Crohn's Disease, Ulcerative Colitis, Inflammatory Bowel Disease; latest updates & great treatments.

Hi, thanks for watching episode #132 of the Doctor Podcast, Sicard File Show, and I'm your host, Doctor Robert Sicard. Please subscribe, follow, like, and repost this episode so we can get more great guests. By the way, Spotify just notified me this week that we are in a top 15% of all video podcasts. I can catch up to Joe Rogan with your help if you click on Like and subscribe. So I'd appreciate it very much. Today we're discussing a very important topic. It's inflammatory bowel disease and specifically Crohn's disease, which is one of the inflammatory bowel diseases.

About 1% of the US population approximately has inflammatory bowel disease. That's almost 3 million people. So it's a very important topic and our guest today is one of the world's leading authorities and experts on inflammatory bowel disease and Crohn's disease. It's Doctor David T Rubin. He is the Joseph P Joseph B Kirsner Professor of Medicine and professor of pathology at the University of Chicago. He's the chief of the section of gastroenterology, hepatology, which is liver disease and nutrition there.

He's the Co director of the Digestive Diseases Center. He's also the founder and director of the Inflammatory Bowel Disease Center at U Chicago Medicine. He's published more than 500 peer reviewed articles on inflammatory bowel disease and medical journals. And he's received back-to-back University of Chicago awards in 2023 for outstanding mentorship and clinical innovation. So thanks very much for taking the time to join us today and sharing your knowledge and expertise and experience. Really appreciate it.

And I'm sure people out there, especially patients who have these conditions are very thankful as well. I appreciate the honor and privilege of joining you. Congratulations on the success you're having, but you're doing a really important service, so it's great to have the opportunity to share the advances we've made in this particular condition and hopefully educate people about it as well. That's great. So to kick things off, Doctor Rubin, could you walk us through your journey and becoming a gastroenterologist?

What drew you into medicine in the 1st place? How did your training at University of Chicago shape your approach to patient care? Yeah, that's a wonderful question. And I am asked this a lot. Usually people who hear I'm a gastroenterologist, let alone a Crohn's specialist, want to know how did you end up in this area of medicine? And the answer is it wasn't my intention initially. I knew I wanted to be a doctor. That was something that was sort of passed on to me as a young boy. And that was clear.

My dad is a veterinarian and there was some exposure to medicine in in animals, but I had always wanted to be a human doctor. And after I came to the University of Chicago to interview for medical school, one of the things that struck me from that interview and that opportunity was that this was a place that taught people how to change the way they think and how to change the field of medicine. And that really spoke to me. And I was just blown away by that. To think that I could be at a place not where I was just going to learn all the important things about being a good doctor, but also about the ways to do it better in the future.

And for me personally, that resonated as a first year medical student. My grandmother said go find out if my doctor's still there. And her doctor, unbeknownst to me, was a very famous gastroenterologist, one of the legends in the field named Joseph Kirsner. And as you heard in my introduction, I'm the Joseph Kirsner professor. Now Kirsner had been here since 1935. And in the 1950s, he took care of my grandmother who had Crohn's disease. And I didn't know she had Crohn's disease, and I didn't know what Crohn's disease was, and I didn't know that she had been a patient here.

So this is how life just hands you some things that you don't expect. So I met him when I was a first year medical student. He was 81 years old at the time. And then, believe it or not, he lived to be 102. So I worked with the guy for 20 years, and I didn't immediately say that I was going to go into Crohn's disease as a field. But on on the other hand, what I realized is that in life, as you're advancing your career, you make decisions sometimes based on the people you meet and your personal circumstances.

And so I came in thinking I might be a surgeon. A lot of gastroenterologists thought they might be surgeons initially, but in my specific instance it was working with Kirzner and then subsequently his protege. One generation above me was a guy named Steve Hanauer, one of the leaders in Crohn's, and worked with him. And then ultimately ended up doing this and being at the University of Chicago and staying there for my career, which I've done by choice, has been really about trying to move the field forward.

Not just for Grandma Pearl, but for my niece and nephew who have Crohn's, and obviously the millions of other people who live with these conditions. So it's been very important and personal to me. That's an amazing story that we're now the Kirsner professor, and he was your mentor, is a medical student. It's a really fascinating story and and very much meaningful that I ended up becoming his doctor at the end of his life. And I took over part of his clinic, of course. And although he didn't teach me how to take care of Crohn's specifically because by that time he wasn't doing that, he did teach me how to be a doctor, You know, how to talk to people, how to help people through difficult problems, how to care for them.

And obviously, the ultimate in taking care of him, my mentor, and returning the favor of what he did for my grandmother all those years before was a really special privilege. And when he passed, of course, I felt responsible to preserve his legacy, which is immense, and try to continue what he always believed in doing. So I appreciate the opportunity to share that story. Yeah, that that's that's an incredible story. Thanks for letting us know about that. Now, you've worn many hats over the years, from chief fellow in gastroenterology to directing a major fellowship program for many years.

How is mentoring the next generation of doctors influence your passion for teaching patients about their conditions and plain language and helping them understand and deal with their condition? Well, the reality is that if we don't pay attention to who's coming behind us and train our replacements, which is what I call it, we're not going to pave the way for a better future. And I think it's it's our responsibility. It's our obligation to take what we learn, the accumulated wisdom of our years and the people whose shoulders upon which we've stood and pass that on to the next generation so that they can continue.

I would say that I think that in many ways, training people who want to stay in academic medicine and you have the resources, tools and stamina to become physician scientists and continue this mission of looking for cures and trying to make sure we do a better job is a big challenge now. Maybe more so than many years before, in part because of changes in funding opportunities and the very real challenge that academic medical centers face, which is that things have become so expensive in order to drive academic medical centers.

There's a very large effort to increase clinical care, which is fine in some ways, but it means that people who are doing scholarly work also have to often do the clinical work to support it. And it ends up being a very challenging time to make sure you protect people so that they can get hooked, excited about what we're doing, and then make the next great discoveries and of course, learn how to be really effective clinicians. But I'll say to you this, Robert, that as long as I've been doing this, I've started to realize every era of medicine, every generation has had their challenges.

