Dr. David Rubin: MAP, the Microbiome and Crohn’s Treatment
Those are tough questions and obviously we have a mixed audience. So first let me introduce myself. My name is David Rubin. I am a physician and a professor at the University of Chicago. I want to thank Stacey and her friends and colleagues for organizing this conference, and I also want to thank my colleagues who came much further than I had to from the South side of Chicago, for coming here and sharing their exciting research. And I want to ask the audience, who has been really remarkably patient and somewhat too quiet maybe, to thank my colleagues and your professors and scientists for sharing this work [applause], because I think this is really important.
I also want to acknowledge that I wasn’t on the original program, and I was invited here after I said, you know, we’re interested. We’re part of the RedHill study, but I want to make sure that people who come here, many of whom I expected would be patients and family members, knew about other things that were going on. Although I will actually admit that you guys covered it really well, and I think the lectures today were wonderful, so I’m grateful to have learned from all of you and I’m looking forward to participating.
I will, however, just end today with a short presentation that I hope you will find to be equally optimistic about where we’ve been and where we’re going. And if you’re not following me on Twitter, you are certainly welcome to, which is my professional Twitter address that’s there.
So here we are at the University of Chicago which is just five miles south of downtown Chicago. And for those from around the area you may not know this but we see almost 600 inflammatory bowel disease patients per month at our IBD center. It’s one of the biggest in the world. And in addition to doing our clinical work, we have a very active clinical research armamentaria. And my mentor was somebody named Joseph Kirsner, which if you read my title I’m actually now the Joseph Kirsner professor.
Kirsner came to the University of Chicago and worked in this building over here in the 1930’s. And he met a woman in 1935 who had ulcerative colitis and then died from the disease. And he was so moved by this woman that he then devoted his career to studying inflammatory bowel disease.
I came to the University of Chicago in 1990 as a first year medical student. And my grandmother told me to go find out if her doctor was still there, and it was Dr. Kirsner. And I said to her, “Why did he take care of you?” and she said, “Because I have Crohn’s disease” and I said, “What is that?” because I had never heard her talk about it that way. I just thought she was just like everyone’s grandmother and had lots of bowel problems.
So I met Dr. Kirsner and then he influenced much of my career. I have many stories about that, except to tell you that towards the end of his life, Dr. Kirsner gave a number of lectures that were quite impressive. At age 98 he gave a lecture on the history of the University of Chicago. And I went to his house every Sunday morning to help him develop his slides and learn about the University of Chicago. But that lecture went so well that after he finished, one week after he finished his 98th birthday lecture, he said I’m going to do it again at 100. And for his 100th birthday, he gave a lecture on the history of GI. And in his lecture on the history of GI, the field of gastroenterology, which really grew up right in front of his eyes, he acknowledged a number of major advances in the field; one of which was the discovery and understanding of Helicobacter pylori as the cause for peptic ulcer disease. And there were a number of others.
And one of the things we got to talk about as I went over to his house every Sunday, was what have we learned in IBD. And what he said was, well we’ve learned a lot and we’ve come around in full circle in some ways. And he felt badly that there was an era in the history of inflammatory bowel disease where these were blamed on psychiatric illnesses. And he publically apologized for that at some point in his career, later in life. And I often asked him, well what is the cause of IBD. After all these years of studying it, Dr. Kirsner, what do you think? And Dr. Kirsner said, I’m pretty sure we’re going to figure out it’s an infection. And I have subscribed to that. I have asked my patients who walk in the door every time I meet somebody new, what is the reason you have this condition? And sometimes they look at me like, well, that’s why I’m here. You’re supposed to tell me. And sometimes they have their own exposure or theory or ideas, or maybe they’ve read something.
So I’m grateful for the opportunity to address you today to tell you that, while we’re continuing to work hard to find a cure, or what I like to say, cures, we have made some good progress. I used to address patients when I gave lectures and look in the room and see people who were all on steroids. And I could just tell by scanning the room. And now I don’t see that very often at all no matter where I go, let alone in the Chicago land area.
