IBD Drive Time: Importance of Diet in the Management of Crohn's Disease

In the third episode of IBD Drive Time, host Raymond Cross, MD, discusses research into how diet can alleviate symptoms—or worsen disease—among patients with Crohn's disease with Dr James Lewis, who conducted the DINE-CD study.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine. James Lewis, MD, is chief of gastroenterology and associate director of the Inflammatory Bowel Disease Program at Penn Presbyterian Medical Center and a professor of medicine at the University of Pennsylvania School of Medicine.

TRANSCRIPT:

Dr. Raymond Cross:  Welcome, everyone, to "IBD Drive Time." I'm Raymond Cross, professor of medicine at the University of Maryland School of Medicine, and I’ll be hosting the podcast today.

I am delighted to have Jim Lewis here with us, who is a professor of medicine and epidemiology and a senior scholar in the Center for Clinical Epidemiology and Biostatistics and associate sirector of the IBD Program at the University of Pennsylvania School of Medicine.

Jim is the past Chair of the NSAC for the Crohn's & Colitis Foundation and lead scientist for the Foundation's IBD Plexus Research Collaborative. He's received funding from the NIH, AHRQ, PCORI, CDC, and numerous foundations to conduct groundbreaking clinical research on medication safety, optimization of therapy in diet and IBD. He is one of our premier clinical investigators in IBD in the world.

Jim, welcome to IBD Drive Time.

Dr. James Lewis:  Thanks, Ray, it's great to be here.

Dr. Cross:  We're just going to jump right in and talk about diet and IBD. It's probably the number 1 question our patients ask us, "What can I eat?" Jim, what do we know about the role of diet as a cause of Crohn's and colitis?

Dr. Lewis:  There's been a lot of research done to try and answer this question. It's really difficult research to do because you have to find people before they have their disease to figure out what they're eating. If you wait until they have the disease, most of them have already changed their diets, and it's too hard to know.

There's been a number of really large cohort studies, most of them designed for other purposes, for example, to look for dietary causes of cancer and things of that nature.

They've gone on to look at the risk of developing IBD. I think you can summarize it to say that people who eat what we think of as "a healthier diet," that's composed of more fruits and vegetables, are less likely to go on to get Crohn's disease and ulcerative colitis than people eating a more high-fat diet, particularly fat coming from meat seem to be more likely to go on to develop IBD.

There's discrepancies between one study versus another, but for the most part that's a fair summary of the story.

Dr. Cross:  Just to follow that up, I know that you've talked about this topic. There's also some growing interest in food additives, and processing, and stuff like that. Do you want to comment on that briefly?

Dr. Lewis:  It's a really interesting concept. It emanated in a large extent out of some work by Andrew Gewirtz and Benoit Chassaing in an animal model, where if you take mice that are predisposed to developing colitis and put some dietary emulsifiers and thickeners in their drinking water, they actually become even more likely to go on to develop colitis.

Physiologically, it looks like this happens through a change in the gut microbiome and likely also thinning of the mucus layer, allowing these microbes to encroach on the epithelium. Whether this holds true in humans is harder to study for a number of reasons.

One of those reasons is that the foods that we eat aren't well labeled in terms of how much emulsifiers or thickeners they might contain. Usually, the label will say what's included, but you don't have any quantification of how much is in there.

I think that an important thing for people to bear in mind is that not all food additives are the same. There's many different thickeners and emulsifiers that are added, and it is likely that they have different biologic properties.

Dr. Cross:  If a patient came in, to summarize, and they said, "What can I do from a diet perspective for my child to help protect them against IBD?" you would say, "Eat real food, more fruits and vegetables, less fatty stuff, including less red meat." That would be good sound advice for our listeners.

Dr. Lewis:  Yeah, and I certainly didn't coin this phrase, but the simple answer is, shop the outside aisle of the grocery store. That's where all the fresh stuff is. Avoid the middle section, where all the prepackaged stuff is.

