November 21, 2022 • 36 mins
In this podcast, we interview Dr. Eugene Chang, a national and renowned physician-scientist from the University of Chicago. In his lab, he and his team study the interactive relationship between intestinal microbes and the gut they live in, a relationship that is fundamental to our health. When the right balance is disturbed, the consequences can be catastrophic. Large shifts in the bacteria that make up the human microbiome (often caused by changes in environment and lifestyle) can trigger the development of autoimmune diseases such as IBD, Celiac, Diabetes, and others, especially in people who are also genetically susceptible. Dr. Chang's lab works tirelessly using cutting-edge approaches to better understand the human gut microbiome to prevent and treat disease.
Written and produced by Anna Gomberg. Edited and mixed by Mike Collins-Dowden.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
The GI Research Foundation was able to produce this podcast with a sponsorship from Takeda.
(00:04):
If we can track these patients from the time that the pouch is created to the time that they
develop their disease, we can determine the progression of events. We can see things happen
before the development of disease. Welcome to Visceral, the new podcast from the Gastrointestinal
(00:27):
Research Foundation's Gut Instinct, where we explore the ins and outs of digestive health
science with leaders in the field and those who have been impacted by living with digestive
diseases. My name is Anna Gomberg and I work at the University of Chicago Digestive Diseases
Center at the University of Chicago Medicine. With me today is my friend Eugene Chang,
we call him Gene, the Martin Boyer Professor of Medicine and Director of the Digestive Diseases
(00:52):
Research Core Center. Gene is also the Associate Director of the Inflammatory Bowel Disease Center
at the University of Chicago Medicine and overall living legend in digestive diseases research.
Dr. Chang has spent his entire career over 30 years conducting basic translational and clinical
research in digestive diseases including the Inflammatory Bowel Diseases, Crohn's disease,
(01:12):
and ulcerative colitis. For the last several years, he has employed his not inconsiderable
expertise in investigating the intestinal microbiome. Thank you for being with us today for this first
episode of this role to get started. One interesting fact about you Dr. Chang is that you were trained
as an MD, a medical doctor, a clinician, a person who treats patients, but you have also
(01:35):
basically built your career in research and all kinds of research, basic translational and clinical
research. I have had the privilege of hearing you speak a little bit about what that means for you,
but maybe you could tell us more about how that perspective informs your work and what has that
meant for your research program in your lab. I see having an MD as being an advantage,
(01:56):
because you're able to see what the problems are and what unmet needs need to be addressed.
So this is what I do day to day. I'm the person who generates the ideas. I decide
the direction of our research. Almost everything that we do in the lab is directed to answering
(02:27):
a particular question that is of clinical relevance. And that truly means that you're
taking basic science research and kind of always are focused on what good that might do for patients
in the end. I should mention, you know, we don't just do basic science research. Our research
program and programs really span from basic to translational to clinical. We actually
(02:55):
have several studies that involve a study of patient populations. I actually, in looking at
your CV and looking at all of the kinds of work that you've done, even prior to, I feel like,
the last 10 years, which has really been microbiome focused, and it is every kind of study
(03:15):
that can be done in this area. What, you know, just in touching on that, what drew you to IBD
research? What drew you to digestive diseases in general as a person, rather than even as a scientist?
So this was interesting, because I really wasn't doing IBD research and I didn't have any clinical
(03:36):
expertise and take care of IBD patients until, I would say, the early 1990s. And at that time,
the chairman of medicine was Arthur Rubenstein. And Arthur decided that we needed to have a basic
science or translational science program in inflammatory bowel diseases. And I think that
(04:00):
was associated with some grant funding that he had received to start the program. And a national
search was done, of which I think that many candidates came to interview for it to run that
program. But as it turned out, they decided that they would look at me as an internal candidate.
(04:24):
And ultimately, that's how I got into IBD. It was very fortuitous, because there's a lot to be
discovered in IBD. There are many unmet needs, huge gaps in knowledge, and this became a primary
interest of mine. Yeah. Well, I've heard you say, kind of thinking about your career, that you would
(04:50):
like to be part of the cure for IBD, the cure and the effective treatment. Do you think that we're
close? No, it's because IBD is not a single disorder. We know, for example, there's Crohn's
(05:11):
disease and all sort of colitis, while there are different types of Crohn's and all sort of colitis
as well. I view it as a set of diseases that present as two clinical phenotypes, Crohn's and
ulcerative colitis. But there are many causes and there are many factors. So to say that, you know,
(05:34):
I would cure IBD in my lifetime, I would say that's probably not going to happen. It's like saying,
you know, I'm going to cure cancer. Well, there's so many different types of cancers that
we can cure some, but we're not going to be able to cure everything, not within my lifetime.
(05:56):
Well, I've also heard building on what you just said about the many different types of IBD, which
is something that Dr. Rubin and Dr. No, everyone who works here would underscore that we just don't
know enough about these clinical phenotypes, as you said, to be as descriptive as we need to be.
One of the things that I remember hearing you say, one of the first lectures I remember hearing you
(06:19):
give, you said, well, I don't really think the colon is one organ. And I've heard you expound a
little bit on the digestive system in general. What is that? What do you mean by the colon might
not be one organ? And what are scientists doing to answer that or to investigate that further?
