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Interviewer: Donor matching for fecal transplants, we'll talk about that next on the Scope.

Announcer: Examining the latest research and telling you about the latest break throughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. June Round, assistant professor in pathology at the University of Utah. Dr. Round, I think most people have heard about fecal transplant by now, but how effective are they really?

Dr. Round: So I think people have heard a lot about fecal transplants being for clostridium difficile infections. So they work quite well for this kind of transient infectious organisms.

However, people have started to try them for other intestinal inflammatory diseases like inflammatory bowel diseases, such as ulcerative colitis or Crohn's disease and they are less effective. And I think if we now understand how these microbial communities are shaped will help us to better understand how we can make fecal transplants more effective in the future.

Interviewer: And that's a good segue to your research. You did fecal transplants in mice and got some very different results depending on how they were done.

Dr. Round: So we're working with three different strains of mice, so they kind of represent three different people. But you infect them with the same amount of salmonella, which is now a fairly low dose, something that a human might take from contaminated food and some of these animals would dropped dead within two days.

Interviewer: Oh, my gosh.

Dr. Round: Other animals would live well over a week and actually clear the infection, so the differences between the susceptibility or resistance of these animals is really huge. And of course there was the third animal which had a very intermediate response. They didn't drop dead, but they got very sick, had a lot of diarrhea, but eventually cleared it after a couple of days.

Interviewer: This is just sort of their response before the transplant, is that correct?

Dr. Round: That is their baseline response right before the transplant, that's right.

Interviewer: Okay. And then once you did the transplants, what were the differences you saw there?

Dr. Round: So the animal that was highly susceptible, the one that would drop dead after two days after salmonella infection, if you give the fecal transplant from the highly resistant strain, that susceptible strain now became highly resistant. Meaning that instead of dropping dead after two days, it was able to live for well over a week and then clear the infection. So you can essentially make a susceptible animal highly resistant by simply giving it a fecal transplant.

Interviewer: So what was different about these different fecal transplants?

Dr. Round: The difference between the fecal transplants was that they came from animals that had a different suite of immune genes, and these immune genes are called Major Histocompatibility Complex or MHC, so there's lots of these MHC genes. So express multiple MHC genes and the very different throughout the population.

Interviewer: So maybe a little bit like we have different blood types, but more complicated than that.

Dr. Round: That's a great example.

Interviewer: Do your findings suggest that people with a certain MHC profile will always combat certain infections better than others?

Dr. Round: The major point of our paper is really that your MHC type dictates the type of microbes that live on your body. So some people I have an MHC type that selects for really good robust organisms that help them fight off salmonella really well, whereas other people might select for organisms that don't allow them to fight off salmonella very well. The same could be true for some . . . that's why some people get inflammatory bowel disease, some people don't, is you're selecting for just different cohorts of microbes.

Certain MHC types are associated with certain infections. Now, people always thought that that was because the immune system was presenting a better suite of antigens and mounting a better immune response. That's what has been thought for decades and decades, so our findings suggest that it's beyond that actually, it's that the MHC is selecting for microbial communities and some microbial communities are better at helping us battle infection.

Interviewer: I've been learning about certain companies that are making so called poop pills, where they take healthy donors and offer those as fecal transplants for, I think, right now it's mostly for people affected with the sedate. But what you're saying is that if they did an additional screening step it may help those therapies work better.

Dr. Round: Yes, I think for things like infections where the infection lasts a week, it's a very short time frame. I think that the best thing to do would be take it from a very resistant person, resistant to that particular infection because they probably have microbes that are able to fight the infection off.

In our case we were testing salmonella infection. Now, if you want to think about the broader picture, the implications of our findings, although I will say that we haven't quite tested it, is that perhaps for more chronic diseases like inflammatory bowel disease you might have to MHC match for microbes.

Interviewer: The MHC complex and what it does is the same system for like graft versus host when you donate a kidney for example you have to make sure that you have a match.