Dr. Cross:  Awesome. What about for patients with established disease, Jim? What evidence is there that dietary interventions can prevent relapse in stable patients?

Dr. Lewis:  I've got to back this up one step even further. The best evidence that any dietary intervention works is exclusive enteral nutrition for Crohn's disease. Here, in the US, we don’t use it a lot, we use it a little bit in pediatrics. We don't use it a whole lot in adult world.

Many, many studies have been done that show that you can get people into remission for Crohn's disease—not ulcerative colitis—with exclusive enteral nutrition. That concept has been extrapolated to using partial enteral nutrition.

Exclusive enteral nutrition is feeding somebody a dietary formula, something like Modulen, or Ensure, or Boost, for essentially 100% of their calories. Partial enteral nutrition means providing them more than 50% of their calories, but well less than 100%. A number of studies have suggested that may be a strategy to help keep people in remission. By the same token, there are some smaller studies that would suggest, for example, that a semivegetarian diet might help keep people in remission. And then, there are other ongoing studies.

The best evidence, I think, in totality, that diet can influence somebody's inflammatory bowel disease is exclusive enteral nutrition and potentially following that up with partial enteral nutrition for Crohn's disease.

Dr. Cross:  When your patient says to you, "Dr. Lewis, what can I eat?" what do you tell them? What's your honest answer to them? My guess is you're not recommending EEN to the majority of your patients in the office.

Dr. Lewis:  Absolutely not. EEN, even partial enteral nutrition, I don't view that as a sustainable, long-term strategy for most people. For most people, I need to delve in with them, are you looking to make a major lifestyle change where, "I want to make diet as a primary part of what I'm doing for my Crohn's disease or my ulcerative colitis? or am I looking for just a globally adjunct therapy? Obviously, Medication is what I'm going to do for most of my management, and, "I want that little bit of dietary that might help me do a little bit better." The vast majority of people fall in the latter group.

For people with ulcerative colitis, my guidance to them is consume more fruits and vegetables. Perhaps, try to consume more oily fish. There's a little bit of evidence that maybe that is beneficial, but more so than taking fish oil supplements for people with ulcerative colitis.

For those with ulcerative colitis, I will encourage them to really try and get red and processed meats out of their diet. Now that is based on one relatively old prospective cohort study and whether that holds up to a clinical trial waits to be determined.

For people with Crohn's disease, I used to give pretty similar advice until we did a randomized trial of dramatically reducing people's red and processed meat in their diets. It showed, at least for symptomatic relapse, absolutely no difference in outcomes in a 1-year trial that we did in IBD Partners.

I tell them, "For your heart, it's probably good to eat less red and processed meat but I can't make you any promises that helps your Crohn's disease." I do think that consuming more fruits and vegetables and eating a somewhat cleaner diet, if you will, is a completely reasonable recommendation for the average patient with Crohn's disease. But I no longer emphasize getting red and processed meat out from the standpoint of their Crohn's disease.

Dr. Cross:  I just want to follow up because when you said about trying to identify with the patient what their goals are and talk about drastic reduction of red meat—do you find that a subset of our patients is contributing to malnutrition by excluding foods in their diet inappropriately? I guess that's a rhetorical question.

Dr. Lewis:  There are people where I try and get them to expand their diet as opposed to restrict their diet. We'll talk about the DINE study in a little bit. That was eye-opening for some people that they actually could expand their diet beyond what they thought they could consume.

We know that poor nutrition is super prevalent in the US. What we would define as potentially malnutrition is much more common in IBD than in other healthy people who don't have IBD. It is important to be cognizant of.

Dr. Cross:  That's a perfect segue. You mentioned DINE. For the listeners, why don't you explain the rationale and the methodology of DINE?