Well, that's a great question. If you look at our GI tract, it's actually multiple organs, right?
(06:45):
Right.
It's not not just like the liver and pancreas, which are outside of the luminal GI tract.
But each part of the intestinal tract is a different organ. Your stomach is different from
your esophagus. Your duodenum, genus, ilium, and colon. And the colon does have the front of the
(07:13):
colon, has a different function from the back end of the colon. So these are organs that have specific
function and gene expression, but they're just connected in series. And so I view the GI tract
as sort of like an assembly line, right? You start with eating food and then it gets digested. It
(07:40):
goes through various processes, goes through the stomach, acid is produced and it's broken down.
And then you enter the small intestine and its role is largely to further digest it and absorb
the nutrients. Then when it comes to the colon, I think part of it is that whatever is left is
(08:08):
a meal for the microbiome. And there, I think that the microbiome produces many, many molecules,
metabolites that have benefit to us and are absolutely essential. And deficiencies,
or imbalances in the microbiome can potentially cause or contribute to the development of
(08:34):
inflammatory bowel diseases. So I look at the GI tract as a very, very complex system. But it's
the complexity that really attracts me to understanding how all these parts come together
and function in a way that we don't even think about what goes on in our digestive processes.
(09:02):
Most of us are not affected at all. It's so complicated with so many moving parts and yet
it works so well for most people. Well, it works so smoothly and so well until it doesn't. And
that is the truly remarkable clinical stories we hear all the time are about patients that are fine
(09:26):
and then they take a trip or they have some sort of, they go to college and then they come back
three months later with full, full-blown and all sort of colitis and we don't really know how that
happens. But I think some of the work that you're looking at is certainly helping to
to elucidate what those mechanisms are. At a recent Continuing Medical Education program we did,
(09:48):
you shared what I have come to think of as one of my favorite slides, which I'll include in our
show notes. And in that slide, you see the rise of the Western diet throughout the world over time
and the corresponding rise of IBD. And I think it's kind of fascinating that your research
focuses primarily on the microbiome, which is like the teeny, tiny interior. And yet you were
(10:13):
zooming out to basically the whole world to see that these patterns were emerging. How does
microbiome research relate to this global phenomenon, these epidemiological trends? And with these
trends can we improve individuals' microbiomes to help stem the tide of inflammatory bowel disease?
And basically, what does that look like to you? Actually, this is what we study. We're looking
(10:38):
at environmental dietary lifestyle factors that impact these trillions of microbes that live within
us. These microbes make up a vital organ. They provide functions that we absolutely need. Now,
(11:03):
that did not come about just by chance. We select our microbes very, very carefully. And I would
even say that we evolved with our microbes. And we evolved in a way that we created through our
(11:28):
own genes and physiology ecosystems that attract certain types of microbes that will benefit us.
That relationship that has happened for thousands of years has now been altered by what we're doing
(11:51):
to ourselves. We've changed our diet. We've changed our lifestyle. The environment has changed. We
eat more animal-based foods rather than plant-based foods. And you can imagine that our genetics and
(12:15):
our biology has not caught up with that. We've shifted this within the past 100 to 200 years.
But this relationship that we have with our microbes in the environment, that has happened
over eons. And so this mismatch leads to higher risk for these disorders that we never saw or
(12:44):
rarely saw a couple hundred years ago. IBD is fairly new age disorder. Back in the early 1800s,
it was uncommon. And now you were seeing trends where it's increasing in prevalence
and incidence in countries that were previously developing and now have become as industrialized
(13:12):
and westernized as the United States is. So it's clearly IBD is an example of a disorder that,
in many ways, was really created by us. Now there is certainly a genetic basis for this,
(13:38):
but it's unlikely that over 200 years that you would have enough drift in population genetics
to explain that. So it really has to be changes in our environment, lifestyle, and diet.
What was it? So in the 90s, let's say when Judy Cho and the team here that worked to develop,
(14:07):
to identify the nod to gene, it must have seemed, I know that from looking at your research, that
was the focus. And then we discovered that there were so many genes associated that it became
sort of a less important focus in the research paradigm. But is there, I guess, what was that
(14:27):
shift like? What did it feel like when we sort of said, okay, well, there's a lot of genetic
associations. We know that, but we need to look deeper and look at something else.
Yeah. So you know, the discovery of nod to as a risk variant for largely for Crohn's disease
(14:49):
was, I think, a landmark finding because what nod to does is it's part of our immune system,
our surveillance of these microbes that live within us. And in fact, the stimulus or the
(15:11):
factor that activates nod to is a product of bacteria, gut bacteria. And when it was discovered,
to me, what I realized was that our immune system has evolved in a way to recognize good from
(15:32):
bad bacteria and or microbes. And I would say that that really underscored the importance of the gut
microbiome in diseases like IBD. At that time, or shortly thereafter, you know, I remember asking
(16:00):
at a conference, well, has anyone looked at the microbiome? And is there a way that we can study
it? And I think the speaker at that point said, no, we can't look at the microbiome. And that was
not a very satisfying answer to me. So I started to look around and it happened that we have an
(16:30):
incredible group of microbiologists and microbiome science people at Argonne National Laboratory.