Dr. Round: That is exactly right.

Interviewer: And if you mismatch then you reject that graft.

Dr. Round: The one thing that's becoming evident is that you can give probiotics to people. You can give them millions and millions of bacteria in a little pill, but it doesn't always stick in the gut. It kind of gets flushed through. And part of that could be because that person doesn't have immune system that selects and allows for that bacteria to live there.

The same is true for fecal transplants. A lot of times to give a fecal transplant to someone and it works for a little bit, it stays in the gut of those people for a little bit, but then eventually those organisms get either competed out, flushed out, they're just not selected for.

So our findings suggest that perhaps we can make fecal transplants stick a little bit better if maybe we match the MHC donor to a recipient. We keep talking about this idea of personalized medicine and I think as far as personalized medicine is concerned, we're going to have to couple the genetics of the person, which is going to include the genetics, their immune profiles as well.

We're going to have to couple the genetics with the person along with the types of microbial communities. I think if in the future we can put those two together that we can have some really powerful therapeutic interventions in the future.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope, University of Utah Health Radio.

Interviewer: A study gives new insights into how good bacteria work with our body to promote digestive health - up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. "The Science and Research Show" is on The Scope.

Interviewer: A study published in Cell Host and Microbe is causing us to rethink what the immune system can do, and how it interacts with the good bacteria that live on our bodies. I'm talking with three authors on the study: senior author June Round, assistant professor of Pharmacology at the University of Utah, and co-first authors Jason Kubinak, and Charisse Peterson.
Dr. Round, what's the take home message from what you found in your study?

Dr. Round: I think the most important thing and the most interesting thing about this particular study is that it really highlights that there is a conversation between our immune system and the microbes that live on our body. It's becoming more and more clear that these microbes are very important for our health, and there's a lot of factors that shape what types of microbes can live on our bodies.
This study really highlights that our immune system has an effect on those types of microbes and that the microbes can send signals that tell our immune system how to develop, and in turn our immune system, as its developing, can also shape the types of microbes and the types of things that those microbes express.

Interviewer: Dr. Kubinak, how does that change our thinking from how we considered our microbiome before?

Dr. Kubinak: Well, I think within the last 10 years there's been a pretty significant shift in the way we view our interaction with the microbial world from initially primarily focused on antagonistic interactions where hosts and their immune systems were focused on eradicating and eliminating pathogens that make us sick. Whereas now, I think there's a renewed interest in the interaction between the hosts and microbes and how it promotes, or facilitates host health. I think our story sort of gets at that by demonstrating that the crosstalk between host and microbe generally is a health-promoting interaction.

Interviewer: So your work, in particular, addresses how the body keeps its balance of species of good bacteria intact, and you're particularly looking at one protein called MyD88. What did we know about this protein before your research?

Dr. Round: Its original function was assigned to recognize pathogenic organisms and basically act as the frontline detection to tell our immune system, "There is something going on here, there is a microbe here, so we better turn on our immune response and get rid of the pathogens." What we're really showing here is something very different, that detecting the microbe doesn't necessarily get rid of it here. It's actually helping to shape the types of organisms that live in the gut.

Interviewer: So how did you come to that conclusion?

Dr. Peterson: What did was we created a mouse that specifically knocked out this protein within a specific immune cell called a T cell. Then it gave us a unique opportunity to ask, what happens when this protein is absent in this immune cell and how does that affect the development of the microbiota as a whole in these animals.

Interviewer: So when MyD88 was knocked out of the immune system, it basically lead to an imbalance of the communities, the different species of bacteria in the gut. What does that do to the mouse, itself?

Dr. Round: What this lead to was that the animals themselves were more susceptible to inflammatory bowel disease, or an experimental model of inflammatory bowel disease.

Interviewer: I don't want to get too graphic, but what does that look like in a mouse?

Dr. Round: It's just inflammation within the guts of these animals. They lose weight.