When when Medicare was first being developed and then came to be an opportunity to fund and support both care for people in their older age as well as training, people thought it was the end of medicine as we know it. When CT scans became popular, people said, oh, the doctor will never examine someone again. And now in this era, we've got our own challenges. It's the electronic health record, you know, sitting in front of a computer screen trying to communicate more effectively or document everything.

And it's certainly the challenges in research funding and other things. We always have challenges. And what we need in the face of challenges, whatever they are, and, and our own challenges we're facing right now in 20252026 are the challenges of our era, our generation. We need leaders. We need people to stand up and say here's where we're going to solve this or here's what we need to do, and to really step out and make sure that we preserve our mission, which is to make people healthy and to keep them healthy and to understand how to prevent diseases in the 1st place.

So I think this is a really important message and I remain optimistic about our future, but I recognize you have to work at it if you're going to get there. Right. I know exactly how you feel. I, I taught ophthalmology residents for approximately 40 years. So I, I was involved in, in the same issues and times change and with AI now who knows where we're headed, but that's, that's a separate issue. Well, I give a talk on the ethics of AI. So part of my training you didn't mention is I also did a fellowship in clinical medical ethics.

And you can apply this, this philosophy and this general skill set to anything that we're doing. And certainly the ethical challenges to applying AI to medicine are no exception. And it's a very important thing for us to understand. Obviously it's a revolutionary time in medicine in many ways, but it doesn't escape the fact that people still need caregivers and they still need people to interpret the AI. And the AI is only as good as the information that it's able to interpret. And we have to make sure that that's high quality.

Right now I want to get a little deeper into Crohn's disease. What symptoms do patients with Crohn's disease have? What what age does it usually start at? Are some people are at higher risk than others? And by the way, why is it called Crohn's disease? Those are a lot of questions. Let me start with with why it's called Crohn's disease. As you might imagine, there was a guy named Burl Crone. It was in New York City in the 1920s and 30s and subsequently, and Crone was working in affiliation with the Mount Sinai Hospital there.

But there was a surgeon there that people don't often hear about named Doctor Burke Berg. Berg had two residents working with him, one named Ginsburg and one named Oppenheimer. And they had operated on a few patients who had inflammation of the end of their small intestine. So where the small intestine joins the large intestine, they had some inflammation and developed some narrowing of the bowel there. And Berg had operated with these residents on a couple of these patients, and then they accumulated a series of them.

Berg said, Why don't you guys write this up and publish it? It's an interesting series. We don't really know what it is. They called it regional enteritis. Regional meaning it was located in a segment. Enteritis is a term that means inflammation of the bowel. And they were working on it. And along came Burl Krohn. He said, oh, a couple of those patients are my patients. Do you mind if I participate? And they said sure. So then he contributed and helped out. And then they finished writing up the manuscript and they said to Doctor Berg, the surgeon, the faculty member, Doctor Berg, do you want to be a co-author?

And he said, Nah, it's OK, you guys publish it. Well, back then, this is now 19311932, authorship of papers was alphabetical. So it was Crone, Ginsburg and Oppenheimer who published this series. That was regional enteritis. And then they and then Crone went on to present it and discuss it. And sure enough, soon after that, people started to call it Crohn's disease. If it had been actually included the senior person Berg, it would have been Berg, Kron, Ginsburg and Oppenheimer. Unless there were actually some contentious feelings between Ginsburg, Oppenheimer and Kron that Kron was given all this credit when in fact they were the ones scrubbing in and doing surgeries and writing up the paper initially.

And that's a whole other story here. But that's where that came from. So there was politics and medicine. Of course. Even back then, 100 years. Now and then. Now when we publish papers for the audience to know, the first author is usually someone who takes a significant leading role in the effort, and the last author is usually the senior person who's guiding it. And everyone in the middle is divided up depending on what they did or whether it's alphabetical. So the important thing to understand is they didn't know what was causing this particular inflammatory condition.

They were seeing it in a number of patients. It had been described in Europe, in Scotland by a surgeon 10 years prior. And so in Scotland and in that part of the world for a while, they didn't want to call it Crohn's disease. They were interested in thinking about it from their perspective. And then years later, someone said, well, here's the same problem, but it's in the large intestine. This is Crohn's disease of the colon. And Crohn himself said, I don't think this is the same disease. So here we are now almost 100 years later, and in fact, we agree that we're starting to realize that what's the inflammation of the small bowel in that one spot, in the inflammation of the large bowel in the other spot?

It may not be the same disease, but the characteristics of it are similar, which is that it's an overactive inflammatory response. Your intestines have an amazing, robust and very reactive immune system. It's evolved over millions of years or been designed that way, whatever it is, to interact with the environment. And the interaction of the immune system of the gut with the environment is very important because other than your skin, your gut is exposed to the environment more than any part of your body.

Every time you eat, you're sampling the world around you. And So what we've come to appreciate about Crohn's disease and its sister inflammatory condition, ulcerative colitis, is that this is an overactive immune response. It almost looks like an infection, but we haven't found an infectious source for it. And it may be loss of control. It's the loss of the ability to shut it off every time we eat. Those who don't have Crohn's become a little inflamed. If you get food poisoning or traveler's diarrhea, you become very inflamed.

If you do a CAT scan on someone who has food poisoning, it looks like Crohn's disease. But what's the difference between someone with food poisoning or someone who's healthy and just eats a meal and someone who has Crohn's is that Crohn's is a chronic condition. It continues and anywhere in the body where you have chronic inflammation, you can get damage. And damage is what gives people symptoms. The symptoms of Crohn's classically abdominal pain, diarrhea, and if they have blood tests done, they may be anemic or iron deficient.