Now, they have been doing microbiome research for years, but really the microbiome that's in the soil
or in the oceans and environment. But they had developed the tools that allowed us to look at
(16:53):
human as well as other mammalian microbiomes. And that's where we began in the early 2000s. And I
think we were among the very first groups to start looking at the gut microbiome. So I think that a
lot of things have happened in the past two decades. What we couldn't do 20 years ago, we can do very
(17:20):
well right now. We have very advanced technologies to look at these trillions of organisms in many
in many different ways and how they can impact our own biology, physiology, development. So
it's really been a thrill to be in this field. It would seem that some of what scientists and
(17:46):
technology have gotten better at in recent years is managing and computing these big data sets,
correct? Like trillions and trillions of pieces of information, which present really big opportunities
but also really big challenges. How does funding factor into the process of doing this research?
And how does independent funding help accelerate and contribute to your discoveries?
(18:07):
Well, so funding is largely through the National Institutes of Health. At least that's
where we get most of our funding. Now the NIH is very conservative in how it funds projects.
(18:31):
You have to show feasibility and merit, which means that you have to do a lot of studies
to convince them that you have something that is going to be turned out to have significance.
(18:53):
That's hard to do, right? I mean, how do you get started to get this data if you don't have other
sources of funding? You have to have an organization like IRF that is willing to take a risk and give
investigators the opportunity to explore areas that otherwise would not would be considered too
(19:19):
risky by the NIH. And that has been, I think, our secret sauce over the past 40 years that I've
been associated with GERF. They have been generous and helped us in really getting into areas that
(19:45):
are uncharted. And that has paid off in huge dividends because we're now very able to compete
for these large grants from the NIH. The most recent one, for example, is called an RC2.
It's focused on ulcerative colitis. It's a team science grant. So the RC2 is a
(20:14):
clinical investigation that uses what we call multi-omic approaches. This is like
the kind of DNA sequencing that we bring, but also things like measurements of metabolites,
so on and so forth. This is a grant or project that involves 30, 40 people that go from clinical.
(20:47):
I mean, David is very much part of it. Sushila is part of it. They help us get the
patient's specimens and they do the endoscopy and get the samples. And then we take the samples
and we do a variety of things. But the bottom line of this is that it's a human model where we can
(21:14):
gain insights into the cause of IBD. Why? Because we followed this group of ulcerative colitis patients
who have undergone the removal of their colon and then they have a pseudo rectum that's fashioned from
(21:36):
the remaining part of the small bowel. About half of these patients will develop a inflammatory
condition within a couple of years called pouchitis. And what this allows us to do is if we can track
(21:56):
these patients from the time that the pouch is created to the time that they develop their disease,
we can determine the progression of events. We can see things happen before the development of disease.
That has not been possible in a regular clinical population.
(22:19):
Patients that we see are patients who have already developed their inflammatory response
and had complications. And so this is whatever we're measuring is after the fact. It's probably a
consequence of the immune and inflammatory process. So with the pouchitis project, we can track the
(22:48):
events that lead up to why a individual would develop pouchitis. And in doing so, we made two discoveries.
And actually this was when we were funded through the initial human microbiome project.
So this project been going on for over 10 years. But two discoveries were made. One on the patient
(23:15):
sign. And this showed that these patients with ulcerative colitis, they're genetically wired
differently. I can tell you that we have indisputable evidence that they respond very, very differently
(23:40):
to microbial signals than you and me. And in the initial 17 patients that we published on,
all of these patients exhibited the same genetic response. And then this a year later,
(24:03):
after we published these results, the University of North Carolina group published almost the
identical response that was seen in Crohn's patients. This does not involve to our knowledge any of
the genetic variants that have been reported. This is something that probably arises from
(24:28):
something that the microbes do in changing the chemistry of our genes. So it's not changing the
backbone structure, but it's adding these groups so that alters gene expression. It's what we call
epigenetics. And yesterday, I saw the data that my colleagues, Sebastian Pot and Oni Basu, who are
(25:00):
in genetic medicine here, they showed me some incredible data from these patients. And it's
and it's very clear that whatever is driving this anomalous response to microbial signals
(25:21):
is being done through epigenetic modification. Wow. And what's the other discovery?
So on the the other discovery is on the microbside. So this was largely work that was done by a
former faculty member here, Marin, a Marat Aaron, right? This, this, this guy is a genius, right?
