[Home] [Headlines] [Latest Articles] [Latest Comments] [Post] [Sign-in] [Mail] [Setup] [Help]
Status: Not Logged In; Sign In
|
Health See other Health Articles Title: The Microbiome: Linking Bacteria, Health, and Disease Medscape: I'm Dr. Robert Rickert, Professor and Program Director in the Infectious and Inflammatory Disease Center at Sanford-Burnham Medical Research Institute. Welcome to this segment of Developments to Watch, from Sanford-Burnham and Medscape. Today, I will be talking to my colleague, Dr. Scott Peterson, Professor in the Center, about the work that he and his team are doing in studying the interactions between the microbiome and health and disease. Now that many of the trillions of microbes that live in the human body have been characterized and categorized, Scott and his team are working in a variety of settings to try to understand how these microbes influence normal and abnormal human conditions -- from changes in body weight to cancer -- and are looking for ways to use this information to improve human health. Scott, could you tell us what roles microbes play in keeping us healthy? Scott Peterson, PhD: That's a very refreshing question, because so much of the focus now in the human microbiome research area has to do with its role in disease. In my way of thinking, that is only just half the story. The answer to that question is still largely unknown. We don't fully appreciate the details of what makes microbes keep us in a state of health. But what we do understand is that for them to occupy our bodies and live in concert with us as their human host, microbes need to pay their dues. They need to either supply us with something that's beneficial, or they need to support other bacteria that live in or on our bodies to enable their existence and selection to coexist with us. It's through that set of assumptions that these organisms are living in a mutualistic relationship with us, and on that basis we assume -- and I think rightly so -- that they're providing a health benefit. We have some limited number of examples so far. We know that there are certain vitamins that microbes make -- xenobiotics, probiotics -- that provide a health advantage to the human host. But we largely don't understand the details of how deep that health benefit goes. The dental community was among the first to really appreciate the role of the microbiome (although it wasn't called that), with the idea of polymicrobial disease and the impact of microbes on dental caries. Association studies more recently revealed, maybe for the first time, that humans who were in a caries-free health state had certain species of bacteria that were more abundant or more prevalent than in those who were caries-active and in a state of disease. Dr. Rickert: So there were clear disease associations? Dr. Peterson: That's right. This is what we really need to appreciate. The fascination and the real power of this notion of human health in the microbiome relationship stems from the fact that we know that microbes and the genes that they encode are enormously diverse -- oftentimes, through biochemical pathways that are unique to a particular species and not expressed in any other life forms. When we consider that the human genome has something on the order of 30,000 genes encoded, the typical microbiome in a particular body site, such as the oral cavity or the human gut, will encode 3 million to 10 million genes. So we really have an enormous capacity for expression of genes and potential therapeutic compounds coming from the microbiome. This is what I hope to focus my attention on -- not only disease, but also the potential for harvesting the health benefits of the microbiome. Dr. Rickert: Can you give us some examples of your current research? Why We Develop Dental Caries Dr. Peterson: My first experience and what attracted me to the microbiome project to begin with was that of the dental caries problem. There was a very clear cause-and-effect relationship that has been established for that particular disease. It's about pH. Maybe I can illustrate here for you to make it clear. If we draw an axis here, with this being time and this being pH, we have a microbiome on the tooth surface that has a pH just about neutral. I'm going to draw another mark here at a pH of 5.5. The significance of this particular pH is that we know that when the pH of the tooth surface goes below 5.5, you start to have enamel erosion. That's what a cavity really is -- the reduction of calcification on the tooth. So within minutes after consuming a meal, the microbiome goes to work eating furiously. That reduces the pH of the environment immediately, and it will dip down. Over the course of time, it will come back up to its original state. This all transpires in about 60 minutes. Now, we know what the healthy profile looks like -- notice that it doesn't go below this 5.5 pH range. But when a person is starting to develop caries or actually has an active caries lesion, their basal pH before eating a meal is reduced. As they eat, it dips under this line. The time that it spends under this line, of course, influences the rate at which you might develop disease. In extreme examples, a person may live at a baseline level that's very close to this and