David Rubin, MD, Professor of Medicine at the University of Chicago talks about IBD and how a recent discovery might help patients down the road.
How many people are affected with IBD?
RUBIN: It is estimated that 3.1 million Americans may have inflammatory bowel disease, which includes about half with Crohn’s disease and the other half with the sister disease called ulcerative colitis.
Can you talk a little bit about the research that was done recently at the University of Chicago and explain exactly what function that provides?
RUBIN: We’ve been doing research at the University of Chicago to investigate the causes and potential treatments of inflammatory bowel disease for many years. We think we have the first IBD center in the United States that started in 1935. The more recent research that’s been performed by colleagues here in pathology was the discovery of a molecule called, divertin, that inhibits an enzyme involved in breaking down the barrier that exists in our intestine. When that barrier breaks down, the theory is that it exposes our immune system to bacteria and other elements of the environment, meaning what’s inside of our bowel that we’ve eaten or have partially digested. One of the theories of what drives the chronic inflammation of Crohn’s disease and ulcerative colitis is something in the environment is stimulating the immune system. Chronic inflammation is what leads to the symptoms and ultimately the damage to the bowel that causes a lot of problems patients can have. We’ve learned more recently that why this is happening may be due to a breakdown in the normal barriers that exist to prevent us from getting overstimulated. In a healthy intestine, there’s a mucous lining that protects us and also has a lot of bacteria living in it. That mucous lining helps kill bacteria and then there’s the normal cells of the human body underneath it. That is the barrier between what’s inside of our intestine and what our body sees in terms of the blood and the immune system. If the barrier, whether it’s the mucous lining or the cells themselves, break down, then our immune system reacts to it, and may think that it’s under attack. The immune system of our bodies is there to protect us. So, part of our theory about what’s going on in inflammatory bowel disease is the healthy immune system that’s there to protect us is being stimulated too much because of a breakdown in defense mechanisms and therefore is causing damage that leads to the problems we know as Crohn’s disease and ulcerative colitis. The small molecule, divertin, works on an enzyme that is involved in breaking down that barrier that exists. If you can use this small molecule like a key in a lock to block that enzyme from breaking down the barrier, you can enhance or protect that barrier so it can continue to protect the person and therefore not result in inflammation. It’s a little complicated, but it offers insight into what might be happening when we see people with these chronic conditions. More importantly it offers the opportunity to develop a treatment, if we can produce this small molecule, and then deliver it effectively to people who have these conditions. We’re hopeful that it might help restore the barrier that’s there to protect us so that the immune system isn’t constantly being triggered and stimulated. That’s part of the way we manage Crohn’s disease and ulcerative colitis. We’re trying to turn off the inflammation. Right now, many of the treatments we use for ulcerative colitis and Crohn’s disease are more global. We’re sort of carpet bombing the immune system and shutting down lots of different targets and pathways. As we get better at this, we know we can be much more precise in our way to try and manage or optimize the immune system’s response to the environment.
You mentioned the molecule works with an enzyme. What’s that enzyme?
RUBIN: It’s called, myosin light chain kinase, and has to do with a specific way the body is protecting itself by maintaining very tight junctions between different cells so things inside the gut can’t leak through the cells and get into the bloodstream and stimulate an immune response or cause you to be sick. The theory used to be the bacteria that live in our bowel were bad and this was a sewer and we should be careful not to ever get exposed to it. We’ve learned it’s much more complicated than that. The bacteria that live in our intestines along with fungi and viruses and lots of other things is part of a very complicated ecosystem. Part of that ecosystem is a very intricate interaction between what’s going on in the bowel and what the body is seeing and experiencing and being exposed to so that we react properly. Many people don’t realize that every time you eat, you’re essentially sampling the outside world. So, other than your skin, the gut sees more of the environment than any part of our body. It constantly must distinguish between what might hurt us and what is just part of what we need for digestion or nutrition. When this barrier breaks down, the immune system gets exposed to lots of things and it gets stimulated. The theory is that it’s getting overstimulated. If we can somehow protect that barrier, enhance it, or restore it by modifying the way this enzyme works, we can then potentially develop a new way for the body to keep itself protected. In parallel to this is emerging work that suggests supplements and preservatives in our foods may be breaking down the barriers. They’re called emulsifiers. If you read about emulsifiers, you find that they’re in all the foods we eat. One of the theories about why inflammatory bowel disease is rising all over the world has to do with the prevalence of emulsifiers in everything everyone’s eating everywhere. If emulsifiers are breaking down the barrier that’s designed to protect us, it might be what’s stimulating some of these problems. On the flip side, if this new molecule, divertin, can strengthen the barrier by blocking this particular enzyme, it might actually provide a new way to protect us and treat IBD or maybe in at-risk people to prevent IBD or prevent relapses in people who are already in remission. There’s a lot of potential clinical opportunities to apply this. That’s where I come in because I’m seeing patients who have these conditions and working with different groups to try and develop new therapies. It’s very exciting.
With this research, what would a potential therapy look like?