(25:49):
He's so far ahead of the field in thinking about and studying the microbiome. But he, he, he
observed that a particular microbial population that we often saw right before the development
of palchitis, he found that there was something genetically different between that organism
(26:16):
that was at the mucosal surface versus that in the luminal fluid. And that's something that
to cut to the chase here appears also to involve epigenetic modification. I didn't know that bacteria
could undergo epigenetic modification, but it is clear that, and this is something again where we
(26:41):
had to bring in an expert, Tal Pan, who is a professor, another very brilliant person, but he
identified parts of the DNA that were being modified by these microbes. And I don't have the answer
yet. It certainly seems like you're getting close. How much longer on the RC2 grant? We have two more
(27:06):
years. Is the study design, which is longitudinal unique? And is it necessary because of the
diversity of the microbiome in individuals? It's the only way to study the microbiome, because
everybody's microbiome is different. So the way that we design our studies is that the patient
(27:27):
or subject is always their own control. And we do longitudinal studies. Again, this is largely
through GERF. GERF gave us funding to get, you know, build a notobiotic facility. This is a
mouse facility where mice are brought up in a germ-free environment. They don't have any microbes.
(27:54):
That was a huge asset for us and opportunity for us to really gain an understanding of what microbes
do to us. We also, GERF, also provided funding for some technologies that allow us to look at gene
(28:17):
expression of single cells. Okay, so this was an instrument called the Codex machine that
Dr. Jabri is now running and making discoveries from. And then there was another instrument called
(28:38):
the Geomix nanostring spatial transcriptomics. Basically, we can see the gene expression of
individual cells in situ. All right, so and this is something that is being used by many
investigators now at the university. And it really enables us to answer questions that we
(29:04):
could not answer before. We're very fortunate because not many institutions would be able to
provide such a wide scope of enabling technologies as well as the sort of infrastructure that's
necessary for really addressing difficult questions. I know that we're getting close to
(29:33):
wrapping up, but I have one more question which I think we can maybe call wild speculation.
Are there any areas in your research that you just have a hunch about or discoveries or
advancements that you think the next few years will bring to the field of digestive diseases?
So we're into prevention. I have, it's a challenge to find a cure or cures. I think it is possible,
(30:00):
but the thing is that if we can prevent disease, we wouldn't have to cure a disease, right?
So that's the problem in our field right now, IBD, that is we don't know if we could figure out
who's at risk, then we could introduce interventions at that early stage. You're
(30:26):
at the early stage, you're outcomes are going to be so much better. So I'm into looking for
biomarkers or other developing metrics to determine whose microbiome might be
(30:46):
imbalanced or unhealthy. We can use that information along with somebody's, let's say, genetic profile.
We could test to see whether they have this anomalous gene expression. You put all that together.
You could probably stratify, not patients, but relatives or individuals that may be
(31:18):
beginning to develop some problems to determine whether they're high risk. If they're high risk,
then you can introduce interventions to lower the risk. What kind of interventions? Well,
I think that it could be as simple as changing diet. Now, I understand that that's very difficult to
(31:43):
do and most people aren't going to stick with it. But you know, it's very interesting. I think that
there are, if we could develop a metric that tells individuals that you have an unhealthy
microbiome, you keep on going this way, you're likely to develop or be at risk for developing
(32:09):
some disorder. But if I could say, look, I'm going to introduce, let's say, a dietary intervention
and show you that your microbiome is getting better, that we're repairing it, rebuilding it.
That's a huge incentive. And how do you know this? How do I know this? Well, we have several
(32:37):
patients where we're monitoring their microbiome. And when they see, when we present their data to
them, even before they're feeling better, and they're so motivated, and this one patient of ours,
we have who came in with a very, very damaged microbiome, having been placed on 18 months of
(33:05):
antibiotics 10 years ago, he developed a lot of GI symptoms. We looked at his microbiome,
and it was damaged. He was missing a lot of major groups that we absolutely need for good health.
So we started building that back up largely because we knew that many of these microbes
(33:30):
really thrive on plant fiber. So we're developing this tool as a way to promote compliance.
And this is actually related to the study I'm doing with Dr. McDonald. He was funded through
the Evans family in GERF, and to do this study in individuals that often are in areas where
(34:02):
there are food deserts and there's really no, you know, where food choices are not being made wisely.
Can you tell me a little bit more about the study that you're working on with Dr. McDonald?
I think we will probably follow up with him in a future podcast episode, but just to get a brief
(34:23):
overview would be, I think, because it's really interesting work. So we're going to work with
Dr. McDonald in using this set of tools to determine as he introduces dietary therapies,
you know, he does it two ways. One is to try to educate patients on how to cook foods and to make
(34:51):
wise choices. The other way is where he has an obesity clinic that he is trying different measures
to try to get them to lose weight. But I think that a tool like this would allow patients to see
that they're moving in the right direction. And then the weight loss when it comes will be a further
(35:17):
reinforcement. That is just really so exciting, and I can't wait to talk to him and to hear more
about the progress that you're making on that project as it develops. And where can people find
you on the internet? I know there's changlab.uchicago.edu. Are you on any social media? When it comes
to social media, I really haven't done very much. I mean, I think I have a Facebook account and
(35:44):
even I have a Twitter account, but I actually have never used Twitter. You write the papers. You say
if we want to know what you're doing, Dr. Chang, we should read gastroenterology and inflammatory
bowel diseases. I get it. That makes sense to me. So we will always be looking for the newest work
that's coming out of your lab. So thank you very, very much. It's been a pleasure. Thank you for
(36:07):
listening to the first episode of the podcast, Visceral, from the GI Research Foundation. This
episode was written, produced and edited by me, Anna Gomberg, and mixed by the incredible Mike
Collins Dowd, who also composed our theme music. We hope you'll join us next time and rate, like,
or subscribe wherever you find your podcast. Until then, visit the GI Research Foundation at
gurf.org. That's G-I-R-F.org to learn more about how to support the research that treats, cures,
(36:33):
and prevents digestive diseases.
