Print BCTV: Microbiome Secrets -- NIH's human microbiome project; links to obesity, cancer

Microbiome Secrets

Transcript of BioCentury This Week TV Episode 151




Dr. David Relman, Assistant Professor of Medicine, Stanford University and President of the Infectious Diseases Society of America

Dr. Martin Blaser, Frederick H. King Professor of Internal Medicine and Chairman of the Department of Medicine, New York University

Dr. Christian Jobin, Associate Professor of Medicine, University of Florida




Max Planck Institute

Human Genome Project

Human Microbiome Project




Steve Usdin, Senior Editor




STEVE USDIN: Your body is home to trillions of bacteria. This week, exploring the microbiome's role in health and disease. I'm Steve Usdin, welcome to BioCentury This Week.




NARRATOR: Your trusted source for biotechnology, information, and analysis, BioCentury This Week.


STEVE USDIN: Our bodies are teeming with microorganisms. A healthy adult is home to ten times as many bacterial and fungal cells as human cells. Until recently, scientists and physicians thought the only good bug was a dead bug. Now, researchers who study the microbiome, the microorganisms that live in and on all of us, are learning that bacteria, fungi, and other microscopic organisms are essential for good health.


To study the microbiome's role in health and disease, NIH has launched a human microbiome project, and is funding hundreds of microbiome studies. This week, we'll hear from three researchers who are pioneering the exploration of the human microbiome, David Relman, a Stanford University Professor and President of the Infectious Diseases Society of America, who will provide an overview of the microbiome.


New York Professor Martin Blaser will discuss how the extinction of ancient bacteria in the stomach may be contributing to the explosion in obesity. And we'll explore the connection between the microbiome and cancer with Professor Christian Jobin. I'm pleased to be joined by Dr. David Relman.


Dr. Relman, when babies leave the womb, they don't have any bacteria in them, they don't have any fungi in them. How is it that they go -- that we go -- from having no microorganisms living in us, to these kind of super organisms that are teeming with pounds of bacteria and fungi?


DR. DAVID RELMAN: It's an abrupt event. We leave the body sterile, or culture negative, as a microbiologist might say, and suddenly, within a day, we're covered and filled with billions of organisms.


STEVE USDIN: So I guess there's-- beyond the fact that it's just tremendously interesting, and we want to know about who we are-- that's one reason to study the microbiome-- but I think the bigger reasons why most people are interested in it is either, because they're interested in its role in promoting health, or in promoting disease. Kind of starting with the health side of it, what do you think? What is the, kind of, the interaction of the microbiome and health?


DR. DAVID RELMAN: We're learning a lot about this now. We have known for some time that the microbiome plays critical roles in nutrition and digestion of food. But now it turns out that the microbiome has, all along, been involved in a whole bunch of other beneficial events, like educating our immune system, helping our body differentiate and develop after birth, preventing it and protecting it from invasion by pathogens, by disease causing organisms, co-regulating our metabolism.


So these are things that some of us hadn't really even thought about, attributing to our microbes. When, in fact, they're playing critical roles in these processes.


STEVE USDIN: So the NIH had this project, the Human Microbiome Project. It's a little bit like the Human Genome Project. It was a mapping project, where they used advanced gene sequencing technology-- you were involved in it, and many other scientists-- to create this map of kind of reference microbiomes. What did we learn from that?


DR. DAVID RELMAN: We learned a number of important things, although first steps. We started from the idea that we are actually partners with trillions of organisms, about which we knew very little. So step one was to ask, who's there? Who lives in and on the human body? Who are these friends of ours that have been friends for so long, about which we knew nothing?


And so that was Phase 1 -- name those organisms, name their nearest relatives, learn a little bit about their genetic potential, which is this idea of sequencing their genomes. But now, I think, in Phase 2 and what will be Phase 3, and Phase 4 and Phase 5, we're going to have to be asking the harder questions, which are, what are they doing?


For whom are they doing it? For themselves, or for us, or both? And I think it will be that latter answer. How are they doing these things? How do they talk to each other? How do they talk to us? What's their communication system? What language are they speaking? And then finally, what is it we can do about this to enhance these beneficial properties, or restore them if they're lost?