Dr. Peterson: They get a severe wasting disease, and they get diarrhea.

Dr. Round: I think, for me, the most exciting part of the experiments was when we realized that this sensitivity to inflammatory bowel disease wasn't necessarily just caused by this defect that we had created in the host's immune system. One of the things that was driving this was actually this imbalance within the gut. Our ability to rescue that just by giving these mice healthy microbiota and rescue their disease susceptibility was, to me, the most exciting finding.

Interviewer: What do you mean? How did you fix the illness?

Dr. Peterson: So many people would refer to this as a fecal transplant. In the lab, we call this a microbiota transplant. You basically get rid of all those bad bugs that have developed in that animal because of their genetic deficiency and you replace them a healthy or with a balanced microbiota, so it's really a microbiota transplant. Obviously this is something that is starting to be done in people with various infections within their guts.

Interviewer: Well, right. I have to say, when I started talking about your work with other people in the office, that everyone became really excited when I said that I was going to be talking to you about fecal transplants, which sounds kind of strange. But, it's kind of this new exciting therapy that seems to have some pretty striking results in people as well.

Dr. Round: I'm glad to hear that people are excited about fecal transplants as, maybe disgusting as they sound. But to me, it makes sense. We have evolved for a very long time with these organisms, they promote our health, they're beneficial to us. So instead of using something that we chemically synthesized that's not natural, we're now using the microbiota as kind of a natural therapy to restore the balance in our bodies. So I think this is really a viable therapy in the future for multiple diseases, not just for inflammatory bowel disease.

Interviewer: I think one of the interesting parts of this study is that it really suggests that there is kind of a co-evolution between the microbiome and ourselves. How do you think about that?

Dr. Kubinak: To me, it speaks to the nature of natural selection to have driven the evolution of immune system machinery to promote benign symbiosis between us and our microbes.

Interviewer: So they're helping us, but we're also finding ways to help them.

Dr. Kubinak: Yeah, I think so. I think our immune systems have developed ways to definitely skew the community toward the presence of individuals who at the very least, are not going to cause us harm.

Announcer: Interesting. Informative. And all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Discover how the research of today will affect you tomorrow. The Science and Research show is on The Scope.

Julie Kiefer: Within each one of us are bacteria that live in our mouth, skin, gastrointestinal tract and on all exposed surfaces of the body, but contrary to common belief, most of these bacteria are actually good. Dr. June Round professor of Pathology studies how our body interacts with these microorganisms and how these microorganisms interact with us. Dr. Round how many of these bacteria live in our bodies?

Dr. June Round: There are billions of these bacteria that live on our bodies. There's actually more bacteria on our bodies than our own human cells. So, we're actually more bacterial than we are human.

Julie Kiefer: So if the body tolerates such a huge bacterial population, they must be doing something useful. What are they doing?

Dr. June Round: In animal models, we have shown that these bacteria are important for development, especially immune system development. There are some studies that show that the bacteria are important for brain function. So they've been implicated in diseases like autism. Some studies have shown that of course digestion is really dependent on these particular bacteria that live on our bodies. So there's a whole range of implications and we're just beginning to find out the importance of some of these bacteria.

Julie Kiefer: Right, and some of the first clues you got were by working with these special mice called "Germ Free Mice." Can you talk about what that is and what happens to them?

Dr. June Round: They are born and reared in completely sterile environments. So they've never seen a single bacteria, a virus or any foreign microorganism. They live in these little plastic bubbles. So, they're essentially "bubble mice." If you take these mice and compare them to animals that have... We call them "conventionally colonized," which means they have thousands of organisms on their bodies. If you compare them to these regular animals, they have a lot of developmental defects.
So there are a few things, like they have to take in more food or more calories to maintain the same body weight, which is not surprising. These organisms are important for digestion. They also have defects like a smaller heart. They are more anxiety prone. If you look at their immune system it's completely defective. So if you challenge them with any bad or pathogenic microorganism, these animals are highly susceptible to those infections. All of this is suggestive that the microbiota, or the commensal microbes are very important for our development and our health.