The GI Research Foundation was able to produce this podcast with a sponsorship from Takeda.
(00:04):
If we can track these patients from the time that the pouch is created to the time that they
develop their disease, we can determine the progression of events. We can see things happen
before the development of disease. Welcome to Visceral, the new podcast from the Gastrointestinal
(00:27):
Research Foundation's Gut Instinct, where we explore the ins and outs of digestive health
science with leaders in the field and those who have been impacted by living with digestive
diseases. My name is Anna Gomberg and I work at the University of Chicago Digestive Diseases
Center at the University of Chicago Medicine. With me today is my friend Eugene Chang,
we call him Gene, the Martin Boyer Professor of Medicine and Director of the Digestive Diseases
(00:52):
Research Core Center. Gene is also the Associate Director of the Inflammatory Bowel Disease Center
at the University of Chicago Medicine and overall living legend in digestive diseases research.
Dr. Chang has spent his entire career over 30 years conducting basic translational and clinical
research in digestive diseases including the Inflammatory Bowel Diseases, Crohn's disease,
(01:12):
and ulcerative colitis. For the last several years, he has employed his not inconsiderable
expertise in investigating the intestinal microbiome. Thank you for being with us today for this first
episode of this role to get started. One interesting fact about you Dr. Chang is that you were trained
as an MD, a medical doctor, a clinician, a person who treats patients, but you have also
(01:35):
basically built your career in research and all kinds of research, basic translational and clinical
research. I have had the privilege of hearing you speak a little bit about what that means for you,
but maybe you could tell us more about how that perspective informs your work and what has that
meant for your research program in your lab. I see having an MD as being an advantage,
(01:56):
because you're able to see what the problems are and what unmet needs need to be addressed.
So this is what I do day to day. I'm the person who generates the ideas. I decide
the direction of our research. Almost everything that we do in the lab is directed to answering
(02:27):
a particular question that is of clinical relevance. And that truly means that you're
taking basic science research and kind of always are focused on what good that might do for patients
in the end. I should mention, you know, we don't just do basic science research. Our research
program and programs really span from basic to translational to clinical. We actually
(02:55):
have several studies that involve a study of patient populations. I actually, in looking at
your CV and looking at all of the kinds of work that you've done, even prior to, I feel like,
the last 10 years, which has really been microbiome focused, and it is every kind of study
(03:15):
that can be done in this area. What, you know, just in touching on that, what drew you to IBD
research? What drew you to digestive diseases in general as a person, rather than even as a scientist?
So this was interesting, because I really wasn't doing IBD research and I didn't have any clinical
(03:36):
expertise and take care of IBD patients until, I would say, the early 1990s. And at that time,
the chairman of medicine was Arthur Rubenstein. And Arthur decided that we needed to have a basic
science or translational science program in inflammatory bowel diseases. And I think that
(04:00):
was associated with some grant funding that he had received to start the program. And a national
search was done, of which I think that many candidates came to interview for it to run that
program. But as it turned out, they decided that they would look at me as an internal candidate.
(04:24):
And ultimately, that's how I got into IBD. It was very fortuitous, because there's a lot to be
discovered in IBD. There are many unmet needs, huge gaps in knowledge, and this became a primary
interest of mine. Yeah. Well, I've heard you say, kind of thinking about your career, that you would
(04:50):
like to be part of the cure for IBD, the cure and the effective treatment. Do you think that we're
close? No, it's because IBD is not a single disorder. We know, for example, there's Crohn's
(05:11):
disease and all sort of colitis, while there are different types of Crohn's and all sort of colitis
as well. I view it as a set of diseases that present as two clinical phenotypes, Crohn's and
ulcerative colitis. But there are many causes and there are many factors. So to say that, you know,
(05:34):
I would cure IBD in my lifetime, I would say that's probably not going to happen. It's like saying,
you know, I'm going to cure cancer. Well, there's so many different types of cancers that
we can cure some, but we're not going to be able to cure everything, not within my lifetime.
(05:56):
Well, I've also heard building on what you just said about the many different types of IBD, which
is something that Dr. Rubin and Dr. No, everyone who works here would underscore that we just don't
know enough about these clinical phenotypes, as you said, to be as descriptive as we need to be.
One of the things that I remember hearing you say, one of the first lectures I remember hearing you
(06:19):
give, you said, well, I don't really think the colon is one organ. And I've heard you expound a
little bit on the digestive system in general. What is that? What do you mean by the colon might
not be one organ? And what are scientists doing to answer that or to investigate that further?
Well, that's a great question. If you look at our GI tract, it's actually multiple organs, right?
(06:45):
Right.
It's not not just like the liver and pancreas, which are outside of the luminal GI tract.