STEVE USDIN: Well, and that's kind of a natural question. It seems like we've got all these bugs in us, and we have an idea that they're doing good things. We take antibiotics. We have other environmental exposures that hurt them. What are the things that we might do that might help them?


DR. DAVID RELMAN: Well, step one could be to ask, what is it that they need in order to do these good things for us? How can we support their efforts? And this is something that we had never really thought about before, because previous to all this, the only good microbe was a dead one.


So now we're trying to think on their behalf. So we know, for example, some of the kinds of nutrients they need, some of the kinds of environmental conditions they need, and some of the things that are harmful to them that we could avoid.


STEVE USDIN: So one of the things, I think most people watching the show are familiar with the idea of probiotics, they're widely marketed. Is there any reason to believe that those products are actually, are they helpful? Are they going to be--


DR. DAVID RELMAN: Yeah, it's an interesting issue today, because we desperately would like to be enhancing this incredibly interesting, complex attribute of humanness. And I think that the concept of probiotic certainly makes sense, and will play out. But my hesitation would be that today's probiotics are largely products from hundreds of years ago, when they had a role in food processing, and may not be actually the key organisms that we most want to be using today.


STEVE USDIN: So the short form on that is, you don't think that there's any reason to believe that these particular products are the right ones for helping the organisms?


DR. DAVID RELMAN: They may not be the optimal ones. I think they do, in some specific circumstances, provide some benefit. But we can do much better.


STEVE USDIN: One of the other things that is really interesting to me is that, the microbiomes between two individuals, like with between you and I, are tremendously different. How do you make sense of that? And how could the microbiome be so important if everybody's microbiome is so different?


DR. DAVID RELMAN: Yeah. Well, so part of it is that we began this whole process by asking, who is there? And then, as I mentioned, we're now asking, well, what are they doing? And I think that's the answer to your question. Even though the two of us have communities of organisms with different names, they tend to be doing the same kinds of things.


The reason why you appear to be quite healthy, probably would tell me that you are healthy, and I feel the same way, and yet have different organisms is that, the key functions that they're providing to each of us are the same-- different names, same services, same functions. And yet, even still, each of us has organisms that are doing slightly different things.


STEVE USDIN: Well thanks. That's really fascinating. Next, Dr. Martin Blaser's colleagues initially dismissed his theories about bacteria and obesity. Now NIH has awarded him over $1 million to study the link between microorganisms and weight gain.






STEVE USDIN: To discuss how the community of bacteria in the human gut may affect obesity, I'm pleased to be joined by Dr. Martin Blaser. Dr. Blaser, you started out your career figuring out how to detect and eradicate bacteria, especially bacteria called H. pylori that causes ulcers. How did you switch from that to thinking about how bacteria in the gut might be necessary for health?


DR. MARTIN BLASER: As you said, we've been working on helicobacter for almost 30 years. And the initial work was to try to figure out, is helicobacter good for us or bad for us? And initially, like everyone, we focused on the bad of helicobacter. And we did a lot of work showing that helicobacter actually increased the risk for stomach cancer.


But the more we studied helicobacter the more clear it was that this is an ancient organism. It's been around for a long time in many people. And I began to think, maybe helicobacter had some benefit. And we did studies looking at some other diseases that have recently been rising, like diseases of the esophagus, like reflux, and asthma.


And we found that helicobacter was beneficial in these diseases. That made me think that maybe there are some other organisms that are going to be beneficial, also.


STEVE USDIN: So going from that to the work that you've done on the microbiome and obesity, what is the connection between the microbiome, between the bugs that are living in us, and obesity?


DR. MARTIN BLASER: Well, almost 70 years ago, farmers discovered if they fed very low doses of antibiotics to farm animals, their animals would grow. This is what farmers call growth promotion. And the reason they do it is because it works. It works from chickens, to cows, to pigs. And the younger in life they start the animals on it, the greater the effect.


And so I thought, well, if that's happening on the farm, maybe all of the antibiotics we're giving to our children are having a parallel effect. And that's why we decided to study it.