I do have a few disclosures. I get asked almost on a daily basis why I do this for a living. So I’ll tell you that in addition to my grandmother, I have other family members who’ve been affected by IBD. I take care of patients. Almost exclusively my patient population has Crohn’s and colitis. And I’ve also served, and continue to serve, as a consultant to pharmaceutical companies. You should know that. I offer my advice and help them develop trials. And I’ve also served as a consultant to insurance companies, disease management companies and even the FDA. Anyone who has anything to do with IBD I try to help or get involved with so that I can learn from them and do something else.
We also have some research going on now that’s not just related to infectious causes of IBD, but related to what Dr. Chamberlin told you about; this concept that the gut bacteria are all disrupted. So we’re looking at something called fecal transplantation, which I’m sure some of you in the room may have read about, which has the general concept of trying to reboot the gut microbiome by giving people stool from a healthy donor. And Professor Borody in Australia’s also a big fan of that as well.
Our institution, as you already heard mentioned a couple times today, is part of the RedHill Biopharma study, so if this excited you and you’re interested in being in that study, you can certainly contact us and we would be delighted to screen you for that trial. I do not participate in promotional speaking. I haven’t for many years, and I’m not being paid today. So those are all my disclosures.
And I’m going to skip through a few slides and just get to the heart and summarize because it’s been a long conference and it’s nice for me to just wrap things up for you. We’ve learned for a while now that inflammatory bowel disease is likely to be the combination of many factors. It’s not just the genetics that you heard a bit about today, nor does it seem to be just about the environment, but it’s a combination of all these things that together have affected the microbes in our body; or maybe the microbes affect the rest of the components. But the characteristic manifestation that gives all the people who have these conditions symptoms is immune disregulation. The immune system is overactive, it’s lost control or it’s being constantly stimulated, or both, and therefore it cases damage. You’ve heard that word a few times today. And the damage is what leads to complications of the disease, whether it’s weight loss, inability to develop or grow properly, or the need for surgery and disability, it causes damage.
And so we have come to understand that each patient we see has some different component of these four variables. And while we’re very excited about MAP as one potential explanation for this, it is much more likely that there are many that would offer a much more heterogeneous combination for what we’re observing on the clinical end.
So I happen to subscribe that some of our patients with Crohn’s likely are walking around with a MAP infection, but Crohn himself, in the 1940’s and 50’s, after people started calling regional enteritis Crohn’s disease, which is controversial even to this day by the way; he said that when people showed him pictures of the colon looking like the small bowel; I don’t think that’s the same thing I saw in the small bowel. Now whether he was right or not we’re still trying to figure out. But there’s a lot of variation, and one of the challenges to finding a cure or cures for these conditions is making sure that we’re describing the different types of patients very carefully, so we don’t overwhelm what would otherwise be a very successful trial with a bunch of patients who don’t belong in the trial. And that’s a very important message for today.
So what might be explaining what’s going around the world. So Amy nicely showed you a study that I was going to quote, so I’m grateful for that. But we see that Crohn’s and ulcerative colitis are rising all over the world. In fact, if you look around the world, does anyone know where ulcerative colitis is rising the fastest right now?
Almost. So we don’t have a enough data in Africa, but Asia. Exactly, Southeast Asia and the Asian countries are seeing a very rapid rise in UC. And they’re seeing a rise in Crohn’s as well, and it’s not clear why. So as has already been said, it’s not because the genetics changed in that part of the world. That’s highly unlikely. It’s much more likely that something’s happened in the environment. And what has happened in the environment? You’ve heard great explanations today; compelling information that I actually would invoke in my explanations to other people. By the way, my father’s a veterinarian, and so shortly after I met Dr. Kirsner, he and I had lots of discussions about what might be causing Crohn’s and UC.