Dr. Lewis:  Sure. DINE-CD was a randomized trial comparing specific carbohydrate diet to Mediterranean diet for people with mild to moderately symptomatic Crohn's disease. One of the things I like to bring up about that study is we did this because patients really wanted this study done. There's a group of patients out there who wonder whether specific carbohydrate diet was effective therapy. For those of you who aren't familiar with specific carbohydrate diet, it's a fairly restrictive diet in the sense that it basically takes all grains out of your diet. It takes all processed meats out of your diet. It takes dairy out of your diet with the exception of some selected cheeses and yogurts that have been fermented for 24 hours. Which means, you have to make yogurt yourself because commercially bought yogurt has been fermented for a couple of hours.

It takes essentially all sugars and sweeteners out of your diet other than honey, if you can tolerate it. So it's quite restrictive on one hand. On the other hand, you can eat almost all fresh meats, fruits, and vegetables. People wind up eating more fruits and vegetables than they were necessarily accustomed to.

We needed a comparator diet to try and figure out if this worked. We spent a lot of time debating two different strategies. One was to just let people eat their normal diet versus having a defined comparator diet. We ultimately picked a defined comparator diet as Mediterranean diet. We picked that diet because of the evidence that we talked about earlier, that eating a more Mediterranean-style diet has been associated with lower likelihood to go on and develop Crohn's disease and a little bit of evidence that following this diet in Crohn's disease was associated with improvement in symptoms and general well-being.

We chose that over their usual diet because we couldn't figure out how we were going to convince people, to say, "Why don't you enroll in these 12 weeks' study? We're happy we're going to do absolutely nothing for you. You just keep eating your regular diet. We want to see what happens." We just thought it was going to be a massive barrier to recruitment.

As a result, we settled on this Mediterranean diet. And the Mediterranean diet had the added benefit that it's essentially what the USDA says we should be eating. It's been shown in many, many studies to be associated with other health benefits, things like longevity, reduced cancer incidence, reduced incidence of heart disease. We settled on that as the comparator.

We set up this trial for people with mild to moderate symptoms to run for 12 weeks. The other unique feature of the trial was for the first 6 weeks, we provided people with all the food they needed. They got breakfast, lunch, dinner, and 2 snacks worth of food a day.

For the most part, we gave people more calories than they needed and told them, "You don't have to eat everything. Just eat what you want of it." It was provided free of cost to them, delivered once a week on Friday to their home, packaged ready to heat and eat, and sourced from fresh ingredients by the vendor who was servicing the trial.

That was, in some ways, pun intended I guess, the carrot to patients to stay in the trial and to try foods that they wouldn't have normally consumed. It also made following specific carbohydrate diet much easier because they didn't have to think about how they were going to do this. We were providing the foods.

For the second 6 weeks of the trials, they were on their own. They had the option to buy food from our vendor if they wanted. Very few people did. It was relatively expensive to purchase the prepared meals. If you think about it, if you were going out to a restaurant for every meal, breakfast, lunch, and dinner, 7 days a week, that adds up pretty quickly. That really wasn't viable for most of the people who were participating in the trial.

Dr. Cross:  Jim, what were the high-level results?

Dr. Lewis:  The main take-home result was that when we looked at symptomatic remission, there was no significant difference between the 2 diets. About 45% in both groups achieved symptomatic remission.

We looked at a number of secondary outcomes. One of these was what we defined as fecal calprotectin response. This was among the group who had an elevated calprotectin at baseline. Did you get your calprotectin below 250 and at least a 50% reduction? That occurred in about 30% to 35% of both groups. This was a relatively small subset.

Then, we had a similar definition of CRP response for normalization of high-sensitivity CRP and at least a 50% reduction there. That was exceedingly uncommon, which I think was one of the shocking things in this trial. There are those who had elevated CRPs at baseline coming in. At week 6, literally in the Mediterranean diet group, it was about 4% and in the specific carbohydrate diet group, it was about 5%, had normalization of their CRP and a 50% reduction. Results were pretty similar at 12 weeks.