It depends though on which part of the bowel is inflamed. The classic Crohn of the original Crohn description is in the small bowel at the end, which is in the lower right part of your abdomen. So people have cramps or generalized discomfort in that location. In the days before CAT scans, they often thought it was appendicitis, but it wasn't. And when you have this continuous inflammation in that small bowel, it can become narrowed over time and lead to cramping and partial obstruction or complete obstruction.

And that inflammation in some people can go through the wall of the bowel and affect other organs or the skin around it. So it can be a very disabling condition. But we've learned a lot more about how to treat it effectively, thankfully, and we've certainly made a lot of progress in that area. Is there a usual age of onset or it could be variable and are some people are higher risk than others? Most people with Crohn's disease will be diagnosed between ages 15 and 30. Seems like it might start in adolescence for some reasons.

We have some theories about it. There's a small but very important number of people who will be diagnosed underage, 10 or even younger. And we've started to realize that those individuals may have what's called a monogenic form of this disease. That means a single gene disorder that leads to an abnormal immune response. Those are very unique but very important group of people. And then there's a second group that we're now finding who are being diagnosed at older ages, 50s or 60s. And those come in two flavors.

1 is the person who's had it their whole life, very mild, very slowly progressive. And it finally reaches A threshold where they have symptoms. And then they finally get diagnosed. Or maybe they just have a screening colonoscopy. And the doctor says, oh, by the way, you've got inflammation. Are you having symptoms? You say, I don't think so. And the biopsies show it looks like Crohn's. And then there's a second group of people in that age group or older who truly seem to develop new Crohn's. We don't fully understand why, but as our population is aging, one of the things we're seeing is that we're having more people who are older that are getting Crohn's and need treatment.

So it's a very important second peak of of incidents that we're observing now around the world. You're seeing more Crohn's appear everywhere you look, even in sub-Saharan Africa now, places where we never thought we would see this. And they're just based on the size of the population in China, For example, if they continue at the pace that we're seeing, they'll have more people with inflammatory bowel disease in China in the next 10 years or so than we have in the rest of the world combined. So this is a very big problem.

And I'm sure your listeners are having some of the same thoughts that we have, which is what's driving all this. It's certainly not that there's been a change in the human genome. It's the environment. And what's what about the environment is doing this? Well, the most proximate part of the environment that our bowel is exposed to is what we eat. So it's not that wholesale. Everyone in China or other parts of the world have changed their diets. In many parts of the world they haven't even when we're seeing this.

But what they have is that the way food is prepared and stored and some of the ingredients that provide it with shelf life may be part of this. Using cooking oil is something that used to be reserved for people who had more money, but now it's much more prevalent. There's a lot of observations and clues to the environment that we've changed that may be driving these immune phenomenon. It's very important to understand that so we can better study it and then of course prevent it in the meantime. It doesn't change the fact that by the time someone does have one of these problems, we have to treat it.

And good news is we have good treatments now that's. Good. Now you mentioned the the immune factor, Is this an autoimmune condition like rheumatoid arthritis or lupus or or conditions like that? It's a great question. The the more accurate term currently is that it's an immune mediated problem and that there is a distinction between saying it's immune mediated and calling it autoimmune. Autoimmune implies in its strictest definition that there's a part of your immune system that's attacking you, that's you have got antibodies against self.

And in fact as much as we've been looking for those, we haven't found that in Crohn's or in ulcerative colitis. There's some newer work that says that some people may have some auto antibodies in ulcerative colitis, but in Crohn's we really have not found that. So I actually go out of my way to explain to people that it's not autoimmune in part because I think conceptually, for someone to think that their body is attacking themselves is different than understanding that their body's trying to do what it's designed to do and protect them.

It thinks it's doing its job to protect you from an infection or some other problem. And it may be a minor difference, but it's important for a patient who lives with one of these problems to not think that their body is their enemy, to understand instead that your body is actually trying to protect you from something, whether it's real or just lost the off switch. And what we're going to do to treat it is just try to turn that down to get you back to a regulated balance and a resting state. And I do think it's important to distinguish those types of conditions.

So I don't call inflammatory bowel disease, Crohn's disease, and ulcerative colitis autoimmune. I call them immune mediated. So I'm really glad you asked that question. Yeah, there's a differentiation there. Now, you mentioned a few people in your family have this condition, Crohn's disease is is this a familial or genetic trait? Can we say for sure at this point? Right. It's an important question, and it's a question that patients ask us all the time, especially when they're planning their own families.

Most people who have inflammatory bowel disease, most people who have Crohn's disease have no family history. There's nobody else in the family who's had it. Sometimes they'll say, oh, my grandmother was always in the bathroom. I bet she had something. Maybe, you know, that's generational, where they didn't talk about things like my grandmother didn't tell me about her problem until I was in medical school. But the reality is that most people don't have a family history. Now, having said that, that doesn't mean it's not genetic.

It means that there's not a dominant genetic inheritance. But actually the first gene for Crohn's was discovered here as well as in France and in collaboration with some investigators in Michigan, and that was in 2001. There's a gene for those who want to look it up called Nod 2, Nod 2. And it's interesting that gene actually is involved in how our body senses bacteria and responds to it in the gut. So make complete sense to think this is if you have a genetic variant of that particular genetic expression in our body, it might lead to something like Crohn's.

But after that was discovered, people said, oh, we're not going to be far from curing Crohn's. Now here we are 25 years later. There are now more than 300 confirmed genetic variants in Crohn's and colitis. Many of them overlap between Crohn's and colitis. They're not unique to the two conditions the way we think of them now. And a colleague of mine who just gave a lecture at the University of Chicago is a visitor this week, said that they have a new analysis of over 1,000,000 individuals 'cause that's the size of these data sets now, and it may be as many as 500 genetic variants.

So what we say to people is that this is not something that you get the gene and you have the disease. It's the common scenario of many diseases than humans of a complex genetic disorder that you may be susceptible with specific environmental triggers. You may have multiple genes, and many of these genes have other functions that we've learned about. That means that they're doing things for our body that are meaningful. So for example, some of the genes that are associated with Crohn's and colitis are also genes that make people susceptible to or protected from infections.