STEVE USDIN: And you studied it first in mice. What did you find?


DR. MARTIN BLASER: We did very simple experiments, where we would put an antibiotic, like penicillin, in the drinking water, versus no antibiotic. And we would observe the mice.


And we found that, like on the farm, they got bigger. They got bigger, more muscle, more fat, it changed their bone growth. And we saw that they could get actually very fat. And so we were able to see that using antibiotics to change the microbiome actually affected how fat they became.


STEVE USDIN: And that's looking at large quantities of antibiotics, right? But you've also done work looking at smaller quantities, more like what human infants might exposed to, and also maybe what we might be getting exposed to in food, right?


DR. MARTIN BLASER: Well, we've done, actually, two different kinds of experiments. One, we've used low doses, constantly, like they do on the farm. And we can show that the animals get fat. And then we've developed another protocol, where we're trying to treat the mice as if we were treating their ear infections, like they were kids. And we were giving them pulses of antibiotics. Just like we were treating their ear infections. And they're getting fat, too.


STEVE USDIN: So you've got that happening in mice. And the natural question, then, is mice aren't furry little people. We're different. What's the connection? How do you make a connection between that research and what might be happening in humans?


DR. MARTIN BLASER: Well, again, I go back to the farm. The farmers have shown it's true for chickens, and turkeys, and cows, and pigs, a big, wide swath of vertebrate evolution. Humans are right there in the middle. Here, in mice, we're trying to figure out what are the principles that are involved?


Is it through metabolism? Is it through immunity? Is it through hormones? And we're working on all of these aspects. But we've also done epidemiologic studies. We've worked with a group of scientists in England who enrolled a cohort of more than 10,000 children in the early 1990s, and then followed them for many years.


And some of that work has also shown that the kids who got antibiotics in the first six months of life, are more likely to have signs of obesity when they are seven years old, than the kids who did not have antibiotics.


STEVE USDIN: That's an enormous time difference, also, from six to seven. So are you thinking that their microbiome, the bacteria in their bodies, was permanently perturbed by early exposure to antibiotics.


DR. MARTIN BLASER: We can show in mice that early life antibiotics are causing permanent perturbations. And it makes us wonder whether the same things are going on in children.


STEVE USDIN: So then, what do we do about it? You can't stop giving kids -- I mean -- you can stop the overuse of antibiotics, but you can't stop the use of antibiotics. They're critical for stopping infections that are deadly.


DR. MARTIN BLASER: Well, just as you said, just about everybody agrees that we are overusing antibiotics. And the question is, how much are we overusing? Some people think we're overusing it by about 80%. So the first place to start is to stop using so much antibiotics for minor illnesses, in which kids are going to get better anyhow.


And everybody's using them because they think there's no cost to antibiotics. That there are no long-term side effects. But if they are, people may start to reconsider whether maybe they should wait another day when their child has a fever, and see if they'll get better. Once you start understanding that there's a biological cost to antibiotics, you see the world a little differently.


STEVE USDIN: So very quickly -- we just have a little time left -- what about the exposure through food, through animals? You said all these animals are getting antibiotics. Is that a concern?


DR. MARTIN BLASER: Well, on the farm, they are supposed to have a washout period. So that between the time of the antibiotics and when they were slaughtered and go to the grocery stores, there are no antibiotics. It's supposed to washout. But we know from many surveys that there are antibiotics in meat, in milk, and some of our drinking water.


STEVE USDIN: So Dr. Blaser, you've talked about the effect of low doses of antibiotics on farm animals, how are humans exposed to antibiotics, besides the therapeutic exposures, besides the pills that we take?


DR. MARTIN BLASER: Well, our kids are exposed -- the average child in the United States is probably getting three courses of antibiotics in the first two years of life. By the time they're 10 they probably get about 11 courses of antibiotics. It's a lot.


But we're also getting antibiotics from the use on the farm, some of the meats in the grocery store, milk has residual antibiotics. In some communities, the drinking water has antibiotics. So there's a very low level of antibiotics from these. But we have no idea what the consequence of that is.