The other thing that was really important to know about the results of the trial is unlike many other trials, we did not mandate that people have confirmed inflammation coming in. It turned out about half of the people did and half didn't. Confirmed inflammation was either a calprotectin over 250 micrograms per gram, an elevated high-sensitivity CRP, or a colonoscopy done for clinical purposes in the weeks leading up to screening that showed clear-cut inflammation. Essentially, we caught some breaks on the colonoscopy.

What was interesting is when you looked at the results amongst people who did or did not have confirmed inflammation, they were almost identical. For symptomatic remission, it really didn't matter whether you had confirmed inflammation coming in or not. Of course, some of the people who didn't have confirmed inflammation had inflammation. We just couldn't pick it up with the test we were using. But I think it's also reasonable to expect that some of those truly did not have confirmed inflammation.

Some of the key important things was yes, symptoms got better in lots of people. Calprotectin got better in a reasonable proportion at 6 weeks, but not different between the groups. CRP very rarely got better. It didn't seem to make a difference whether you had inflammation when you came in or didn't.

Dr. Cross:  I don't know if I saw this. I'm sure you know. What happened to their body weight, Jim, during the 6 to 12 weeks?

Dr. Lewis:  People generally lost a few pounds during the course of the study. It wasn't massive weight loss. I don't have the exact number in front of me, but it was a kilogram or 2 of weight loss. There were a portion of people who did actually achieve what we might think of as a meaningful meta weight loss for fatty liver disease. There were a proportion of people on both diets who achieved that 5 to 10% body weight loss. We're not always rooting for that in our people with Crohn's disease. By the same token, it's not like all people with Crohn's disease are skinny today.

If you go into this, even though we were providing people with plenty of calories, weight loss did occur in both of these. I think it's because they were both eating markedly healthier diets than what they were accustomed to.

Dr. Cross:  I know you haven't published this yet, Jim, but remind me, are you following these patients longer term to see what happens if they try to continue on their own or if they go back to their regular eating?

Dr. Lewis:  Only out through 12 weeks. We're doing some analysis of...We know exactly in terms of continuing on up to 12 weeks. We don't have beyond that.

We're doing a little bit of research now, trying to understand what people's personal experience was with the diets. For example, we have some questions that we ask people about how being on the diet impacted their social isolation. Did they find it hard to do? What did they miss the most?

I can tell you it's no surprise things like pizza and ice cream appeared consistently on things that people missed. Pizza, bread, and ice cream. That, I don't think, comes as a huge surprise.

Dr. Cross:  Not at all. I think the strengths of the trial are obvious. You might get some criticism that inflammation wasn't confirmed in everyone, everyone didn't get a biomarker at 6 and 12 weeks or a scope at 12 weeks.

But in your defense, pragmatically, that's increased the cost of the study to such a degree that it's only going to be done if it's part of an industry trial for a new medication. For a diet study, it's just not going to happen.

Dr. Lewis:  Yeah. We would certainly have loved to have done that, but as you said, financially, this was an expensive trial to do even without that. Providing people with food for 6 weeks is a cost that you don't usually have to incur in these things. That was a pretty big expense.

It was not practical for us to be able to do it. As we think about where does research on diet and nutrition and IBD go, eventually we have to start having endoscopy as part of these trials. It's really, really, really important. You started early in the podcast asking what do I tell patients when they start asking about diet.

One of the most important things I tell them is that if you tell me you want to use diet as primary therapy, I will support you through that exercise, which largely means I'm going to send you to my dietician to have them help support you through it. But you have to agree going into this that the rules of engagement are the same as if we put you on a medication.

So even if you're feeling great 6 to 12 months down the road, we're going to reassess and see what things look like. We'll follow your biomarkers, but you should have a colonoscopy or imaging, depending on where their disease is, 6 to 12 months down the road so we can see what's going on.

If there's a lot of persistent inflammation there, understand that I'm going to push you, that I think that this is probably not enough. If you have very limited inflammation, yeah, sure, we can negotiate that, but if there's still a lot of inflammation there, we have to reassess.