But each part of the intestinal tract is a different organ. Your stomach is different from
your esophagus. Your duodenum, genus, ilium, and colon. And the colon does have the front of the
(07:13):
colon, has a different function from the back end of the colon. So these are organs that have specific
function and gene expression, but they're just connected in series. And so I view the GI tract
as sort of like an assembly line, right? You start with eating food and then it gets digested. It
(07:40):
goes through various processes, goes through the stomach, acid is produced and it's broken down.
And then you enter the small intestine and its role is largely to further digest it and absorb
the nutrients. Then when it comes to the colon, I think part of it is that whatever is left is
(08:08):
a meal for the microbiome. And there, I think that the microbiome produces many, many molecules,
metabolites that have benefit to us and are absolutely essential. And deficiencies,
or imbalances in the microbiome can potentially cause or contribute to the development of
(08:34):
inflammatory bowel diseases. So I look at the GI tract as a very, very complex system. But it's
the complexity that really attracts me to understanding how all these parts come together
and function in a way that we don't even think about what goes on in our digestive processes.
(09:02):
Most of us are not affected at all. It's so complicated with so many moving parts and yet
it works so well for most people. Well, it works so smoothly and so well until it doesn't. And
that is the truly remarkable clinical stories we hear all the time are about patients that are fine
(09:26):
and then they take a trip or they have some sort of, they go to college and then they come back
three months later with full, full-blown and all sort of colitis and we don't really know how that
happens. But I think some of the work that you're looking at is certainly helping to
to elucidate what those mechanisms are. At a recent Continuing Medical Education program we did,
(09:48):
you shared what I have come to think of as one of my favorite slides, which I'll include in our
show notes. And in that slide, you see the rise of the Western diet throughout the world over time
and the corresponding rise of IBD. And I think it's kind of fascinating that your research
focuses primarily on the microbiome, which is like the teeny, tiny interior. And yet you were
(10:13):
zooming out to basically the whole world to see that these patterns were emerging. How does
microbiome research relate to this global phenomenon, these epidemiological trends? And with these
trends can we improve individuals' microbiomes to help stem the tide of inflammatory bowel disease?
And basically, what does that look like to you? Actually, this is what we study. We're looking
(10:38):
at environmental dietary lifestyle factors that impact these trillions of microbes that live within
us. These microbes make up a vital organ. They provide functions that we absolutely need. Now,
(11:03):
that did not come about just by chance. We select our microbes very, very carefully. And I would
even say that we evolved with our microbes. And we evolved in a way that we created through our
(11:28):
own genes and physiology ecosystems that attract certain types of microbes that will benefit us.
That relationship that has happened for thousands of years has now been altered by what we're doing
(11:51):
to ourselves. We've changed our diet. We've changed our lifestyle. The environment has changed. We
eat more animal-based foods rather than plant-based foods. And you can imagine that our genetics and
(12:15):
our biology has not caught up with that. We've shifted this within the past 100 to 200 years.
But this relationship that we have with our microbes in the environment, that has happened
over eons. And so this mismatch leads to higher risk for these disorders that we never saw or
(12:44):
rarely saw a couple hundred years ago. IBD is fairly new age disorder. Back in the early 1800s,
it was uncommon. And now you were seeing trends where it's increasing in prevalence
and incidence in countries that were previously developing and now have become as industrialized
(13:12):
and westernized as the United States is. So it's clearly IBD is an example of a disorder that,
in many ways, was really created by us. Now there is certainly a genetic basis for this,
(13:38):
but it's unlikely that over 200 years that you would have enough drift in population genetics
to explain that. So it really has to be changes in our environment, lifestyle, and diet.
What was it? So in the 90s, let's say when Judy Cho and the team here that worked to develop,
(14:07):
to identify the nod to gene, it must have seemed, I know that from looking at your research, that
was the focus. And then we discovered that there were so many genes associated that it became
sort of a less important focus in the research paradigm. But is there, I guess, what was that
(14:27):
shift like? What did it feel like when we sort of said, okay, well, there's a lot of genetic
associations. We know that, but we need to look deeper and look at something else.
Yeah. So you know, the discovery of nod to as a risk variant for largely for Crohn's disease
(14:49):
was, I think, a landmark finding because what nod to does is it's part of our immune system,
our surveillance of these microbes that live within us. And in fact, the stimulus or the
(15:11):
factor that activates nod to is a product of bacteria, gut bacteria. And when it was discovered,
to me, what I realized was that our immune system has evolved in a way to recognize good from
(15:32):
bad bacteria and or microbes. And I would say that that really underscored the importance of the gut
microbiome in diseases like IBD. At that time, or shortly thereafter, you know, I remember asking
(16:00):
at a conference, well, has anyone looked at the microbiome? And is there a way that we can study
it? And I think the speaker at that point said, no, we can't look at the microbiome. And that was
not a very satisfying answer to me. So I started to look around and it happened that we have an
(16:30):
incredible group of microbiologists and microbiome science people at Argonne National Laboratory.