STEVE USDIN: Has anyone done, or tried to do, any kind of sampling so you could look and see what the effects, acutely or chronically, on the microbiome are from this low level of exposure to antibiotics?


DR. MARTIN BLASER: As far as I know, no one has -- people have shown that they can be present -- but no one has shown what the consequences are.


STEVE USDIN: And what about comparisons between people in the United States, say, and people in Western Europe, or in developing countries, where the exposures to antibiotics would be quite different?


DR. MARTIN BLASER: Well, in Europe, they banned the use of antibiotics for growth promotion on the farm. And so the European consumers wouldn't be getting it in their meat. And in developing countries, it's paradoxical because in many places, antibiotics are available without a prescription. You can just go into the local grocery store and buy antibiotics. So there's a lot to use.


STEVE USDIN: So one of other things I wonder is, does it make sense to also start looking at using narrower spectrum antibiotics that are more targeted to pathogens, and less likely to hurt the bacteria in your body that you don't want to kill?


DR. MARTIN BLASER: I think that's exactly where the field is going. We will have to develop narrower spectrum antibiotics so that we can avoid all the collateral damage from the broad spectrum antibiotics. That's a completely different economic model.


There's really no incentive for manufacturers to make these narrow spectrum agents. They all want to make the broad spectrum agents. So we're going to have to change public policy.


STEVE USDIN: Well, doesn't it also require much better diagnostics to be able to know which pathogens, in particular, to target?


DR. MARTIN BLASER: It will definitely require better diagnostics. And that's going to be part of the challenge in the future, as well.


STEVE USDIN: Do you think that there could be a connection between the microbiome and adult obesity?


DR. MARTIN BLASER: We have rising trends for both childhood obesity and adult obesity. And in many cases, we know that the adult obesity is starting in childhood. So I think that there is definitely a connection. And what is going on in early life may be very important for life decades later.


STEVE USDIN: Coming up, the microbiome and cancer.






STEVE USDIN: We're talking with Dr. Christian Jobin about the connections between the microorganisms in the human body, and cancer. So, Dr. Jobin, how could microorganisms in the body, bacteria or fungi, how could they affect cancer?


DR. CHRISTIAN JOBIN: Well at this point, if we're talking about microbiome, the most evidence we have is bacterial microbiome, so let's focus on that. It's either their number that is out of whack with what they should be -- so there's an increase, expansion, of microorganism that suddenly produces either toxin, or a product that can hit the host DNA, which we need to keep intact. And if you introduce mutation, this could lead to cancer. So these microorganisms may be secreting toxin that hit the host and increase cancer susceptibility.


STEVE USDIN: And I understand the one where there's the most evidence for that kind of a connection is with colorectal cancer.


DR. CHRISTIAN JOBIN: Colorectal cancer. We have from the sequencing enterprise with the microbiome we have association, what we call dysbiosis. So microorganism that are expanding in a cancer patient, a different grade of cancer. So pre-cancer to tumors -- full tumors -- different microbiome compared to a normal healthy subject. Now those are associative disease connections, so you don't have a cause affect.


STEVE USDIN: So that leads to the question, do you know, is it the disease that's changing the microbiome? Or the microbiome that's changing the disease? Or perhaps the drugs that are being used to treat the disease that are changing the microbiome?


DR. CHRISTIAN JOBIN: Exactly. So at this point, you need to have an animal model. Right now with a human, you can only make this connection and take an educated guess on these microorganism and go back to prove a principle, that they could cause cancer. So you need an animal model where you could introduce a specific group of bacteria that you identify in this patient. Either a clinical isolates that you got from the patient, introduce it to an animal model, and look at the evolution.


Do they have cancer? Which kind of microbiome are you going to get if you introduce this bacteria? And which mechanism is it? The DNA damage that I was talking about the beginning, is it a susceptibility to instability of cancer of DNA integrity? And that will be your cause-effect with the animal model.


STEVE USDIN: And so how far along are you? Do you have an animal model for colorectal cancer and the microbiome?


DR. CHRISTIAN JOBIN: Yes we do. I mean, investigators have their own pet model. So they use different models. So there's no single flagship model of colorectal cancer. We use an animal model that introduces inflammation as one of the driving force of cancer. And if we do that, we identify a simple bacteria that everyone knows, esherichia coli.