So it's fascinating to see that when you have a gene that somehow is selected through evolution to have a good function, it might end up setting you up for something else like a loss of regulatory control. So the answer is yes, IBD is genetic, but no, it's not dominant. And my message to patients is always the risk to your child is very low, 5% or less. And this is not something that should ever result in you not planning to have kids and do all the things you want in your life. So in my family, just as an example, my nephew, my my sister's son, he has Crohn's.

Well, you know, my grandmother had Crohn's and actually my brother-in-law has Crohn's. So there's a genetic link you could draw. Maybe in our family he got it from both sides, his mom and his dad. But on my wife's side of the family, no family history at all. It's her sister's daughter that got Crohn's and there's no link. So in our own family, we can see the two extremes here. Right, which makes me think is there an infectious component and maybe if somebody has a right gene, right environment and they have a certain type of bacteria in their gut that triggers it so.

We've been looking and looking and looking and, you know, it doesn't mean that we haven't missed something, but we've even done the other part of this, which is to say, OK, if we can't find the cause, let's just treat with broad spectrum antibiotics and see if we don't cure some people. That hasn't worked, unfortunately. And the other part of the story is if there was an infection, at least most of the types of infections we understand when we use our immune based therapies, which are very effective in Crohn's, we would expect at least a subset of people to get much worse because we're suppressing their immune response.

And there if there was an infection we were missing, we might have expressed, seen it express itself and we haven't seen that either in any of our studies with any of our therapies. Now, having said that, Crohn's disease of the small intestine can look just like tuberculosis of the small intestine. So you always, in certain parts of the world where it's relevant, you have to make sure you look for and treat TB before you say it's Crohn's. But we haven't found it yet, and there's been obviously incredible amounts of work.

What we haven't completely explored in the ways that we might need to is the virus component of all this. As much as we learned about bacteria in the bowel and maybe fungi, there's a huge amount of virus components and particles that live in our bowels. And there's some other pieces to this. But so far, every way we've tried to look at it, we haven't figured out an infection for Crohn's. Interesting. Now what about do patients with inflammatory bowel disease, both Crohn's and ulcerative colitis have associated mental health issues due to chronicity and or recurrent sort of disease and, and the symptoms they have and you mentioned it's a chronic condition.

Well, we certainly appreciate that anyone who lives with a chronic health condition can have depression or anxiety related to the condition, but there's a unique history of that in the inflammatory bowel disease space. It was recognized many years ago that people who had Crohn's disease or ulcerative colitis tended to be more likely to have anxiety or depression. And there was a time, I would suggest it was a darker time in our history of this condition where the personality of the individual in the presence of those disorders was blamed as the reason they got the inflammatory bowel problem in the 1st place.

That the anxiety drove the bowel inflammation. And that led to, unfortunately, stigmatization of the individual who had Crohn's, as well as stigmatization about mental health, which has long existed in our fields across medicine. Then there was a time when they even went so far as to say that they would perform lobotomies, remove part of the brain to treat Crohn's disease or colitis. Fortunately, that was very short lived and was not successful and therefore didn't continue. But then there was a general understanding that it wasn't that the anxiety or depression was causing the IBD, but that there were several possibilities about this relationship that were important to think about.

One was what I call reactive depression, anxiety, meaning that if you have a condition that by its very nature makes it harder for you to eat or enjoy food or socialize. And think about, especially now we're recording this near near the holidays, think about how everything we do in our lives socially is around food. Every holiday we celebrate, whether it's religious or otherwise, has some foods associated with it and the fact that people with bowel conditions need access to restrooms if they're not being treated effectively.

And you can imagine why, you can become anxious or depressed or develop avoiding food disorders related to these things. So that's the reactive part of this, which is completely understandable and I would suggest very treatable. If we fix the disease and we work with people, we might address that appropriately. But what my lab is studying and what we've become more interested in is what many in the world now call the gut brain interaction or that relationship. And what I mean by that is understanding the biology of how inflammation may actually affect our moods or our emotions.

So first you have to go back to the understanding of what actually causes us to have anxiety or depression and the neurotransmitters, those chemicals that affect the way our brain works or the way we feel, which is a hard thing to get your head around sometimes. But those neurotransmitters, many of them are metabolites of an amino acid in our diet called tryptophan. And so some people listening will understand tryptophan is present in Turkey among other foods. And, and one of the other metabolites of tryptophan is melatonin, which is why people feel a little groggy after eating their Turkey dinners.

But the main metabolite that we look at is serotonin. 95% of the serotonin in our bodies comes from the gut and comes from metabolizing tryptophan, which is an amino acid in foods we eat. It's called an essential amino acid because it's only acquired by eating it. It's not made in our body naturally. And then there are many other metabolites that occur from tryptophan breakdown and then from many other compounds and digestive components in our gut. So if you start by understanding that the bowel is filled with a trillion bacteria among other organisms, that those bacteria are constantly interacting with one another and interacting with the host through the lining of the bowel.

And then you appreciate that when someone's inflamed, the lining of the bowel has lost some of its protective ability, the mucus lining, the tight junctions between cells. You can understand that an inflamed gut may have a different component of bacteria in it. It may metabolize some of these amino acids differently, and that metabolism and those byproducts may be getting into the bloodstream more than we're used to seeing, not to mention how inflammation itself may be driving some of this. So we've been looking at whether you can predict anxiety or depression by looking at metabolites of some of these components from the bowel.

And our hypothesis is that an inflamed gut has an abnormal amount of some of these metabolites that actually drive the emotions and moods that we call depression and anxiety. And the part of the this hypothesis is if we were to treat the inflammation will improve the anxiety and depression, but the converse may also be true. We believe that when we treat the anxiety, for example, we might down regulate the inflammation and maybe bi directional. So we're doing this work now in our lab and, and we've actually identified some compounds that look like candidate markers to help us understand this.

And it's really remarkable. And there's so many implications for people living with these conditions. Every time I tell a patient about this, they feel relieved because they often thought it was their fault that they have IBD because they were nervous when they were younger or their mom or somebody told them that they were too stressed out in their job or at school. And there's always this blame game that people feel about illness. So this first of all starts to offer a biological explanation for some of that.