Julie Kiefer: And commensal microbes, that means those the good... Well, we thing they're good. The bacteria that reside in our body, that live in our body.

Dr. June Round: That's right. I probably should have defined that earlier. Yeah, the commensal microbes, when I say that, I'm referring to those organisms that we are born with.

Julie Kiefer: So your specialty is investigating the interaction between these microbes and the immune system. Can you talk about that research?

Dr. June Round: We're especially focused on immune system development within the intestine and how the microbes that live on our bodies shape those responses. So the diseases that we're really interested in are diseases like inflammatory bowel disease, colorectal cancer. We even have one of the projects in the lab that's focused on Multiple Sclerosis, so that's actually not an intestinal disease, but there's a pretty tight connection between Multiple Sclerosis and the intestine.
Some of the models that we use are animals where we have gotten rid of specific immune system genes and then we ask, "How does that influence what microorganisms can colonize us?" It's actually a two-way street. The microbiota can influence our development but then our genetics can actually influence what type of microbes can live on our bodies. Again, we can use these germ free mice to put in specific microorganisms and ask, "Is it this organism that can protect from colon cancer? Or does this organism exacerbate colon cancer?" So we can really tease apart the systems in germ free mice as well as in organisms that we've isolated from humans.

Julie Kiefer: Right. So there are many, many species of bacteria in our bodies. How many, about? Or do we know?

Dr. June Round: So the estimates are... Any one person is probably walking around with about 500 to 1000 different species and of these species there can be hundreds of different strains. So that's the current estimate in a human, at least.

Julie Kiefer: So how do you figure out which ones to test in your experiments? If you're introducing one back, how do you know which one is the interesting one?

Dr. June Round: That's actually a really good question, Julie. I get that question a lot. What most people have done, and one of the things that we've done as well, is to start looking at the differences between people who are healthy and people with Inflammatory Bowel disease. With the current technology we're able to basically understand all of the different organisms that are colonizing various people. So what we do is we take, "What organisms are colonizing healthy people?" and "What organisms are colonizing people with the disease?" and we ask, "What's different?" Specifically, I'm interested in the organisms that are colonizing healthy people that are gone in people with disease, suggesting perhaps that the people with disease are lacking these "good organisms."
We found several strains of bacteria. One of the organisms that we work with in the lab is called Bacteroides fragilis. We can take these organisms that are in healthy people, put them in the germ free mice, induce disease and ask, "Does this protect during these disease models?" So, that's how we start to focus our attention. In turn there are also organisms that colonize people with disease that are not found in healthy people. We can ask in our animal models, if we take that one organism that this diseased person has, put it into our germ free disease animal systems, "Do you induce disease?" In many cases, it does seem to be true. So, that's how we begin to focus our attention on these organisms.

Julie Kiefer: You've discovered that one of these species can protect from Irritable Bowel Syndrome, I believe?

Dr. June Round: Yeah. Inflammatory Bowel.

Julie Kiefer: I'm sorry Inflammatory Bowel syndrome. Do you have a sense of how that works?

Dr. June Round: Those are the studies that I did as a post-doc that we've carried on in the lab here. That organism is called Bacteriodes fragilis. I mentioned that one earlier, or B. fragilis. If you colonize animals with this organisms, and it doesn't even need to be a germ free animal. You can actually give it on top of the regular, conventional organisms that these mice have. This is much like a treatment with a probiotic. When you induce Inflammatory Bowel disease, or IBD, then you can actually protect these animals from the development of that disease.
What's more, is that we identified this particular organism makes a sugar molecule that it puts on its surface, it's a polysaccharide, and this one molecule when taken away from this organism and colonize these animals they are no longer protected. So, we identified that it's the specific molecule that this bug makes that is actually influencing the protection. We've identified that it's a particular T-cell subset that this commensal organism can influence that causes protection.

