IBD Drive Time: Peter Higgins, MD, on the Etiology of Inflammatory Bowel Disease

In this episode of IBD Drive Time, Drs Millie Long and Raymond Cross talk with Dr Peter Higgins from the University of Michigan about the etiology of inflammatory bowel disease, including what is and what is not known, the hygiene hypothesis, and the (possible) role of the family dog.

Raymond Cross, MD, is professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore, Maryland. Millie Long, MD, is a professor of medicine, vice chief of education and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.  Peter D.R. Higgins, MD, PhD, is the Timothy T. Nostrant, MD, Collegiate Professor of Gastroenterology, director of the IBD Program, and chair of the GI & Hepatology Research Advisory Committee at University of Michigan Medicine in Ann Arbor, Michigan. 

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TRANSCRIPT:

Hello and welcome to IBD Drive Time. I'm Millie Long from University of North Carolina, and with me today is my co-host, Dr. Ray Cross from University of Maryland. We're here to talk about IBD as always and we have a fantastic guest, Dr. Peter Higgins, who is Professor of Medicine and Director of the IBD Center at Michigan, as well as the incoming chair of the National Scientific Advisory Committee for the Crohn's and Colitis Foundation. So Peter, welcome to IBD Drive time.

Peter:

Thank you, Millie. Hello, Ray.

Millie:

Well we're excited to get started. We have a number of questions for you, and we're focusing on questions surrounding etiology of inflammatory bowel disease and a lot of questions that our patients may ask us when they're initially diagnosed. So one of the most common questions I get is, "Why did I get this? Why did I get inflammatory bowel disease?" How do you respond to that? We want to learn from your pearls.

Peter:

Yeah, and I generally say, "Number one, you got unlucky. The vast majority of people with even genetic risk factors for IBD never get IBD, and it's not terribly inheritable." Only about 10% of parents with Crohn's have a child with Crohn's, and only about 5% with UC will have a child with UC, so there are a lot of environmental factors rather than genetic factors. I think when it comes down to initiation of IBD, the two key things that probably happened in each patient is that the barrier between the bacteria and viruses in their gut and the immune system right behind the intestinal wall was broken in a significant way that activated that gut immune system. Then something else happened that either chronic simulation or something mechanistic in immunology made it not turn off and stay on. Most people who get gut infections are able to take care of it and turn it off. Some people, it just keeps going.

Millie:

It's fascinating. I mean, when you think about all of the autoimmune diseases out there, we still don't understand the etiology. We're still throwing up these Venn diagrams of integrating factors, and we're not certain exactly what causes this.

Peter:

There's a little bit of association data that's getting stronger that suggests EBV is really important as an infection in multiple sclerosis. There's some data that it might be true in IBD, and there's a lot of data from Scandinavian countries that have good registries that prior gut infections are really important in at least developing IBD in the next 10 years. I think we generally know that the younger you develop IBD, the more important the genetics factors are and the older you are, the less important the genetics factors are, for what that's worth.

Ray:

Hey Peter and Millie, just to jump in real quick, and this is a little facetious, but I tell patients, if someone tells them exactly why they have Crohn's disease, they should find another doctor because no one knows why they have Crohn's disease for certain.

Peter:

We don't have a good answer in the vast majority of patients.

Millie:

Very telling. One of the hypotheses out there that's been out there for a really long time is the so-called hygiene hypothesis. I have patients that ask me about this, sometimes in the context of trying to understand if things like pig whipworm eggs will help them and things like that. Peter, how do you discuss the hygiene hypothesis?

Peter:

I'll say there is reasonable data from population-based studies in New Zealand that if you grow up as a child and you have a garden and you eat a lot of vegetables, your risk of developing IBD is lower. It's not massively lower but lower, so avoiding sterilizing a child's environment is probably a good thing. Having them play in the dirt and get infections and build up the strength of their immune system is probably important in terms of normalizing how our immune systems are trained. There is generally good data that as countries westernize and develop modern sewage and prevention and a lot of our antibacterial things which may be problematic, antibacterial soaps, wipes, et cetera, they have rising rates of initially ulcerative colitis and then 10 to 15 years later Crohn's disease. Some of that may be ascertainment bias because it's harder to diagnose Crohn's, but that pattern's been seen in multiple countries, and it really suggests that environmental factors is incredibly important.