Now we have made great progress. I’ll just summarize in one slide to tell you that we have a much better understanding of what happens to people who aren’t treated. So whether we cure it or not, we know what happens when the disease is not under good control, and we’ve learned how to measure such things and improve quality of life and avoid hospitalizations and surgeries. We would love to do that in a way that results in a complete eradication of the disease. We also now have multiple therapies that are approved and available. We just want to use them the right way, and I think Dr. Chamberlin started off the conference by mentioning the distinction between treating the inflammation and understanding the cause of the disease, and that’s absolutely correct.
One of the greatest advances we’ve had in the last four years, in my opinion, is the ability to monitor the disease less invasively. So just as important as it is to have a better and more sensitive and specific test looking for an organism, it has become equally important that we have accurate ways to measure disease activity. So we know that whatever treatment you receive, or whatever treatment someone’s exposed to, we are actually and accurately capturing what happens to the disease so we know it’s working or not working. So my general approach to patients who ask me, can I try a diet or can I be on antibiotics, and I’ve prescribed Anti-MAP therapy even before we were involved in the trial, has been sure, it makes sense for you for this reason. But let’s agree that we’re going to know how to measure your disease activity to know if it’s doing what we want, so we don’t end up with complication down the road. And that, to me, is one of the major advances in our field.
So you’ve seen this in a different form, but I’ll summarize what you’ve already heard, which is that the treatment strategies that currently exist for IBD are really focused on our observations and what’s happening in the body; not the cause. And that includes modifying the immune system. I loved that picture we saw today of the volume dial, because that’s exactly what I tell people. Our goal is not to immune suppress you when we treat this disease. Our goal is to turn down the volume enough so that your body can take over and do what it’s supposed to do, which is heal and stop the injury. And so the therapies we’re using, and there’s more and more coming, are enabling us to do that. And maybe this new steroid therapy will offer that as well, and I’m hopeful it will.
But there’s also the concept of stimulating. So if we’re not just modulating or suppressing part of the immune system, can we stimulate a different part? And there’s the study that some of you in the room may have heard of, where we use the pig whip worm eggs. You’ve heard the worm therapy therapy for IBD some of you may, but if that sounds interesting to you and you hadn’t heard of it before, that trial’s ongoing in ulcerative colitis. Unfortunately it was negative in Crohn’s disease. And there was some very interesting and early data that stimulates the bone marrow that worked until the third phase of the trials was negative and then that was stopped. But people want to go back to it.
And then there’s the whole idea of how can you manipulate all of those organisms that live in your gut? You already heard that we’re 90% bacteria, and only 10% human. That’s true. There’s actually ten times as many viruses in your gut as there are bacteria. So that means that we’re even more virome than we are microbiome with bacteria. And so there are lots of things that you can do. And one of the quickest way you change the microbiota in your gut is changing your diet or flying from one end of the U.S. to the other or to anywhere else in the world. As soon as you get to a new environment, your gut microbiome changes. Many of you know that already when you’ve been to different places like when you’ve been to Mexico or when you travel somewhere and you get constipated. That’s your gut microbiome changing that fast when you arrive somewhere, and it happens a lot. And so there’s lots of interest in this.
But I completely subscribe to what Will said earlier and what has been said, which is that the gut microbiome, as interesting as it is to all of us, is probably just the result of something else going on and not necessarily the cause. But that remains to be proven. And it wasn’t until very recently that we had the tools to even start asking questions about what’s going on in the gut.
So our modern goals of treatment for IBD are about turning off the inflammation; making people feel better. That’s important, yes. Maintaining it as long as possible and avoiding steroids when we are, and hopefully healing the bowel, that’s important, right? And then preventing complications, monitoring the therapies, monitoring disease and keeping people well. What has happened though, is that nowhere on that list of goals for modern treatment of IBD do I see cure, right? And that’s a problem. So I keep bringing up in different forums, and this group is obviously way onto it, that one of the goals for the treatment of IBD must be cure. And if it’s not even on our slides, how are we even going to be talking about it in a reasonable way. So that’s what needs to happen, and that’s what’s starting to happen now.