Now, they have been doing microbiome research for years, but really the microbiome that's in the soil
or in the oceans and environment. But they had developed the tools that allowed us to look at
(16:53):
human as well as other mammalian microbiomes. And that's where we began in the early 2000s. And I
think we were among the very first groups to start looking at the gut microbiome. So I think that a
lot of things have happened in the past two decades. What we couldn't do 20 years ago, we can do very
(17:20):
well right now. We have very advanced technologies to look at these trillions of organisms in many
in many different ways and how they can impact our own biology, physiology, development. So
it's really been a thrill to be in this field. It would seem that some of what scientists and
(17:46):
technology have gotten better at in recent years is managing and computing these big data sets,
correct? Like trillions and trillions of pieces of information, which present really big opportunities
but also really big challenges. How does funding factor into the process of doing this research?
And how does independent funding help accelerate and contribute to your discoveries?
(18:07):
Well, so funding is largely through the National Institutes of Health. At least that's
where we get most of our funding. Now the NIH is very conservative in how it funds projects.
(18:31):
You have to show feasibility and merit, which means that you have to do a lot of studies
to convince them that you have something that is going to be turned out to have significance.
(18:53):
That's hard to do, right? I mean, how do you get started to get this data if you don't have other
sources of funding? You have to have an organization like IRF that is willing to take a risk and give
investigators the opportunity to explore areas that otherwise would not would be considered too
(19:19):
risky by the NIH. And that has been, I think, our secret sauce over the past 40 years that I've
been associated with GERF. They have been generous and helped us in really getting into areas that
(19:45):
are uncharted. And that has paid off in huge dividends because we're now very able to compete
for these large grants from the NIH. The most recent one, for example, is called an RC2.
It's focused on ulcerative colitis. It's a team science grant. So the RC2 is a
(20:14):
clinical investigation that uses what we call multi-omic approaches. This is like
the kind of DNA sequencing that we bring, but also things like measurements of metabolites,
so on and so forth. This is a grant or project that involves 30, 40 people that go from clinical.
(20:47):
I mean, David is very much part of it. Sushila is part of it. They help us get the
patient's specimens and they do the endoscopy and get the samples. And then we take the samples
and we do a variety of things. But the bottom line of this is that it's a human model where we can
(21:14):
gain insights into the cause of IBD. Why? Because we followed this group of ulcerative colitis patients
who have undergone the removal of their colon and then they have a pseudo rectum that's fashioned from
(21:36):
the remaining part of the small bowel. About half of these patients will develop a inflammatory
condition within a couple of years called pouchitis. And what this allows us to do is if we can track
(21:56):
these patients from the time that the pouch is created to the time that they develop their disease,
we can determine the progression of events. We can see things happen before the development of disease.
That has not been possible in a regular clinical population.
(22:19):
Patients that we see are patients who have already developed their inflammatory response
and had complications. And so this is whatever we're measuring is after the fact. It's probably a
consequence of the immune and inflammatory process. So with the pouchitis project, we can track the
(22:48):
events that lead up to why a individual would develop pouchitis. And in doing so, we made two discoveries.
And actually this was when we were funded through the initial human microbiome project.
So this project been going on for over 10 years. But two discoveries were made. One on the patient
(23:15):
sign. And this showed that these patients with ulcerative colitis, they're genetically wired
differently. I can tell you that we have indisputable evidence that they respond very, very differently
(23:40):
to microbial signals than you and me. And in the initial 17 patients that we published on,
all of these patients exhibited the same genetic response. And then this a year later,
(24:03):
after we published these results, the University of North Carolina group published almost the
identical response that was seen in Crohn's patients. This does not involve to our knowledge any of
the genetic variants that have been reported. This is something that probably arises from
(24:28):
something that the microbes do in changing the chemistry of our genes. So it's not changing the
backbone structure, but it's adding these groups so that alters gene expression. It's what we call
epigenetics. And yesterday, I saw the data that my colleagues, Sebastian Pot and Oni Basu, who are
(25:00):
in genetic medicine here, they showed me some incredible data from these patients. And it's
and it's very clear that whatever is driving this anomalous response to microbial signals
(25:21):
is being done through epigenetic modification. Wow. And what's the other discovery?
So on the the other discovery is on the microbside. So this was largely work that was done by a
former faculty member here, Marin, a Marat Aaron, right? This, this, this guy is a genius, right?
(25:49):
He's so far ahead of the field in thinking about and studying the microbiome. But he, he, he
observed that a particular microbial population that we often saw right before the development
of palchitis, he found that there was something genetically different between that organism
(26:16):
that was at the mucosal surface versus that in the luminal fluid. And that's something that
to cut to the chase here appears also to involve epigenetic modification. I didn't know that bacteria
could undergo epigenetic modification, but it is clear that, and this is something again where we
(26:41):
had to bring in an expert, Tal Pan, who is a professor, another very brilliant person, but he
identified parts of the DNA that were being modified by these microbes. And I don't have the answer
yet. It certainly seems like you're getting close. How much longer on the RC2 grant? We have two more
(27:06):
years. Is the study design, which is longitudinal unique? And is it necessary because of the
diversity of the microbiome in individuals? It's the only way to study the microbiome, because
everybody's microbiome is different. So the way that we design our studies is that the patient
(27:27):
or subject is always their own control. And we do longitudinal studies. Again, this is largely
through GERF. GERF gave us funding to get, you know, build a notobiotic facility. This is a
mouse facility where mice are brought up in a germ-free environment. They don't have any microbes.