And the second part of it, of course, is it may destigmatize having a mental health disorder if you start to understand the biology of it, if you start to say you feel this way and you're it's affecting you this way because of the following things. And here's some new ways that we might be able to treat it. So it's a very important area of research for us. And we're also doing the work of treating anxiety with some novel tools. We have an NIH grant to look at using virtual reality to treat anxiety, and part of that grant is to measure if it changes inflammation.

So this is a very interesting area. And it's, it's particularly meaningful to me when you look back at the history of Crohn's disease and how people have been affected by all this and the the things that have happened to them through the ages that we've tried to sort this out. And I think we're making really good progress. That's great. I'm glad you're doing this work because I remember when I was a medical intern many, many years ago, we had many patients hospitalized for severe Crohn's and ulcerative colitis flare ups.

And some of my gastroenterology attendings imply that this was really a mental disorder condition that affected the bowel instead of the the other way. So I'm glad we're we're learning better. I think it's super important for us to understand this. And then of course, very importantly, and this is 'cause you're doing such great work, is communicating and sharing it with others. Right. What about the microbiome? I think we mentioned that. Could you tell us a little bit of what the microbiome is And new patients with Crohn's disease and ulcerative colitis have a different microbiome.

And which came first, the different microbiome or the disease causes a shift in the bacterial population? It's a wonderful question. So the microbiome refers to the organisms that live on or in our bodies. And you have a different microbiome depending on the part of the body you're looking at. In the gut, it's probably the most abundant microbiome on our bodies. So the gut microbiome is filled with all those organisms I mentioned already and it's its own ecosystem. In fact, some of the research that we do on the microbiome here is in conjunction with the marine biological labs in Woods Hole, Massachusetts, which is part of the University of Chicago actually.

Because people who study the ecosystem in the ocean are very prepared and, and helpful to us when we're trying to understand the ecosystem of the organisms that live in our bowels. You know, nature's remarkable in that regard. You can take the macro and look at the micro and there's a lot of similarities. So what we've learned about the microbiome in the bowel is that when someone has Crohn's disease, their microbiome is different than when someone has, does not have Crohn's disease. When you're inflamed for your Crohn's is active, it's different than when you're in remission.

But the question you asked about whether it's a chicken or an egg, whether the microbiome is what causes Crohn's or drives it, or whether the Crohn's and the inflammation from an abnormal immune response results in an abnormal microbiome is not fully understood. I gave a lecture in 2012, so earlier in my career now, and it was called Understanding the Microbiome in IBD, the final frontier, because we thought, you know, when we started to develop the tools to study it, and it's very complicated to be able to study this, that we were going to find all sorts of answers as to what's driving Crohn's or colitis and then we would develop new treatments based on those findings.

And the reality of this, similar to our excitement about the genetic discovery, is that it ends up being much more complicated. We are, however, making some really interesting inroads into this. One has to do with large scale studies that we're doing in conjunction with colleagues of ours in Hong Kong, where we're characterizing the microbiome in newborns. So most of your microbiome is acquired from mom when you're born. As the baby travels through the vaginal canal, or even if they're born by cesarean section, they acquire mom's microbiome.

And it's interesting to understand that. But the separate point is understanding whether the the microbiome when you're born is in any way predictive of your health when you become a child or when you get older. One of the prior observations about the microbiome in Crohn's disease is that one of the risks for getting Crohn's is if you had excessive antibiotic exposure as an infant or as a child, and presumably it changed your microbiome in some way and set your immune system up to not respond in a controlled way.

So we're studying this prospectively now in a huge number of newborns. 1 cohort of these newborns were born during the pandemic. So they also have this interesting observation and condition where they weren't in daycare, they weren't socialized, they didn't get sick like kids do when they go to daycare and when they're exposed to others. And so you might think that that's a good thing. It's probably not. Getting sick and having exposure to infections when you're little, and certainly before you reach your formative years as a teenager, is part of how you train your immune system to respond properly to the environment.

So there's this whole cohort of kids born during the pandemic who were isolated or interested in what happens to them. There's a large cohort of infants born just during our regular times. We want to know what happens to them, and we're hoping to figure some of this out. In the meantime, we don't have a probiotic or a prebiotic or even fecal transplants, which we tried to do, that have been effective at controlling and certainly not curing Crohn's or ulcerative colitis. Unfortunately, there have been some sporadic instances where we've seen fecal transplants provide a little bit of benefit in ulcerative colitis, but it hasn't been at all what we hoped it would be.

So we're not there yet. We're just getting better at figuring out how to measure it and what to look for, but there's a lot more work to be done. Interesting. Maybe AI will help us figure out the the statistics which are. Yeah, it's absolutely true. We're applying that tool to a lot of our complex statistical analysis now. We're finding new signals and new patterns, so that's part of how we might do this. Right now, clinically, for somebody who's diagnosed recently with Crohn's disease, what are the everyday basics they need to know about managing it, like diet tweaks, stress triggers, and when they should call their doctor because their symptoms are more serious?

I think that's really important. Let me start by saying that people who have a diagnosis of Crohn's disease need to know more about their own condition because as I say when I lecture to patients and teach this, your Crohn's is your Crohn's. What I mean by that is you need to understand what you have because the location of your inflammation is where it's likely to always be for you. So as much as you can read in our textbooks or online that Crohn's disease is an inflammatory condition of the bowel that can affect you anywhere from your mouth to your bottom, your anal canal.

The reality is that for most people, it's going to affect either that last part of the small bowel where Crohn, Ginsburg and Oppenheimer described it, or it's going to affect a part of your large intestine, but it'll be in the same location for your lifetime. So you need to know that first so you understand what you have. The second thing you have to understand about this is that it is very treatable. The expectation for someone diagnosed with Crohn's disease is that they should be in what we call remission.