Dr. Cross:  I completely agree. We all have patients who are reticent to take biologic therapy, or we don't have really good if any therapies for mild Crohn's disease, so implementing diet like this could be a reasonable strategy.

The other thing that drives me nuts is...I've actually heard people say the patients feel better but it didn't do anything with their inflammation. It still is important for people to feel better. Feeling better is still an important end point.

Dr. Lewis:  I don't know if it's shocking or not, but close to 50% of these people met a definition of symptomatic remission going on a diet. The shocking part of this is, to many people, is that this is a diet that they were upping their fruits and vegetables.

We often tell people with symptoms, "Oh, try this low-fiber diet," etc. In the meantime, here, we're telling them to increase their fruits and vegetables. I would point out that if you look at some of the other diets that are getting studied, this is sort of a common theme.

There's a lot of interest in Crohn's disease exclusion diet today—a centerpiece of that are apples and bananas and things like that. Dogma of “my patient with Crohn's disease can't eat a lot of fruits and vegetables” is not necessarily true.

I encourage people to start with cooked vegetables and see how that goes and work your way up. I certainly don't recommend this for someone whose got a tight ileal stricture, but for the person whose just got inflammatory disease and some symptoms, they do not need to have this ultimate low-fiber diet for long periods of time. People can actually tolerate this and feel better.

Dr. Cross:  It's $64 million question, followed by fun question. Has this changed your practice, Jim?

Dr. Lewis:  I think it has changed my practice in that it's reinforced for me that diet is a good adjunct, particularly to help manage people's symptoms. It's definitely reinforced for me that you have to continue to monitor people's inflammatory markers because they may feel better and the inflammatory markers won't get better.

I already was largely in the habit of recommending Mediterranean diet as my sort of, you would call it your platform diet, for people to start from, and so that I don't think has changed. If somebody wants to try SCD, I will support them through that. If they want to try one of these other diets, Crohn's disease exclusion diet, I will support them through that. If they want to try an autoimmune protocol diet, something like that, we can support them there.

It definitely reinforces that this is a nice adjunct, but you can't forget about everything else that we had tried in med school, residency, fellowships, etc.

Dr. Cross:  Although it certainly sounds much more appealing to have a nice glass of red wine, a piece of fish, and some vegetables on the side than that exclusion diet with some Modulen.

Dr. Lewis:  Absolutely

Dr. Cross:  All right, fun question, Jim. Tell the listeners something about yourself that they may not know.

Dr. Lewis:  I'm going to tell you two things. I grew up in West Virginia, and I love to play tennis. When I was a little guy, at ages 11 and 12, I actually was a top-ranked, under 12-year-old tennis player in the state of West Virginia. Of course, there's not that many tennis players in West Virginia, so I'm not sure that's that much...

Dr Cross: You were still number 1!

Dr. Lewis:  [laughs] Exactly. I think the other thing that people wouldn't know, is even though you, in the intro, pointed out that I spent all this time doing research on inflammatory bowel disease. If you have young listeners who are thinking about their career, I would just say, I didn't come into fellowship thinking that's what my career was going to be.

I had the whole scale career change during my gastroenterology fellowship, and only for the best. It's been a great journey. I've gotten to meet incredible people like you, travel the world when it's not a pandemic, think about interesting things. I had a wholesale career change. Maybe some listener out there will as well.

Dr. Cross:  I think that's great advice, and that makes 2 of us, Jim. I certainly didn't want to be a researcher in fellowship training either, so you can change your mind. You don't have to be razor-focused.

Jim, thanks for joining us. I'm sure our listeners loved this. We can finally give our patients some dietary advice. I'd be remiss not to remind everyone that this is sponsored by the Gastroenterology Learning Network and AIBD.

Join us in two weeks. David Rubin is going to teach us all about ozanimod and how to integrate it into clinical practice. For those of you thinking about the regional Advances IBD courses, the next regional course will be in Chicago, virtually, on August 7th, so I hope to see you there.

Thanks, again, Jim.

Dr. Lewis:  Thanks so much.