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Dr. Campsen: There's a new treatment available for hepatitis C without the horrible side effects, and we are preventing the recurrence of hepatitis C and the need for retransplantation of the liver due to reinfection. I'm Dr. Jeffrey Campsen. I'm a liver transplant surgeon at the University of Utah, and that's next on The Scope.

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Dr. Campsen: I'm here with . . .

Dr. Gallegos-Orozco: Dr. Juan Gallegos-Orozco. I'm an Assistant Professor of Medicine at the University of Utah School of Medicine, and I'm part of the liver transplant team.

Dr. Campsen: Juan, thanks for joining us today. The study that we're talking about today is a study that we're involved with for our patients that are receiving liver transplant for hepatitis C. What's exciting about it was that it's never been available, especially in the state of Utah, and its available now to our patients as a trial. The way that the trial is set up is that these patients are listed for liver transplant because of their cirrhosis, but they also have a Hepatitis C infection. They also probably have had a cellular cancer on top of it. They are then treated with the antivirals that you described, and hopefully the hepatitis C virus is cleared down to an undetectable level. At time of transplant, they receive their liver transplant and are given an immunoglobulin called Civacir that then continues after transplant. Hopefully, in combination of the antivirals before transplant, the liver transplant, and then the immunoglobulin after transplant will keep them from ever having hepatitis C again.

Dr. Gallegos-Orozco: Yes. This strategy is very exciting because following the footsteps of the hepatitis B immunoglobulin, which are antibodies against hepatitis B and was a big step forward in transplanting patients with hepatitis B, which is another kind of viral infection that can also cause chronic hepatitis, cirrhosis, and liver cancer. In hepatitis C, we're following this strategy, and our goal is to prevent the reinfection of the new or healthy liver that's being transplanted. The way we achieve that, like you mentioned, is not only with treatment before the transplant, but also with this immunoglobulin or antibodies against hepatitis C in an effort to neutralize any residual virus and, hence, preventing the reinfection of the transplanted liver. We hope that this strategy, in combination with the antiviral therapies, will ultimately lead us to prevent infection of hepatitis C, which, as you know, is a big problem in transplantation.

Dr. Campsen: It's a huge problem. So if you get a liver transplant and then the Hepatitis C comes back, it's basically a brand new infection in the liver transplant. It can really blossom to the point to where those patients won't survive the year after the liver transplant because the virus is so aggressive in how it comes back, which is demoralizing and tragic to everybody involved.

Dr. Gallegos-Orozco: I agree.

Dr. Campsen: Let's talk about this study. We started this study this past year, and we enrolled our first patient in the study. Can you tell us a little bit about him?

Dr. Gallegos-Orozco: Yes. This gentleman that we enrolled was a patient with chronic hepatitis C. He had developed cirrhosis and complications of his cirrhosis, and one of those complications was liver cancer. The patient was listed for liver transplant, and we followed him very closely during his course. We treated his liver cancer successfully, but he still required a liver transplantation. We knew that he had hepatitis C. He had the genotype one, which is one of the most difficult genotypes of hepatitis C to treat, and we were fortunate enough that we were able to get him through treatment with these new antivirals that did not require any interference. Just the combination of two pills that he took everyday for several weeks were good enough to decrease the amount of virus in his blood to basically undetectable levels.
At that time, a liver became available, and he was transplanted successfully with this healthy liver. Because of his participation in the trial, he also received this hepatitis C immunoglobulin or antibodies against hepatitis C, and he's completed the first six weeks of this treatment after transplant. So far, there's been no evidence of recurrence of hepatitis C in his blood, and his liver graft is doing very well.

Dr. Campsen: How exciting is that? Basically, what we did was we cured the hepatitis C if you can use that word. It's a strong word, but that's what I believe. We also cured him of his liver cancer, which is something that you probably couldn't have done a year ago.

Dr. Gallegos-Orozco: Correct. I agree, and I think that's a very exciting time, not only in the treatment of the hepatitis C overall, but certainly in the treatment of hepatitis C in our liver transplant patients.

Dr. Campsen: As with any medical procedure, there are concerns as to the safety of the procedure. Liver transplant in and of itself is a high-risk procedure. At the University of Utah, we have excellent outcomes, and our patients have done very well. However, when you add other new medications on top, there's a concern. Specifically for the Civacir trial, the hepatitis C immunoglobulin trial that we're speaking about today, I feel that it is a very low-risk procedure. How do you feel about it?

Dr. Gallegos-Orozco: I agree. So far, the evidence of the side effects from this clinical trial that we're participating in have shown that this procedure is safe and very well tolerated. It basically requires the patients that are participating to receive this immunoglobulin after an IV infusion, and they do that for several times during their first few weeks after liver transplant. So far, they've tolerated the procedure well. It hasn't been associated with any significant adverse events, and we feel that it's similar to the hepatitis B immunoglobulin and other types of antibodies that are used in medicine that overall it's a safe procedure. Of course, in the setting of the clinical trial, we're very vigilant about side effects, and we monitor our patients very, very closely.

Dr. Campsen: We're one of the centers that are involved in this trial. I think there's about 20 centers across the United States that are involved in the trial, and they're seeing very similar results to ours. Which are one, the safety profile of the drugs seems to be excellent, and then, two, the efficacy, meaning does it actually work, also seems to be very good. There are different arms of the study, but the study arms where the patients are actually getting the drug that we're talking about, no one's had a recurrence of the virus, which, I think, is an excellent result.

Dr. Gallegos-Orozco: I agree, and definitely, that's what we're wishing for with this, hepatitis C antibodies to prevent reinfection of the liver. So far, that's what the trial has shown.

Dr. Campsen: But with any study, it's the long-term follow-up that really makes the difference. So today we're talking about the early success of this, how excited we are to do something that we've never been able to do before, but, again, we're going to monitor it at a university setting along with our other universities that are involved and see if it truly is a therapy that will be used long-term.

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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.

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