RUBIN: It depends on how it might be delivered. If it’s a small molecule, that means it’s small enough to get absorbed in the small intestine and get into the bloodstream. I don’t know enough about how they’re thinking to develop the molecule further, whether it’s something that would circulate in our bloodstream and then work where it’s needed, or whether it might work better if it’s delivered topically. What I mean by topically is that we use a delivery system in a capsule or a tablet where it won’t release the molecule until it gets all the way down into the intestine where it’s needed. There are ways we do that now with some of our other anti-inflammatory treatments, so if it works more on the lining of the bowel, maybe that’s a better way to deliver this molecule. However, that’s a few steps down the line before we get there.
IBD is a very destructive condition. What would this mean to someone going through that condition?
RUBIN: People who live with IBD live with a few struggles. One of them is when the disease is active. Depending which parts of their bowel are inflamed causes a lot of symptoms that can be very disruptive to their daily activities. Symptoms like too much diarrhea or abdominal pain or an inability to eat. The second problem is when they’re on medicines that seem to be working, they often stop working. So, you can be feeling well and in what we call remission, and then the disease will relapse. One of the big challenges to living with a chronic condition like inflammatory bowel disease is that even though you’re on a treatment that seems to be working, there is a risk that the disease may come back and cause what patients call a flare, or what we call a relapse. The idea of having a therapy like this that restores the barrier function that might help the body protect itself is exciting. It’s a very interesting and novel concept because currently, most of our treatments used for maintaining remission and preventing patients from relapsing are based on suppressing the immune system in some way. This is a concept that would be potentially enhancing our body’s immune system. It’s the opposite of that. Perhaps this would be a therapy that would work best in a maintenance phase to prevent relapse and would use some of our existing therapies that were quicker in the short-term when people are sick to turn off the inflammation.
What general things can be harmful or helpful for remission?
RUBIN: People have theorized that food or diet may be driving the condition. However, people have also thought about what foods can treat the disease or what dietary types of foods might improve the disease. Up until now, there’s been very little progress in that regard. As much as it seems logical that a gut disease like Crohn’s and Colitis might be driven or caused by food, and as much as we’ve thought about whether these preservatives might be breaking down the barrier and causing the disease, we don’t have diets that we can recommend to patients that will treat their disease. On the other hand, there’s been great interest in something called an anti-inflammatory diet, or a Mediterranean style diet. In general, that means more olive oil and fish and some healthy nuts. There are less inflammatory, at least in theory, than foods like red meat which we’re not designed to eat a lot of, and foods that are high in processed components or a lot of preservatives, which I’ve already mentioned may be breaking down some of our barriers. We don’t have a diet that we know works. It certainly doesn’t replace the treatments we currently use. We do make recommendations on a regular basis to consider healthier diets and favoring something like a Mediterranean style diet or diets that are not focused on processed foods. We’d like to see much more work in this area. There’s an actual trial going on now by the NIH to look at diet and Crohn’s disease that’s almost done. Right now, we know for an individual patient diet can help their symptoms, but it doesn’t fix the inflammation. Some people find out they’re lactose intolerant, and some people find out certain foods like tomatoes or onions make them feel worse. Many patients with IBD say they have difficulty digesting red meat and it makes them feel worse. So, there’s some obvious things that we work with people to figure out. For a patient who finds out there’s lots of foods that they can’t tolerate, it’s much more often their bowel’s inflamed so everything they eat makes them have symptoms. In that case, it’s very important we try to treat the disease and get them feeling better while we support them and make sure they’re getting enough nutrition.
There was an Australian study that said if kids got more sunlight, it would help reduce their chances of getting IBD. Are there lifestyle changes that you can offer that would help?
RUBIN: The strongest trigger of Crohn’s disease that we know of in the environment is smoking cigarettes. People who smoke cigarettes are more likely to have Crohn’s and more likely to be resistant to medical therapies. From a behavioral point of view, the number 1, 2 and 3 recommendations if you’re a smoker is to quit smoking. However, it’s the opposite with ulcerative colitis. People who smoke don’t usually get ulcerative colitis. That doesn’t mean you should smoke if you have ulcerative colitis. From the standpoint of things like living in a sunny climate and being exposed to the sunlight and getting more vitamin D, that’s a complex question. We have learned that people who have inflammatory bowel disease have low vitamin D levels. We’ve also learned the more inflammation you have, the lower your vitamin D. So, the question has been raised if we can get somebody more vitamin D, does that either prevent IBD or does it provide another treatment strategy? The first thing to recognize is that vitamin D is not a vitamin. It’s a hormone. The second thing to note is the type of vitamin D you get from sunlight does not seem to be enough to treat the IBD related to low levels. It hasn’t been enough to treat the IBD itself. One small study that used very high doses of vitamin D had some benefit in the short-term in patients with ulcerative colitis. So far, observations like living in sunny climates, whether it’s the north of France or south of the United States or parts of Australia, that they have less IBD is just an association. It doesn’t necessarily tell us cause. In the meantime, what we recommend on the clinical side is that people with inflammatory bowel disease should know what their vitamin D level is. If it’s low, they should be taking supplements.
END OF INTERVIEW
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