We have the challenge of recognizing that we haven’t yet cured very many human diseases. There are lots of chronic human conditions. We’d like to think that they might be related to other infections, but we don’t know that for sure yet, but we’re also seeing rise of other immune diseases in the population. Asthma’s on the rise. When I was young peanut allergies were unheard of. Something called eosinophilic esophagitis, some of you in the room may have heard of now, that’s a relatively new condition that’s thought to be an immune, or even allergic reaction in the esophagus. But other things like multiple sclerosis, rheumatoid arthritis. There’s all sorts of immune problems that are rising in the population, and we don’t know why. So we have to be open minded and we have to develop the right research studies to look for the causes, and then we can develop the cures.
So why haven’t we cured IBD yet? Well, in my opinion, it’s because we’re dealing with many different disease all overlapped. That’s one possibility. And we’ve just lumped them all together and we can’t figure it out yet. Or we just don’t understand what we’re dealing with in terms of the cause, so how can we develop a cure?
So, I’m just going to summarize with a few more slides. But you’ve heard today all of the different theories that have been related to curing IBD. In the early days they thought it was a cancer, then they thought it was some type of infection. You heard about the psychogenic or psychiatric theories about IBD. Infection keeps coming up throughout the history. Then there was a lot of work done on genetics, and more recently people say it’s some imbalance of the stool, although that was seen in the early days.
The picture you’re looking at there though, is just a reminder. It has to do again with maybe the nice quote we saw about looking at facts differently. In this case, this is someone who comes with right lower quadrant abdominal pain, and they have their appendix removed, so what’s missing in this picture is the appendix. Except that’s the wrong diagnosis. The patient clearly has Crohn’s disease. That used to happen all the time. Now of course, everyone gets CAT scans and they think they can figure it out, but it still happens occasionally. So the point is, we really need to step back and say OK, we’ve been removing a lot of appendices, let’s figure out what the other problem is, as an example.
So how do you find a cure? You make observations. You have to figure out which patients they’re occurring in. You then need to assess causality, and that starts with associations but it’s not enough to be associated. So finding M.A.P. in lots of people with Crohn’s doesn’t mean it’s the cause, that’s obvious, but it’s the next step. And then you have to look at direct links like proof of exposure and development of disease, which we’ve heard some really compelling stories about today. And then you develop studies of eradication, and hopefully you can show that those are time tested and you can change the disease and cure.
That’s my mentor, Dr. Kirsner. He first described some patients in families who had these diseases. So one of the things you may be asking about is, well, if one person in my family has this condition, and it’s an infection, then how come more people don’t have it? And that was in part thought to be, maybe there’s some differences in the genetics of those different family members. Or maybe it’s just bad luck in one family member. But even if you look at identical twins, where the genes are the same, and one has Crohn’s, a couple different studies now have only showed that the likelihood that the other one has it is only 50%. So it’s clearly more than just genes, right? And it doesn’t quite make sense in other ways.
The first gene that was discovered was this one called NOD2. Everyone thought, “Yeah! We’re on our way to a cure!” In fact people wrote papers where they said, now that we’ve found this gene, and it describes this type of Crohn’s disease, we’re going to figure out what the cause of Crohn’s is and we’re going to cure people. Well, that was in 2001 and we haven’t. Not only that, but look at how many genes were found after that.
We’re actually up to 199, so Will said maybe 70. It’s 199 now genetic variances associated with Crohn’s and colitis. And over 110 of them exist in both conditions, so there’s lots of overlap. And what that really just tells you, is that there’s; this is about susceptibility. You heard this in a nice way today, but all these genes are related to other conditions too. Look at all these other immune conditions that have similar genetic associations, just like Crohn’s and colitis.
So what we’ve started to realize, is that these are similar immune mediated conditions, and I try to use that instead of the term auto-immune. And in part because we haven’t found the self-antigen that the body’s attacking. But I think it’s just more accurate until we figure out a little bit more. So these are immune mediated disease and there’s an overlap between Crohn’s, colitis and many of these, including susceptibility to infections like this one, leprosy, which is similar to MAP.