Millie:

No, absolutely. One of my favorite studies included the data from the GEM study that showed that if you have a dog, it may actually be protective, meaning maybe this is that same hygiene hypothesis theory. Certainly we have a dog that licks my children's faces all the time, so maybe that's a good thing,

Peter:

It probably is.

Ray:

Or like your grandmother said, just rub a little dirt on it, so maybe grandmothers were always right all along and we just didn't know why.

Millie:

Very fair.

Peter:

Yeah, very fair. Every time I see a young parent trying to wipe every inch of dirt off their child, I worry. It's probably a bad strategy.

Millie:

Well, what have we learned about risk factors from some? You mentioned some of the Scandinavian studies where we actually truly have population-based data. I think these studies are great for trying to help to understand risk factors for etiology or potentially even Nurses' Health may be another example from here in the US. What have we learned from some of these longitudinal studies about risk factors for development of IBD?

Peter:

So, common infections of the gut, including things like salmonella, shigellam and campylobacter are associated with higher rates of new-onset IBD in the next 5 to 10 years. That is probably speaking to that barrier idea that you're breaking down the barrier and activating inflammation. Nurses' Health study, they've been digging in more into vitamin D status, ultraviolet and diet. It's a little bit different because it is focused on older folks who are already in their careers and have obviously later-onset IBD, so it's different from somebody who gets diagnosed at age 15 or 20, so probably less genetic and more environment.

There's a fair amount of data that there are pieces of diet and generally having a healthier, more vegetarian or Mediterranean diet as opposed to eating a lot of meat or processed foods is probably a good thing. There is some animal data to suggest that emulsifiers may damage the lining of the gut and approach that same barrier problem. I'm a little skeptical in that we've been using eggs which contain emulsifiers like lecithin for thousands of years, but it's possible that the newer emulsifiers, things like carrageenan and some of the acronyms you'll see on the food that make them creamier and smoother may be contributing if you consume significant amounts.

Millie:

Interesting. Interesting, so last question for me. We're thinking about environmental triggers, things like this, so obviously we see in our clinics a population of patients with IBD, with existing IBD, so do we have data on any of these environmental exposures that may be associated with relapse of disease in terms of triggers?

Peter:

We have pretty solid data that anything that causes inflammation increases your risk and that includes gut infections like norovirus and C. diff. I've seen some association and there's some data, although it's not great, basically any kind of infection, whether it's a pneumonia or something else that activates inflammation will generally activate your immune system and put you at a little bit greater risk. Anything that affects barriers like NSAIDs or other infections obviously are affecting the barrier can increase your risk. Although it's not massive, but it is a risk factor, and if somebody's really abusing nonsteroidals rather than getting that ACL surgery they should have had, it does increase their risk.

Millie:

It's interesting because obviously we're still in the COVID-19 pandemic. We're still seeing COVID-19 infections, and certainly even with COVID alone, I've seen a hemorrhagic type colitis. While I do think that patients have had some GI effects of COVID, I haven't seen two great, like a series of flares right after COVID. I don't know if you've seen something similar.

Peter:

No, we really haven't, and we've seen a lot of COVID. We've had the 2020 wave and then later waves. A lot of our patients are actually really good about getting vaccinated, and six months after the bivalent we started seeing, "Oh yeah, people are losing their immunity and getting flares again." It's fortunate most of our patients have done really well and not had a lot of flares after COVID.

Millie:

Yeah. No, I agree, but I have definitively seen this with other GI infections.

Peter:

Yeah, yeah. I really worry. The challenge when you see a C. diff infection in an IBD patient is trying to figure out is this just a C. diff infection or has the C. diff activated their IBD? The majority of the cases that end up in the hospital tend to be. Yeah, it's both.

Millie:

It's both. Yeah, the majority of the severe ones I think are both. I agree with you.

Peter:

Yeah, we have some outpatients who just get run-of-the-mill C. diff and if they're on a good IBD therapy can ride through it with some vancomycin, but the folks who make it to hospitalization are usually both.

Ray:

Peter, I wanted to follow up a little bit on some of these risk factors, and I'm going to start talking anyway, so it's good timing I suppose. One is, you mentioned infection, so is it the infection or is it the antibiotics used to treat the infection or a little of both or impossible to disentangle?

Peter:

It's usually impossible to disentangle. I could see antibiotics shifting the microbiome of the gut and particularly making people at risk of secondary C. diff. I worry that it's just hard to sort out. I think some of it probably is immune activation. That's where I would lean, but I could certainly see the antibiotics leading to C. diff.