Julie Kiefer: So do these results suggest ways that we can treat IBD in humans?

Dr. June Round: Probably one of the most important implications, I think, from those studies is that these organisms have evolved these very specific molecules to influence our biology. The reason I find it really exciting is that we can actually purify that molecule away from that bug and we can get all of the same effects. So, I know people are a little leery of taking a pill with a bunch of live bacteria in it. With these studies we've shown that we can actually identify these molecules and potentially use those as therapies, as opposed to colonizing people with bacteria and doing that, you can actually control the amount that you give. Once you get colonized with a bacteria, it's actually very hard to get rid of it. So that's why I think those studies are particularly exciting, is because we can now isolate those and use them as therapies.

Julie Kiefer: One of the interesting things is, we have the pathogenic bacteria, the ones that make us sick and then these commensal bacteria that don't. So they must interact with the immune system differently.

Dr. June Round: Yeah. So that's actually one of the central questions in my lab... The main function of the immune system is to discriminate what is self and what is non-self. In discriminating between non-self, which would be anything foreign on your body, such as a bacteria, the immune system has to make a choice between, "What do I react against? What's bad?" and then, "What is helping me? Or what should I tolerate?" so to speak. So anytime you eat piece of food and your body doesn't react to it. It tolerates it.
So the same is true for the commensal organisms. Our body has evolved mechanisms to distinguish between what is good and what is bad. In part, these bacteria express different molecules that can tell our immune system, "I'm a good one." And the bad ones don't necessarily tell us that they're bad, but they elicit responses that our body knows are bad.

Julie Kiefer: If this goes wrong, could this be the basis for some of these auto-immune diseases?

Dr. June Round: Yes. That's exactly right. Especially in the case of Inflammatory Bowel disease one of the major thoughts about why this disease happens is because our body loses its tolerance to all of those commensal microbes that are living within the intestine. So now we have an immune system with tons of immune cells hanging out within the intestine and now all of a sudden all of them are starting to attack these good bacteria. Since you can never really get rid of these good bacteria, it's a constant war zone. You have the immune system continually mounting these inflammatory responses. If you have chronic inflammation, that can lead to other disease like colorectal cancer. Ten percent of people who have IBD go on to develop cancer. With respect to IDB, that is one of the major reasons IBD happens, because you lose tolerance to those good microbes.

Julie Kiefer: It seems like there's been a rise in IBD and disease like this in the population. Is that true? Is there an explanation for that?

Dr. June Round: So this was a phenomenon that was noticed, maybe about a decade or so ago. David Strachan was actually the first person who noticed that over the course of maybe 20 to 30 years that auto-immune diseases especially were increasing at a very rapid rate. They were increasing over such a short period of time that it couldn't have been due to genetic drift or changes in the population. These were diseases such as Inflammatory Bowel disease, Multiple Sclerosis, allergies, asthma... Even if you look over that short period of time, obesity, which is not considered an auto-immune disease, dramatically increased in these populations. Diabetes is another one. The hypothesis there is that something environmental must be triggering this.
Coincident with the increase in these auto-immune diseases was the heavy use of antibiotics. Of course, antibiotics are great because we got rid of all these terrible disease like Polio and Tuberculosis. They eradicated them from our societies but they also, at least the hypothesis is, that the heavy use of antibiotics and increased use of sanitation conditions in these Western societies also got rid of all of our good microbes. Antibiotics have no way of discriminating between pathogenic versus commensal organisms. Every time you take a dose of antibiotics, you're also getting rid of a lot of the bacteria that live on your body. Then the thought was that by increasing our sanitation, getting rid of all these good microorganisms that we're predisposing ourselves to increased auto-immunity.

Julie Kiefer: If that's true, you would think that people in third-world countries who don't have access to the same sanitation or to antibiotics, they might have these diseases less frequently. Do we know if that's true?