And there are other immune conditions which are misdiagnosed as Crohn’s. So if you want to get even more confusing, people are told they have Crohn’s when they’re actually walking around with something else that’s a different problem. So this is all about why it’s so complicated. And until we find the actual pure group of people that we can study the right way, and I would say that having a really sensitive and specific assay for an organism we can treat is a very important step to doing that, we’re going to get confused and there’s a lot of overlap that has to be sorted out.
So IBD’s a complex, genetic disorder. Some people have very high genetic susceptibility; what you see in the green line here. The example would be a Crohn’s disease manifestation in a child. And other people have a low genetic susceptibility and they develop it later in life, like someone who’s 45 and quits smoking and for the first time develops ulcerative colitis. That’s real. That does happen, and so where would you be on this curve? And there’s clearly many different ways that this can play out.
I’m going to skip through this and I’m going to get on to just a summary, because you guys have been here a very long time here today; and just tell you how you can get involved in research. And just to tell you, that while you’re waiting for the cure, don’t bypass effective therapies and monitoring your disease. So the woman who asked about taking antibiotics instead of going on infliximab, Remicade, I think she ran out to the pharmacy already. She’s not here anymore. It’s fine to be interested in these things, to get involved in the research. Make sure that you’re monitoring your disease.
A side note is that clofazimine, which is one of the three drugs that is recommended and has been studied the most for this, is not available in the U.S. So when we’ve treated people we’ve used a variant and do it a little differently.
So we’re in this area studying the gut flora which has been called variously the gold rush, and I called it the final frontier. Maybe this is where all the answers are that we’ve been missing all these years. And we’ve learned an awful lot about what’s going on in your gut from the standpoint of the microbiota, but we don’t yet know that this is actually causal. This may be an effect. It may be just the result of abnormal immune activity rather than actually what’s driving your disease. And in fact in Crohn’s, I think that that’s likely to be the case. Maybe in ulcerative colitis it’s a little different. We have some research in our institution that has identified a different organism that seems to evade testing and evade treatment, and may be similar to the way we’re thinking of M.A.P. that may be driving ulcerative colitis.
So just a few more tidbits for the next time you’re at a party and don’t know what to say to someone in small talk. Your gut microbiome is most similar to your mom’s, especially if you were born vaginally. So that is when you normally get your gut microbiome established. And in healthy people it’s very stable. So you can be on an antibiotic, you can get food poisoning, you can have lots of things happen and for the most part it bounces back to be just like you had it when you were younger. In people with IBD it’s not stable, it’s very instable, and there seems to be even spontaneous changes in the gut microbiome that occur. Now whether that’s a result of the spontaneous changes or driven changes of the immune system, we don’t know yet. But we’re starting to learn how to tie all this together.
So you can imagine a time in the near future when you might have a panel of genetic markers. You would understand your gut microbiome. You’d be tested for known organisms. You’d be treated for those organisms, maybe with a vaccine, and you would then be treated for any residual inflammation. So don’t throw out the baby with the bath water when we say that we’re going to figure out a cure. It may be a combination of all these things that’s going to get people better. Maybe we need to turn off the immune system, then treat the organism, and then get people well and go on with life. And that might be the way we’re going to do this in the future.
So I’m just going, because it’s been a long day, I’m going to skip ahead to the very end and show you how you can get involved in clinical trials if you want. And it’s not just about the University of Chicago. I’m very happy for you to go online and find them anywhere you’re from, or anywhere that may be more convenient. We also have another educational conference you’re all welcome to come to in October, and our clinical trials number’s there as well as our website; clinicaltrials.uchicago.edu. But you can also go to ClinicalTrials.gov and the CCFA does list some active clinical trials, and I’m sure many of you have looked there and it I think is a useful resource when you need some more information.