DR. CHRISTIAN JOBIN: E coli, that all of us have. The beauty of, I think, these analyses is that in colorectal cancer, and susceptibility to bacteria induced cancer, we have an enemy within. So these bacteria stay within us, they don't cause anything. But they could be awake by an environmental trigger -- inflammation, treatment, lifestyle -- and suddenly, they become more prominent in your environment, there's more of them, and they produce toxin.


So what we have, in our animal model, we were able to reproduce that. An expansion of microbes that are believed to be benign -- commensal -- but if they interact with the host the wrong way, which will be very close to the bowel, and produce this toxin, because they are out of regulation and this toxin causes cancer, then you have the sequence from dysbiosis, microbial activation of genes, and the host responding in an aberration, which is cancer.


STEVE USDIN: So you've actually shown that disrupting the microbiome in a mouse can cause colorectal cancer?


DR. CHRISTIAN JOBIN: Right, in function of inflammation. So as the inflammation set in in that mouse, the microbiome changed its organization. So they have more of these these bugs, and then they could cause cancer.


STEVE USDIN: We'll continue the conversation about cancer and the human microbiome in a moment. First, a look at the diversity of the microbiome. Researchers at the Max Planck Institute found hundreds of bacterial species in the saliva of healthy volunteers. Here's a chart listing some. Those found in higher concentrations are larger.






STEVE USDIN: We're talking about the microbiome in cancer with Dr. Christian Jobin. Dr. Jobin, assuming that this disequilibrium of the microbiome does cause cancers like colorectal cancer, what would be some interventions that we could do, based on that information?


DR. CHRISTIAN JOBIN: Right. I mean, if we get into specific microorganism that comes in, could we trace or predict susceptibility? So if we have biomarkers and we see expansion of these microorganisms, one could maybe introduce what we think would be a change in microbiome composition with probiotics, maybe, probiotics with some diet.


If it was just to toss out, or eliminate this bacteria, which is very difficult with antibiotics, you could, but you would perturb the entire ecosystem. You don't want a nuclear bomb into that. If you more refine and find a toxin that is causing this cancer associative cancer, then you could target it, maybe, with a different molecular strategy.


STEVE USDIN: So you could say, for example, that the bacteria creating a certain metabolite that is in turn, promoting the cancer. And you might be able to find a small drug, small molecule drug that you could use to attack it? It could become a target for drugs?


DR. CHRISTIAN JOBIN: Exactly, neutralize the production of the toxin, either at the beginning, or neutralize the activity of the toxin, or prevent the toxin from adhering to a cell. So different ways along the pathway that you could intervene. And having this knowledge will be transformative for cancer.


STEVE USDIN: Now how big a role do you think environmental influences like diet have to do with changing the microbiome in ways it could cause cancer?


DR. CHRISTIAN JOBIN: Well, we know diet is associated with cancer. It's one of the risk factors, your lifestyle, especially red meat. So we have gathered data on diet and microbiome. We have not connected, very well, the microbiome diet and cancer. It's just you're just thinking about these three pieces. But there's no real sequence of events. But it will not be surprising that you could get a diet that enrich bacteria that cause cancer. We lacking the data right now.


STEVE USDIN: And I'm wondering also, going back to the earlier interview with Dr. Blaser, if there could be a connection between disruption of the microbiome that causes obesity and cancer, because there are connections between obesity and cancer?


DR. CHRISTIAN JOBIN: Exactly. Obesity introduces a wealth of differences -- inflammation -- obese people have a sub-chronic level of inflammation. They have a lot of metabolic disorder going on your hormone system. So all this good cause changes to microbiome, our own activity of the microbiome linked to cancer. So another layer.


STEVE USDIN: Well, thanks. That's this week's show. I'd like to thank my guests, Dr. David Relman, Dr. Martin Blazer, and Dr. Christian Jobin. Remember to share your thoughts about today's show on Twitter. Join the conversation by using the hashtag #biocenturytv. I'm Steve Usdin, thanks for watching.