(27:54):
That was a huge asset for us and opportunity for us to really gain an understanding of what microbes
do to us. We also, GERF, also provided funding for some technologies that allow us to look at gene
(28:17):
expression of single cells. Okay, so this was an instrument called the Codex machine that
Dr. Jabri is now running and making discoveries from. And then there was another instrument called
(28:38):
the Geomix nanostring spatial transcriptomics. Basically, we can see the gene expression of
individual cells in situ. All right, so and this is something that is being used by many
investigators now at the university. And it really enables us to answer questions that we
(29:04):
could not answer before. We're very fortunate because not many institutions would be able to
provide such a wide scope of enabling technologies as well as the sort of infrastructure that's
necessary for really addressing difficult questions. I know that we're getting close to
(29:33):
wrapping up, but I have one more question which I think we can maybe call wild speculation.
Are there any areas in your research that you just have a hunch about or discoveries or
advancements that you think the next few years will bring to the field of digestive diseases?
So we're into prevention. I have, it's a challenge to find a cure or cures. I think it is possible,
(30:00):
but the thing is that if we can prevent disease, we wouldn't have to cure a disease, right?
So that's the problem in our field right now, IBD, that is we don't know if we could figure out
who's at risk, then we could introduce interventions at that early stage. You're
(30:26):
at the early stage, you're outcomes are going to be so much better. So I'm into looking for
biomarkers or other developing metrics to determine whose microbiome might be
(30:46):
imbalanced or unhealthy. We can use that information along with somebody's, let's say, genetic profile.
We could test to see whether they have this anomalous gene expression. You put all that together.
You could probably stratify, not patients, but relatives or individuals that may be
(31:18):
beginning to develop some problems to determine whether they're high risk. If they're high risk,
then you can introduce interventions to lower the risk. What kind of interventions? Well,
I think that it could be as simple as changing diet. Now, I understand that that's very difficult to
(31:43):
do and most people aren't going to stick with it. But you know, it's very interesting. I think that
there are, if we could develop a metric that tells individuals that you have an unhealthy
microbiome, you keep on going this way, you're likely to develop or be at risk for developing
(32:09):
some disorder. But if I could say, look, I'm going to introduce, let's say, a dietary intervention
and show you that your microbiome is getting better, that we're repairing it, rebuilding it.
That's a huge incentive. And how do you know this? How do I know this? Well, we have several
(32:37):
patients where we're monitoring their microbiome. And when they see, when we present their data to
them, even before they're feeling better, and they're so motivated, and this one patient of ours,
we have who came in with a very, very damaged microbiome, having been placed on 18 months of
(33:05):
antibiotics 10 years ago, he developed a lot of GI symptoms. We looked at his microbiome,
and it was damaged. He was missing a lot of major groups that we absolutely need for good health.
So we started building that back up largely because we knew that many of these microbes
(33:30):
really thrive on plant fiber. So we're developing this tool as a way to promote compliance.
And this is actually related to the study I'm doing with Dr. McDonald. He was funded through
the Evans family in GERF, and to do this study in individuals that often are in areas where
(34:02):
there are food deserts and there's really no, you know, where food choices are not being made wisely.
Can you tell me a little bit more about the study that you're working on with Dr. McDonald?
I think we will probably follow up with him in a future podcast episode, but just to get a brief
(34:23):
overview would be, I think, because it's really interesting work. So we're going to work with
Dr. McDonald in using this set of tools to determine as he introduces dietary therapies,
you know, he does it two ways. One is to try to educate patients on how to cook foods and to make
(34:51):
wise choices. The other way is where he has an obesity clinic that he is trying different measures
to try to get them to lose weight. But I think that a tool like this would allow patients to see
that they're moving in the right direction. And then the weight loss when it comes will be a further
(35:17):
reinforcement. That is just really so exciting, and I can't wait to talk to him and to hear more
about the progress that you're making on that project as it develops. And where can people find
you on the internet? I know there's changlab.uchicago.edu. Are you on any social media? When it comes
to social media, I really haven't done very much. I mean, I think I have a Facebook account and
(35:44):
even I have a Twitter account, but I actually have never used Twitter. You write the papers. You say
if we want to know what you're doing, Dr. Chang, we should read gastroenterology and inflammatory
bowel diseases. I get it. That makes sense to me. So we will always be looking for the newest work
that's coming out of your lab. So thank you very, very much. It's been a pleasure. Thank you for
(36:07):
listening to the first episode of the podcast, Visceral, from the GI Research Foundation. This
episode was written, produced and edited by me, Anna Gomberg, and mixed by the incredible Mike
Collins Dowd, who also composed our theme music. We hope you'll join us next time and rate, like,
or subscribe wherever you find your podcast. Until then, visit the GI Research Foundation at
gurf.org. That's G-I-R-F.org to learn more about how to support the research that treats, cures,
(36:33):
and prevents digestive diseases.
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