And remission is defined in two specific ways. 1, you should have no symptoms. That means no pain, no diarrhea, no bleeding. You should feel perfect. That's the goal. And two, you should have it last forever. That's my goal for patients. I tell them this all the time. What does that mean? Well, it means that we have to treat you beyond the symptoms to make sure that we've controlled the overactive or unregulated immune response. So how do we do that? Well, that's where some of our therapies come in that we can chat about, but it means basically we're turning off that immune response so that the body can go back to its resting state and heal.

And when we get to that level of control, it usually means you're going to stay there as long as we continue using the therapy we have. It's not perfect, doesn't work in everybody, but it should work in most people. We have some newer data in the last year that demonstrate that if you get someone on one of our newer therapies within a couple weeks of their diagnosis, you can achieve almost an 80% clinical remission rate. 80% that was not, you know, you're, you're, you're nodding your head and raising your eyebrows because this is something we didn't think was possible.

Certainly when we were in training that was never discussed. So we've learned a lot more about doing this now, but that's what remission is supposed to be in my clinic and in ways that I try to teach more about this. I we'll also talk about a third type of remission, which I call functional. That means no joint pain because that can sometimes be part of this. It means no depression or anxiety. It means being able to work, raise your family, have kids. Everything else you want out of life is the third part, which is functional remission.

So we do it in order. We want you to feel better right away. We want it to last forever. That means we have to get to the point where the inflammation is shut off and the bowel heals. And we want you to function and have an unrestricted high quality of life. Right. How do you specifically diagnose Crohn's? Are there blood tests? Are there certain biomarkers? Or do you have to do an endoscopy and actually get a biopsy? Because the the symptoms can occur in many other conditions, they're not that specific.

Sure. I think that's an important point because as I mentioned, people are often young when they have Crohn's. And the most common thing that a young person has when they complain of a stomach ache is an irritable bowel or food poisoning or something else that's transient or a functional condition like an irritable bowel that can be more chronic but isn't progressive. It shouldn't be waking them from sleep or they shouldn't be seeing blood or certainly be anemic. So in order to diagnose it, the first thing is you have to have a suspicion someone might have it.

So it includes having doctors, nurses, school nurses, gynecologists, everyone who interacts with people when they're young. Knowing about it so that they can think about it. And for people listening and learning about this, they should know that. But ultimately, in order to make the diagnosis, it's a combination of knowing the symptoms the person has had and recognizing it's been going on for months or some chronic period of time, and then pairing that with seeing the inflammation. And ultimately the diagnosis is confirmed when you make sure it's not an infection and when you have a biopsy that under the microscope shows chronic changes that confirms it's a chronic inflammatory condition.

So for Crohn's disease, in order to stage it, you do end up meeting at baseline, A colonoscopy where you also get the scope to look in the end of the small bowel and some form of what we call cross-sectional imaging like ACT scan or often an MRI to look at the rest of the small bowel in the large intestine. So you have to do blood tests, scope and scanning to get the diagnosis. We've made incredible progress in how to monitor and manage the disease after that, where we use things like intestinal ultrasound and stool and blood markers to know how people are doing without having to repeat scopes all the time.

So some people listening to this who have Crohn's might be still getting scopes annually. That's not really needed in most people anymore. So obviously they should talk to their healthcare team about that. But the the reality is, once you're diagnosed, then the next part is to make sure that you monitor your condition, to know if it's relapsing or if it's progressing, to make sure your therapy is working and doing what it needs to be done so that you don't get sicker or have a problem. Right now you mentioned 80% success rate, which is fantastic, but it wasn't that way in the past.

Could you take us through the evolution of how Crohn's has been treated during your career, which medications were originally used and how that's changed and improved and progressed? I remember using a lot of steroids in the past when I was an intern with the patients. Well, steroids are still used a lot, and they're overused actually, unfortunately. But I'll tell you there were three revolutions in the treatment of Crohn's disease. The first revolution occurred when steroids were discovered and then developed to treat Crohn's.

And in fact, steroids for Crohn's were first studied in Europe, and then they were brought to the United States by a couple of investigators, one of which was my mentor, Doctor Kirzner. My grandmother was in the steroid trial for Crohn's. He told me after I met him, and it was a revolution because these are fast acting and they're broad acting on the immune system. And they worked. So people felt better. Of course, we learned very quickly after that, or they did, that there was toxicity, that it didn't heal the bowel.

And in fact, people ended up with diabetes and high blood pressure and moon phases and insomnia and mood disorders and brittle bones. And it's just not an acceptable strategy any longer. It's never acceptable as a maintenance strategy. And we actually try to avoid them completely now. But that was the first revolution. The second revolution in Crohn's was the development of the first monoclonal antibody that targets an inflammatory protein in our bodies. So for those out there who know this or remember it, it was called Remicade, the generic name infliximab.

It's an antibody that targets something called TNF. The name doesn't matter so much. The interesting story is that the antibody was originally designed to help treat a septicemia infection. And it didn't work. And then a brilliant person said, well, why don't we try it in a chronic inflammatory condition like rheumatoid arthritis? And it did. And then they treated it for Crohn's. It was the first drug that actually had FDA approval for Crohn's, was Remicade for Crohn's disease in 1998, which for you and me was yesterday.

For many people out there, it's a long time ago, but that was the second revolution, and then there were many subsequent monoclonal antibodies of different targets that became more specific. So they're focused instead of more systemically active, which means safer and maybe more effective in some people. And we got better and better and better at using these monoclonal antibodies, which is why we have so many of them now, and we have to know which ones to use. I called the third revolution where we are now the arrival of what are called small molecules and the advances of these special oral therapies that actually target different parts of our immune system.

And the reason they're a revolution in in the book of my book and thinking about Crohn's is because one of the challenges we have with monoclonal antibodies in people with inflamed bowels is sometimes the monoclonal antibody, the protein leaks out of the inflamed bowel. So you can't get enough of the drug to do its job with a small molecule. Aside from the fact that you can take it orally, which is convenient, it also has a very predictable absorption profile and therefore works more effectively in many people.