So with that, I’m going to end and just tell you about all the people in our IBD center who are waiting to meet you and doing all this work here in Chicago. And I want to thank the organizers again and congratulate them on a very important topic; a very important conference. And I wish my scientist colleagues the best in their next step, in their careers and in their work because we’re waiting for the results. OK, thank you.
So the questions is, can you have inflammation in the small bowel in the ileum but not have any serologic markers of inflammation like CRP or ESR? And the answer is absolutely. CRP is genetically determined. 20% of the population or maybe even a little more doesn’t make CRP and ESR can be notoriously insensitive to problems.
That’s a great question. Does it imply a different cause of the Crohn’s? I don’t know the answer to that. It’s an interesting thought. I would just say that in any patient when you use a surrogate marker of inflammation that isn’t actually looking with a scope and taking tissue and doing it directly, you have to partner the surrogate marker with the scope. So for some patients that is not the blood test. It’s a stool marker that we use now. For other patients we know that we just have to take a look because they always have problems and we find out too late because they end up hospitalized. So everybody’s different. That’s very important. Thank you. Yes ma’am.
Audience: You mentioned a non-invasive way of monitoring this disease. What is that?
That’s what he was asking about, so some of the blood tests called CRP or ESR. And there’s a stool test called fecal calprotectin. Calprotectin’s a protein that’s made by white blood cells and it pours into the bowel. And so you can often pick that up if there’s inflammation in the intestine. And there’s ultrasound that’s done, not so much in the U.S. but in Canada and other parts of Europe they do what’s called small bowel ultrasound right in the office where they can look and see how much inflammation might be there. All of these things instead of having to have another colonoscopy, because I know everyone loves those. Yes, hi.
Audience: How often do you see this in infants?
Infant onset, meaning under two years old of Crohn’s is rare. And it usually leads you to wonder about one of those immune deficiencies, and those are different. And so if you do have someone, a baby, who has this, then they really need to be seeing a pediatric hematologist or immunologist and have them work this up specially. There’s a group that’s particularly interested in all of this in Boston, that I’m certainly happy to give you a name for if you need it…OK, so you know. Yes, but it’s rare and it not; it may not be what we call Crohn’s. Remember the human body only has a few ways of expressing itself when it’s injured or when it’s under attack, or when it thinks it is. And those ways can look the same, so no matter what the cause is, it’s going to look similar to us. And that’s the challenge. So when we see inflammation, after we look for the obvious things that we learned in medical school, people then start calling it Crohn’s when in fact it may be another infection that we just can’t test for yet. Thanks. The vector guy. Yes.
Audience…It is intriguing that you mentioned that Asia is the fastest part of the world for Crohn’s disease, it’s increasing. And there’s some people out there, Chinese scientists, are linking that Crohn’s is increasing in Asia because the people are now drinking milk. So I think, to me, that seems like a very good indication that the role of Mycobacterium is there.
Well, some…I don’t disagree with you at all. Something in the environment, something they’re exposed to. What’s happened in China is the most significant migration of people from rural to urban areas that’s ever been seen in human history. And that’s unlike; undoubtedly something related to this. And it could certainly be what they’re consuming.
Audience: I know for a fact, because I’ve had contacts with people in China that farmers that have infected animals instead of disposing the carcass in the proper way, they throw the animals in the river which obviously… So I think that China obviously has an environmental issues that’s quite profound. It’s the poster child for…in ways that I think have been obviously underestimated.
I agree with you. First time I went to China which was ten years ago, I was asked to give a lecture on ulcerative colitis management and nobody had any questions. The second time I went, which was three years ago, and I was in Korea at the same time, there were lots of questions about managing ulcerative colitis. But they all said, we don’t see any severe disease and our colectomy rate is only 3%. In the U.S. it’s about 10-15%. And they said our disease here is different. I was just there in June, and I had more questions about how do you treat fulminate colitis than anything else that I got asked the whole time that I was at the conference there. So it is absolutely changing and rising, and the longer it’s there, the more they’re going to see what we see and maybe it is a similar causality in both parts of the world.