But it’s more complicated than that at the tissue level.
What we and other groups are working on right now is trying to understand if the manganese levels change in the gut and what happens in inflammation. The gut is a particularly interesting area for manganese, in that much of the manganese that we eat is excreted. We only absorb a small amount of it. And so, manganese levels within the gut lumen may actually be quite high – and may be even higher in inflammation. But there are things we don’t understand about that and how it relates to mucosal levels of manganese and Crohn’s disease. The ileum, the site of the Crohn’s disease that’s specifically associated with this mutation, might be particularly sensitive to changes in the manganese levels or the downstream processes that changing manganese availability affects.
One of those processes is glycosylation. Manganese is important to properly glycosylate your proteins. Many enzymes help cells put sugars on proteins, and many of those enzymes need manganese to do it. Glycosylation of proteins is important so cells know where those proteins should go, and the sugars help them stay where they need to be. When you change protein glycosylation, you can stress the cells. We know individuals who carry this mutation have changes in the glycosylation of their proteins. What we’re working on right now is understanding which key proteins might change when that happens, and why that’s a potential problem, especially in the ileum.