Dr. June Round: That is true. So if you go and look at the rural countries that don't take these antibiotics they don't suffer from diseases like Inflammatory Bowel disease, Diabetes or obesity even. They just don't have the same problems that we do. Of course, they're oftentimes suffering from pathogenic infections but the fact is true that they don't have these problems.

Julie Kiefer: Right. There are trade-offs.

Dr. June Round: Yes. There are trade-offs.

Julie Kiefer: That's fascinating. I mean, it's hard to think about how things like obesity fit in to the picture. Can you talk about that a little bit?

Dr. June Round: Sure. So this is not my research focus in this particular lab, but a lot of people have been studying how the microbes in our gut can influence obesity. Because wouldn't everybody love to take a pill that causes them to lose all the weight? The fact is that the microbiota is very important in how we digest our food. The food that we intake is also a fuel source for the microbes. So let's say you eat a lot of fat in your diet, and you're going to have microbes that are really good at metabolizing that fat.
Some can do it better than others. So if you happen to be colonized with some organisms that are really good at extracting a lot of energy from that fat, that's also more energy your body gets. So the microbes get it but also your body gets it. So if you don't use that energy then it gets stored as fat. The thought is that... The interesting part is that they can take microbes from people who are obese, stick them into germ free mice and then those germ free mice, even though they're eating the same food, they begin to start getting fatter. There are a lot of studies supporting this notion that the microbes that live in your gut can actually just help you extract more energy and then make you gain weight.

Julie Kiefer: So you're not just feeding yourself, you're feeding these little microorganisms within you too.

Dr. June Round: That's right.

Julie Kiefer: What are your thoughts about using antibiotics, or cleaning your hands with alcoholic cleansers?

Dr. June Round: I certainly wash my hands, but I don't use those cleansers and I don't have my kids use them either. Because I do think that we get a lot of our microbes from our environment. I think that that is important. I do buy into this idea. Another thing is that, especially for kids, a lot of parents, if their kid gets an ear infection, they will go to the doctor and request antibiotics. That's something that I haven't pushed for my children. I make them suffer a little bit longer, not take the antibiotics and clear the infection themselves. There's these startling studies out there that there are correlations between a lot of these auto-immune diseases and the number of times you've taken antibiotics as a youth. So people who have taken antibiotics up to four or five times, they tend to develop diseases like Inflammatory Bowel disease later in life. Because I'm raising young children who are in this window, I am concerned that if I give them too many antibiotics, I could predispose them to these diseases later.

Julie Kiefer: It seems like the healthcare field has already some of these findings into consideration. I've noticed just in the last few years, that doctors are more reluctant to prescribe antibiotics right away. Can you think of other examples where the healthcare field is really being proactive in how they think about the good bacteria?

Dr. June Round: One thing that comes to mind, prominently because I talk to my colleagues about it a lot, is this fecal transplant idea. A lot of people, especially gastroenterologists who treat people with Inflammatory Bowel disease, are really starting to think about whether or not they can just replace the bad organisms in their patients with IBD by just giving them a fecal transplant from someone who is healthy. This has already been done several times for Clostridium difficile infections and this has worked in human populations where people who are suffering from Clostridium difficile, which is a pathogen that goes into the intestine and basically causes a lot of diarrhea and pain for a lot of people. They can get rid of the infection simply by taking a person who's not infected and performing a fecal transplant. So people are starting to think about these things when it comes to disease like Inflammatory Bowel disease. It's just replacing the bad organisms with good ones from other people.

Julie Kiefer: So it looks like we may be on the cusp of some big changes in how we deal with IBD and similar diseases. Do you think that's true?

Dr. June Round: I absolutely think that's true. Yes, I think the old way of going in and just obliterating all the microbes with antibiotics is hopefully going to be a thing of the past and that we're going to start to better understand how we've co-evolved with our commensal microbiota. Then we'll start to use them as kind of natural therapies.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.