spend a significant amount of time following a meal below this key pH. Dr. Rickert: This, of course, is greatly affected by the diet one chooses. Dr. Peterson: That's part of it. Your mother knew best. She told you to brush your teeth after a meal and to avoid sugar. All of these things are very much related to what we understand now about the disease. It's through this that I became so impressed by the extraordinary power of the microbiome to influence something as simple as pH. It gives one a very clear way of approaching a problem, because we know it's about that. This is quite different from infectious agents, where we think of an etiologic agent being a single entity. Here, we're talking about a community. This particular community is made up predominantly of organisms that really know how to utilize sugar. It's through that utilization of sugar that the pH is so tremendously affected and how it can cause disease. What we're trying to do is make use of twins -- both monozygotic and dizygotic twins -- who were reared in the same homes eating the same diet (for the most part, these are children) in areas where there's no fluoride in the water system. Dr. Rickert: Why would that be important -- that there's no fluoride in the water system? Dr. Peterson: In general, the most informative studies that one can do in any kind of microbiome are longitudinal studies, because one wants to track the progression of the microbiome as an individual transitions from a state of health to a state of disease. Many human diseases can't be captured in the time frame of typical funding. Without fluoride in the water, it's very common that, if you enroll 100 kids into a study, 25 of those kids will develop caries over the time of your study. So the longitudinal aspect of our studies gets greatly powered by that reality. On top of that, we're including twins. By controlling for the genetics of your host environment, as well as environmental factors, such as diet, we can narrow the number of confounding effects and study the impact of the microbiome and how it changes from the state of health to that of disease. These kids are discordant -- one twin pair is caries-free, and the other one is caries-active. They're remarkably similar when they're both caries-free or both caries-active, but when they diverge their phenotypes, that's when we see differences in their microbiomes and how we can start to attribute relationships between particular species in the microbiome and disease. Dr. Rickert: That's a very good example. Could you give us some other examples of your current research that address that topic? Do Antibiotics Influence Obesity? Dr. Peterson: Another study that we're involved in with scientists at New York University involves the study of obesity and the relationship with the gut microbiome.[1] This was prompted by a collaborator's understanding or recognition of the fact that in the agricultural industry, for more than 50 years now, they've been feeding livestock low doses of antibiotics. That had the effect of increasing their body mass. This was an agricultural trick that has obvious economic utility, but he got to wondering whether that could be used to establish a model of obesity in mice. So he developed a mouse model in which they fed mice low doses of antibiotics from a young age. Sure enough, they developed an increased fat percentage in their body. Their weight actually doesn't increase as a result of the antibiotics, nor does their lean body mass, but their fat content and the percentage of fat in their body increases. Dr. Rickert: So the mice are getting obese? Dr. Peterson: Essentially, they're getting obese, and it's through this connection of altering and influencing the microbiome, through that low dose of antibiotics. It's not wiping it out, but just altering it enough that it's affecting the metabolism within the gut as a result of the change in the bacterial population. That affects the human host in the form of obesity. This is a fascinating study. We're learning a lot about things that have previously not been recognized from the host perspective -- it is much better understood what happens in the obese individual compared with the lean individual. But connecting it now to the microbiome as a major influence of obesity is a new thing. We really are pleased with our initial findings with this antibiotic-treated mouse model. Connections Between the Microbiome and Colorectal Cancer Dr. Peterson: A third example also involving the gut microbiome is a study we're involved in with Johns Hopkins University, in which we're studying the microbiome and its relationship to colorectal cancer.