Ray:

You know, patients ask this all the time. "My primary recommended an antibiotic. What do I do?" The answer is, if your primary thinks you need antibiotic, you take the antibiotic and then we'll deal with the sequela if it happens. Then we focused a little bit, mostly on physical stressors or physiologic stressors, but what about mental stress? So I've had patients that were doing beautifully on drug with good drug levels or they're on a therapy where drug levels don't matter and they go through a horrible divorce, and all of a sudden they have a flare. So, is that just coincidental or is there something to that, Peter?

Peter:

It's probably not, but it's probably also confounded. I think those folks under great stress are probably less likely to be adherent to their meds anyway, so there's a risk factor. I do absolutely have patients who reproducibly have stress that leads to flares. Although it's interesting—my favorite is a tax accountant who tends to have flares in March, April when his life is crazy because he's got an April 15th deadline. A lot of those were absolutely inflammatory flares in the first couple years I saw him. When we changed him to a more potent med, he would get symptomatic flares of IBS still, but he wouldn't get inflammatory IBD flares after that, so it may be a mixture of secondary IBS and actual IBD flares, and I've seen both.

Ray:

I just want to remind our listeners that we are sponsored by the Gastroenterology Learning Network and Advances in IBD and speaking of Advances in IBD our next regional AIBD will be virtual, April 20-21. There's still plenty of time to register and attend that great virtual course, for which Millie and I will both be speakers. 

So Peter, the GEM study was mentioned for the listeners. It's a really, really cool study in Canada sponsored by the Crohn's and Colitis Foundation of Canada. They're following first-degree relatives of patients with Crohn's disease, and they're checking microbiome and serum for various markers, as well as epidemiologic factors as well and following them over time. That's where Millie mentioned having a dog may be protective for that, so we have this longitudinal registry where we'll hopefully learn a lot. Then also we can take advantage of the biorepository from the US military where fortunately we had blood specimens years before some of these young men and women developed IBD, so what can or what have we learned from those longitudinal studies, Peter?

Peter:

So one of the cool outcomes, and we participated in the GEM study at Michigan and enrolled a number of children, and a lot of them were children of patients with Crohn's disease who are very motivated to get their kids in and try to understand this. One of the big things is that you can do a test for leaky gut essentially, which some of our patients are very obsessed with, by looking at the lactulose to mannitol ratio. Lactulose should stay in the gut. Mannitol should go to the kidneys. If the lactulose is crossing that gut barrier, it suggests your gut barrier is not in good shape. Those children who had a poor gut barrier were much more likely to develop Crohn's in the follow-up period of five years or so, which is really important in terms of reinforcing that barrier idea, but it also gives us a potential test to screen children for risk of Crohn's.

As far as I know commercially, there's a really obscure lab somewhere in Asheville, North Carolina ... I don't know if Millie's ever been there ... that will actually do this test for you. It's a little bit involved. You have to get the kids to drink lactulose and mannitol and then get the bio samples about an hour later, but it's an interesting test. It provides us the opportunity to possibly do what the Crohn's & Colitis Foundation is calling interception, when you start to have these presymptomatic problems and can we intervene to prevent Crohn's from happening at all?

This barrier problem means that the immune system of the gut is starting to attack whatever's in the gut and that's how you end up with these serologies. Most of the serologies we talk about are things like anti-OmpC, which is against the flagellin in bacteria, ASCA, ANCA. Again antibodies against the components of the microbiome in the gut. Those are the result of barrier problems and the result of the gut immune system attacking the bacteria in the gut and are basically long-term markers of at some point in the past you had a gut barrier problem. Those serologies, if they're high enough, are again risk factors for future IBD.

On the whole, different pieces are coming together to tell us that barrier function is probably one of the earliest presymptomatic IBD problems and that developing these serologies that are against bacterial components adds to that risk and shows that you had barrier problems for a while. We're narrowing in on can we identify a presymptomatic phase, which maybe at some point and the Foundation is really interested in this, have some kind of intervention to try to restore that barrier or prevent that from progressing to IBD.

Ray:

I'm asking you to speculate, but if we were going to try to intercept onset of Crohn's disease, would that be an adoption of healthy behaviors, Mediterranean diet, sleeping well, stress reduction, exercise? Would that be just tighter monitoring to try to pick it up as early as possible? I wouldn't think those [inaudible 00:30:42].