So the arrival of some of our small molecules I consider to be the third revolution because it bypasses one of the challenges we have of monoclonal antibody delivery. The 4th revolution is around the corner in my opinion, and it'll be more precision approaches to medicine and IBD and Crohn's. That means that we'll be able to predict which therapy to use in individuals or maybe which therapy not to use in some people. And I think that'll be revolutionary because then we won't be guessing so much anymore.

We'll be able to choose a therapy just like they do in oncology that's based more on the individual profile, the person in front of you. We're getting there. We have some very intriguing new studies that are ongoing. Now you've been involved in some very major and important clinical trials for finding drugs and biologics and other medications for treating Crohn's disease and all sort of colitis. Can you tell us about those clinical trials? Well, they're fortunately for our patients and for us. There are now many new therapies that are available, but they're all in the general theme that we've talked about, which is targeting the immune system in different ways.

We've gotten better at designing the trials in the sense that we are measuring outcomes that really matter and we think change the Natural History of the disease. Most recently, we've had the arrival of three therapies that all work similarly on an inflammatory protein called interleukin 23. I tell people the numbers don't matter so much. There's 50 interleukins, This is number 23, but it happens to be that interleukin 23 is the dominant target in treating psoriasis of the skin and it's a dominant target in many people who have inflammatory bowel.

And it's an interesting target because it's only expressed where you are inflamed and when you are inflamed. So when you target it as an anti-inflammatory strategy, you're only treating the inflammatory protein where the disease is. And when you go into remission and the bowel heals, the amount of Illinois 23 is not elevated anymore. The drug is only there to prevent it from coming back. Very interesting concept. Ends up being a really safe therapy. So there are three of these that have been developed and are available for both Crohn's disease and ulcerative colitis.

And I was involved in the development of all of them in different stages, although I took the lead on one of them for ulcerative colitis. And I think that that's a very nice option for many patients. And we're learning a lot more about how to use these therapies. They also happen to all the therapies that in the maintenance phase there are self injections, meaning you can do them at home. You have the convenience of being able to self dose and therefore you don't have to go somewhere and get infusions.

I always remind people that infusions and injections of these drugs is not because they're dangerous like chemotherapy, but rather because the size of the protein, the size of the molecule is too big to take orally and it won't be absorbed through the lining of your small intestine. So it's just about getting the drug into your body. But there are three of those that are now available, and there's a variety of new ones coming. Can you give us the names of those three drugs for people in the audience in this condition?

Make sure they're getting one of them. So the trade names of these drugs are, and I'm sure people are seeing some of the commercials on TV, but one is called Skyrizi, 1 is called Tremfya, and the third one is called OMVO. And they're made by AbbVie, Johnson and Johnson and Lily. And so these are therapies that all work on the same mechanism. They have slightly different dosing strategies, but they all have a similar nice effect in people with Crohn's and you see ulcerative colitis. So those are those drugs.

And then we of course have our oral therapies. I mentioned to you in Crohn's disease, there's only one that's currently available and that's the drug called Rinvoq and that targets an an enzyme related to inflammation called Janus kinase. And Rinvoq is a very fast acting oral therapy that works beautifully in Crohn's disease and it's been a game changer for many patients. And are these sometimes combined like an oral agent as well as the subcutaneous injection? So we've learned over time that combining these agents, if it's safe, can yield much better results in some patients.

And so especially when we're trying to get someone into remission as opposed to the maintenance phase to prevent it from coming back, the induction phase for some people is much better when we use two drugs together. And we've been studying that now and looking at ways to do that. It happens to be that those interleukin 23 inhibitors are so safe that they're a perfect option to combine with either the RINVOQ therapy, for example, or we can combine it with our older drug like the Remicade or some of the injectable anti TNFS.

And when we combine them, we're seeing some really remarkable nice either additive benefit or even synergistic benefit makes both drugs work better. So it doesn't. It's not rocket science to think that if you hit two targets of the immune system at the same time, you might get a better control of the disease. But I do think it's important to recognize it has to be done with some safety. And we're starting to appreciate the science behind it. We're not just throwing drugs at people. We don't want that.

Of course, I emphasize all the time to folks to remember you're not being immune suppressed. That's not our goal. Our goal is to turn down the overactive immune system long enough for your body to do the rest, and that's what we're trying to accomplish. Right. Are there any head to head trials being done for these different drugs that I see advertised on TV all the time? Right. So the biggest question we have in our community and the the talk that I'm often asked to give is how do you sequence these therapies?

How do you know which drug to use? And if you're a patient out there, how do you know which drug that you should ask for or know more about? And the answer is that it depends a little bit on a few things. Ideally, we would have clear head to head trials where we say, well obviously drug A is superior to drug B in people with Crohn's and therefore we should start with A and not waste our time. We don't have as many of those head to So we appreciate that there are some data to guide us here, but we've also learned that a bigger variable that predicts response to any therapy is starting early, not waiting until someone's been on steroids for a year or even for two months.

Getting someone on one of these newer drugs right away is what gets you that high rate of remission that I mentioned. There are other head to head trials that people are designing and trying to perform now, and there are other trials combining therapies that are ongoing. And of course, one message for everybody is that without patients participating in clinical research, we can't do any of this. So we need people to understand more about what we're trying to accomplish and to participate in new trials so we can do the work that's necessary to do this better in the future.

Now in Chicago, obviously people are going to see you to get enrolled in clinical trials. What about in the rest of the country? How does a patient who has this get involved in a clinical trial? Is there a website or some other way they can do it? Yeah. Well, first of all, I appreciate you bringing that up. I will say that many community practices now are participating in clinical trials. So you you may just need to ask your doctor about it. But I would refer people to two places. The first one is the Crohn's and Colitis Foundation's website in the United States.

That's the major source for patients and professionals as a shared organization that helps advocate and their website is just Crohn's Colitis Foundation, all one word, nospaces.org. The other place I send people is clinicaltrials.gov. So clinicaltrials.gov, and you can type in at the clinicaltrials.gov site, Crohn's disease, and it'll show you all the trials that are ongoing. You can scan through it. It's easy to read through and identify. Maybe there's one that you're interested in or that you've heard of, and it'll also tell you what sites are participating, so you can look for someone nearby.