[2] The study design we're using there involves looking at the microbiome that is physically associated with colon tumors and comparing that with the microbiome that exists in healthy tissue flanking that tumor by a few centimeters. So we're within a single individual comparing physically close relationships of microbiomes. We see both tremendous similarities as well as some conspicuous differences, depending on whether the population is associated with a tumor or not. We've identified a few unique species that appear to be associated with the tumor itself and not associated as strongly with the healthy flanking tissue. What we don't know, and what oftentimes gets to be a problem with microbiome research, is the chicken-and-egg issue. Does the change that we observe reflect the fact that there's a disease state, which then alters the environment and the microbial population that's resident there? Or does the change in the microbiome population have some influence on the progression or onset of a disease? That's a question that I think we'll wrestle with over the next several years. Dr. Rickert: So it seems to be a 2-way street -- the microbiome is affecting the tumor, and vice versa? Dr. Peterson: Right. One of the important things -- and I think of it as a consolation prize -- is that we win either way, because we also have interest in finding diagnostic biomarkers for disease. The dental caries issue is a very good example. In these longitudinal studies, we see the progression of events that lead to a caries-active state. So we can start to define molecular markers -- proteins, RNA, or DNA -- that represent early stages of disease onset. For colorectal cancer, it's a lot more difficult to do longitudinal studies, but we still have this notion that we can use the bacterial populations as a set of biomarkers that could potentially represent very early diagnostic indicators. We have really good reason to believe that these will be powerful tools, because we know that bacteria are extraordinarily responsive to their environment. Their fitness is easily affected by just small changes in the microenvironment. So the idea that a disease state could influence what's selectively advantageous in terms of that microbial population becomes something very plausible for us to hopefully find early diagnostics that could save a lot of lives. Applications for Clinical Practice Dr. Rickert: What's the potential for integrating your research into the clinic, and what do you think some of the obstacles might be? Dr. Peterson: One of the most exciting stories that I've heard in a very long time represented an event that took place in a hospital. A woman who had a serious Clostridium difficile infection had lost many, many pounds and was very close to death. Because she was in such a critical state, her clinician decided to try something radical, which was a fecal microbiome transplantation.[2] He took the fecal microbiome from her husband and implanted it into her colon. Remarkably, whereas antibiotic treatment completely failed in this particular patient, the microbiome transplantation allowed the woman to recover within days to a state of health. She was literally near death and within 48 hours was showing a remarkable improvement in her state, just as a result of this microbiome transplant. That's one example. I think the critical nature of that particular case allowed the clinician to take this radical approach, but with so many diseases of the gut, such as Crohn disease, inflammatory bowel disease, and irritable bowel disease -- all of these seem to me to be practical applications for a similar type of treatment. The list can go beyond the gut as well. The idea that this would gain acceptance as a routine practice and get US Food and Drug Administration (FDA) approval is the challenge. Of course, it will require animal model testing and all sorts of things that clinicians as well as basic scientists are used to engaging in. It's a process. With respect to the sort of therapeutic compound approach that I referred to previously, that's another mechanism where I can imagine the microbiome basic research programs entering into clinical practice. If my notion is correct, then there will be lots of drug-like molecules that are produced by the microbiome. The difficulty is, again, the complexity of the microbiome -- there are hundreds and hundreds of species living in a particular environment. We need to develop methods and mechanisms for identifying which microbes are producing therapeutic compounds -- those that can improve human health or help to maintain human health, in the same way that we think of vitamins and herbal remedies helping to sustain human health. Then we can learn to recognize those molecules and find ways of harvesting them from the particular bacteria that produce them in the first place. Dr. Rickert: So a challenge for the future would be to identify some of those natural products that would have these abilities? Dr. Peterson: Exactly. Very typically in science nowadays, as you start to become interested in a field, you open your eyes and realize that there are people already out there who have a head start and who have been studying natural compounds. All of the things are in place for this to take off. It's not a grassroots effort in that respect. It's a matter of connecting the right sets of expertise, and we're in a fantastic place in time to be able to do that and make good on that idea. Dr. Rickert: As you can see, the work being done in the laboratory today is a first step in bringing new treatments to the clinic. Thank you for joining us today. I hope you'll join us for additional programs in the Developments to Watch series on Medscape. Post Comment Private Reply Ignore Thread
|
||
|
[Home]
[Headlines]
[Latest Articles]
[Latest Comments]
[Post]
[Sign-in]
[Mail]
[Setup]
[Help]
|
||