Peter:

Yeah. Well, I mean it's interesting. I think healthy interventions for healthy diet and avoiding possibly meat, possibly emulsifiers would be very reasonable. I think close monitoring is very reasonable. I think it would be really interesting to ask parents. "If your child had these markers, whatever they were, lactulose/ mannitol ratio or serologies, would you be willing to try to do something for eight weeks, six months to restore their barrier?" Would it be worth it? An alternative and say eight weeks of budesonide or eight weeks of a JAK, would it matter? Don't know. Would parents even be willing to do it?

The other approach, which is really interesting in the context of Type 1 diabetes, so there was a really fascinating natural history study in Australia where they have a national health system and pay for everybody's insulin where they started on a national basis immunizing children against rotavirus. It turns out, rotavirus infection is associated with onset of Type 1 diabetes. What they found was about five years later, the number of new Type 1 diabetes cases started dropping, suggesting that if you could prevent that rotavirus infection, you could reduce your Type 1 diabetes rate nationally by 30 to 40%. It raises the question, and it's a commercial/marketing issue as well. If we had a multivalent vaccine to neurovirus, Shigella, Salmonella Campylobacter, C. diff, we'll throw in for fun, and you said, "Okay, parents with IBD, can you give this vaccine to your patients, to your children?" Can we randomize them and actually see if over the next 10 to 20 years that actually reduces IBD by protecting the barrier from these infections? That would be pretty cool. You would need to be a very patient researcher, to wait for that outcome.

Ray:

Yeah, for sure, but that's very interesting. Peter, I mean, there's many reasons we have you on the podcast today, but one of them is when we were at the National Advances in IBD meeting, we were sitting together. I get most of my information from the sports page, so you leaned into me and said, "Have you heard about this thing about the plague and IBD and autoimmune diseases?" I'm embarrassed. I'm like, "I have no idea what the heck Peter is talking about," but the story you told was absolutely fascinating. Do you mind sharing that with the listeners?

Peter:

Sure. For folks who are nerdy enough to follow me on Twitter, this was the subject of a Twitter thread back in 2019, and it was in response to several papers published on this. First there was a PNAS paper that looked at survivors of the plague and their descendants compared to genetic analysis of people who died in the plague in Europe, as well as genetic analysis of similar populations that never migrated to Europe. What they found was survivors of the plague had a big shift in their genetics around immunity. Part of this was it was a massive natural selection. 30 to 50% of people died in cities affected by the plague. They found that in those cities that got hit really hardened by the plague, there were really high Crohn's rates, and this is particularly for Crohn's and Nod2.

So that was really fascinating that there was this association and there was this clear genetic change in specific immune genes including Nod2. As people studied Nod2 as a source of Crohn's, they found that mice that had Nod2 mutations make a lot more TNF, especially in their terminal ileum where Yersinia pestis actually impacts this. So, it's suggested that they were able to fight off plague a little better, and when they infected them with plague compared to mice without the Nod2 mutations, the mice without Nod2 mutations died at a really high rate. The ones with the Nod2 mutations survived, so it suggested that that's a pathway to surviving the plague.

It's crazy to think about that, but JP Hugot and his colleagues in France basically published a paper. I'm trying to remember the title exactly, but something like Is Crohn's the Price to Pay Today for Having Survived the Black Death? It really suggests that there is a tie-in between the Nod2 mutations associated with Crohn's and being able to generate enough anti-TNF and inflammatory markers in your intestine to survive the plague. It is one of those powerful selection pressures that may have changed, especially for those of us of European descent, the genetic basis of their population, and it shifted them towards a lot more Nod2 mutations.

Ray:

Lessons learned from another pandemic and probably a lesson to me that I should expand my sources of reading. So Peter, last question is the fun question that Millie and I like to ask. Tell us and the listeners something about yourself that they may not know.

Peter:

An odd fact was I happened to finish my PhD off-schedule and had to wait about six months before my next MD year started up in the middle of my MD PhD. I used that time to go on Jeopardy and won a grill that is still sitting on my deck in the backyard.

Ray:

Wow, I didn't know that. I thought you were going to tell the listeners the price of a tuba because when I visited you in Michigan, the astounding price of a tuba. Now I understand in New Orleans why people tape their tubas together to hold them up. Peter, this has been wonderful. I learned a lot. I'm sure Millie learned a lot as well. Thanks. Thanks for doing this, and we hope to have you back in the future.

Peter:

Great. Thank you very much.