The Crohn's and Colitis Foundation website also has a clearing house that provides some of the same information. So I would really encourage people to understand this. Clinical trials are designed with safety first in their designs and provide people with new therapies or older therapies that are being used are being used in new ways. But also the patients who participate in these trials then have access to the newest ways of measuring disease activity and some of the newest care that's being provided to manage these condition.

And then there's all sorts of trials like from my lab and others that are looking at things like the mental health aspects of this. And I have my own website for my patients and lab. But there are many different places people can look. And I encourage your audience to be open minded and to learn about how we do science so that we can make progress because we didn't get to where we are now without very generous patients over all these years. And waiting until you're desperate or it's the last thing you want to think about is a clinical trial is the wrong time to do it.

Right, great point. I'll make sure I post those websites so people can see it as they're watching this program. Now you mentioned these drugs are are very effective, which is great. What about the side effect profile of some of the new drugs? Are there occasionally serious side effects or are they very rare? Yeah, I think it's important and we always discuss this with patients. The the first thing to know is that whenever you target part of the immune system, you want to know if there's a risk of infections.

And when we use a drug like the old Remicade or anti TNF strategies, we know that there are risks of opportunistic infections and infections that we monitor for or work to prevent with the interleukin 23 inhibitors. Interestingly, the patients in the Crohn's trials who got placebo were more likely to have infections because their Crohn's got worse because they were in an arm of the trial that didn't work for their Crohn's at the time. And there's not considered to be an increased risk of serious infections with these therapies at all.

So we've really made some progress in thinking about that. Similarly, there's a drug called Entyvio, which only works on the white blood cells that go to the bowel, no infections, long term safety. And that's another platform therapy that we add or combine other drugs to. It's a very nice option, but people want to know about that. And then there are other side effects that we always think about. One of the unique side effects of the oral therapy Rinvoq is that about 1/4 of people might get acne when they're on the high dose during induction, and it's not the same as the acne people get when they're teenagers.

It's a different type of acne. Thankfully it's dose related, so when you go on the lower dose and maintenance, it usually goes away. But that's a side effect that we talked to people about. And then rarely, if you're doing a self injectable drug, people describe injection reactions, which are usually just rashes or a little irritation at the site where you inject. So those are the things we think mostly about. We've gotten away from some of our older therapies when I was in training where we really emphasized using thiopurine based therapies.

Those were drugs, oral drugs that we adopted from pediatric oncology and used at lower doses in Crohn's and colitis. They had some good efficacy, but there were some safety concerns about long term use, increase the risk of skin cancers, increase the risk of lymphoma. So we don't use those anymore in the US. They're still used in other parts of the world, so it's important to know all these things, but we've gone to a place now where the therapies we use are so targeted that they offer some great safety.

And there's really not a good reason for people to hesitate getting on an effective strategy as early as possible so they can achieve those levels of remission we talked about. Right. Is there any increased risk of cancers with the IL 23 inhibitors? We have not seen any cancers and that class of therapy has been around long enough that we would have by now. So thankfully this is not a target that influences the development of cancers. It's very good information for people to know and not to be worried about.

On the other hand, we know that untreated bowel inflammation can lead to bowel cancer. Like anything in your body, if you have chronic inflammation that's untreated, there can be a risk of cancer downstream. So we do recognize that treating the inflammation is the most important benefit compared to the risks otherwise. Great to know that. What do you see as the future in the next 5 or 10 years for inflammatory bowel disease, Crohn's and ulcerative colitis? Do you, do you think we'll ever find a a cure, a permanent cure?

Well, I, I think we're going to find cures plural, because these are probably going to be recognized as 40 or 50 different diseases that are all similar in their appearance. And in fact, we're working out with the International Organization for the study of IBD, which I'm currently chairing to reclassify IBDA little bit like what oncology did years before, which is to think first clinically separating out what Kron himself said, small bowel versus colon and recognizing those are different conditions and how they might respond differently to different therapies.

But also then doing it in a molecular and genetic level so that we can do the research necessary to really characterize these things in more effective and and detailed ways to actually result in those cures. But before we get to that, and as much as we're working on all this, we should acknowledge that we have available to us right now a whole armamentarium of effective therapies. In the near term, we're going to have a couple of completely new mechanisms and even some of our old therapies, including these Illinois 23 inhibitors are going to be available with longer half lives where you're only dosing it every four months or every six months.

So you might be in stable remission, but only getting the dosing of your therapy 3 * a year. So there's going to be some other things that come along that are going to be much more effective. And I also expect that we're going to continue to improve how we monitor the disease. So another area of research that we're involved in and others are working on is continuous passive monitoring to predict when people are inflamed. Just like people with diabetes now can wear a continuous glucose monitor and know exactly what's going on in their body.

There's very nice research that that is going on and that we've participated in and that we're doing ourselves now that shows that you can measure inflammation in direct and indirect ways, indirectly, heart rate variability and sleep patterns direct ways. There's some novel technologies in development that will in fact measure some of these inflammatory proteins continuously in your bloodstream or in your bowel wall, and you'll be able to monitor exactly what's going on and predict if you're about to have a relapse.

So I think people can really look forward to the future, but I always remind them not to save your treatment now for something that we are waiting for in the future. Use the best available therapies today. Get into remission. The right kind of remission now, until something better comes along, which is going to happen. So everybody will have a wonderful Thanksgiving dinner and holiday dinners without all the gastrointestinal problems, right? That's the plan. That's great. Well, this has been very educational for me.

I certainly learned a lot and I'm sure the audience will love this as well. I want to thank you for taking your time and sharing your knowledge and wisdom and experience and expertise with us. It's really been a pleasure. Thank you it. Was really my pleasure. I appreciate the opportunity of sharing all this with your audience. I want to congratulate you again on doing such great work. Thanks.

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