>> From the Library of Congress in Washington, DC. ^E00:00:04 ^B00:00:24 >> Tomoko Steen: Welcome everyone, I am Tomoko Steen at Science Technology and the Business Division here at the Library of Congress. Today's event is sponsored by our division. It's my great pleasure to introduce distinguished speaker today, Dr. Giorgio Trinchieri. Dr. Trinchieri is the Director of the Cancer and Information Program and the Chief of the Laboratory of Experimental Immunology at National Cancer Institute. NCI is a part of the National Institute of Health, as many of you know and research focusing on the cancer is conducted. Dr. Trinchieri received a medical degree from the University of Turin in Italy in 1973. He was a member of Basel Institute for Immunology in Switzerland and investigator at Swiss Institute for Experimental Cancer Research. You can see the detailed biography in the handouts right there if you are interested and has also most recent publication on the reverse side. After moving to here in the United States Dr. Trinchieri and his team discovered a molecule called interleukin 12 in 1989. Interleukin is a key component for immune system. Especially this interleukin 12 involves managing infections and also autoimmunity. So for example, the MS, the multiple sclerosis and irritable inflammatory bowel disease type of mechanisms also involved by the interleukin 12. One of the most recent research he has been doing is human and all other animals gut system. In your gut system you have microbiome, there's a variety of bacteria in there in controlling your health. As an expert in immunology and also medical doctor, Dr. Trinchieri is today talking about your gut system, immunology and also cancer. So before further ado, please join me in welcoming Dr. Trinchieri. ^M00:03:31 [ Applause ] ^M00:03:39 >> Giorgio Trinchieri: Thank you Tomoko, thank you very much for inviting me here, thank you all of you for coming. And what we are going to talk today is the effect of microbiota on health and disease and I will try to introduce you with the meaning of microbiota and what can be used and this knowledge can be used in medicine, both for disease prevention and disease therapy. In the 17th century the Dutch drape maker, Antonie van Leeuwenhoek liked to play making lens and he build some of the first microscope that I show here. And by this small microscope was probably just giving of magnification if you fold, it was actually the first one to describe microbes just the way that he draw them and he look at in the plaque between his own teeth and the way he describe in the letters to the Royal Society in London is [inaudible] almost saw a great wonder that in said matter there are many little living animalcules, very prettily a-moving. So that was really the first description of microbes and the first description that this microbe can live actually in our body. We made big progress obviously in technology, we can look the microbes in our mouth, as well as other site of the organism. Microscopy has been advanced greatly and also for the ear, we learn how to culture the microbes, the bacteria in Petri dish, but even if this technology is improving very much, we can still only culture fractions of the bacterial species living in our body. So the real progress in understanding this population of microbes in our body and in general has been with the progress in DNA sequence technology in the last 10 years or so. Obviously, that technology was much very involved in the identification of the human genome and the human genes. And with this technology now we can really characterize the gene in the population of microbes and understand the old component regardless of the fact that we can isolate and grow them in vitro. So now we define as a human microbiota, the ensemble of microbes that resides in our body and the human microbiome is an ensemble of genes that are present in this population of microbes in the microbiota. So obviously there's been incredible progress, scientific progress since the 17th century to today. Obviously the good news that this new technology, molecular technology system biology, now we can really start to understand what value and [inaudible] under this primitive microscope. The bad news that this new technology generate an incredible number of information that become very difficult to interpret or analyze, we need really computer tool, bioinformatics tool to be able to understand and the task to identify this is really an enormous task. Still we made major progress in understanding the role of the microbiota both in health and disease, but if we really want a full understanding of the mechanism of the molecules that are involved and use that, apply that for prevention and treatment of disease, we really need to continue with larger study, in particular should be coordinated multidisciplinary effort because we need now different scientific disciplines to get together and allow us to understand this complexity. So I want just to give you an evolutionary idea what's happening is obviously the microbes and bacteria were the first organism present for billions of years on the earth and more than two billion years ago something happened and bacteria start to join each other, which is called an endosymbiont and form organisms to bacteria. And the cell type, the eukaryotic cell type is the one that formed all animal, including ourselves, they really derive from the fusion of a type of bacteria-like cell it was called archaea that phagocytose engulf and other bacterium that was able to fix oxygen and that become the [inaudible] eukaryotic cell and this allow our cell to utilize oxygen and to breath. And eventually these eukaryotic cells start to form multi-cellular organisms, the early metazoa. And these organism, primitive organism like still today will live really in a sea of bacteria, bacteria microbes are everywhere. So they form endosymbiont with the multi-cellular animal with bacteria and some bacteria will define as endosymbiont or commensal because they don't damage, but actually they have each other, they live together and they help each other. But some as we know, some microbes, some bacteria become pathogenic, they can cause disease and the organs need to defend against this disease in using microbes. And other that have been defined more recent, they're called pathobiont. Now pathobionts are microbes of bacteria, they are present normally in our body, but because of the equilibrium and the population of bacteria we have in our body, they don't create any problem. If this equilibrium is broken and this bacteria can then expand and become a larger number and change some of those genetic characteristics, they can become pathogenic, they can induce disease. Now the interaction between the host and the commensal, this crosstalk, especially in the early organism was very important for the metabolic regulation in the organism [inaudible] for the formation of the different organs, the different parts of the organisms. Regulate physiology in general, homeostasis and they're also involved because of the interaction between microbes and the organism in the mechanism of you're resistant to infection with a pathogen, those bacteria become able to induce disease. ^M00:10:00 And very early in evolution there was a specialized cell type that become very important, this type of interaction with the commensal microbes and the resistance to infection and these are the phagocyte. They were described by Metchnikoff in the 19th century [inaudible] as a mobile phagocyte. These are basically cells that are able to phagocytosis, they can engulf, they can eat, for example bacteria and destroy them. So they really play a major role in this crosstalk between the microbes and the organisms. And in our body now we know--I mean in medicine we now know this cell very well and they are called monocyte, microphage and neutrophage and other cell type. They play a major role in immunity to infection. Now when we move to this very simple early metazoa to the higher vertebrates in humans, there's this crosstalk between the commensal and the host remain very important. It plays a major role in the resistant immunity to infection, but still have a role in the regulation of our own metabolism, regulation of our physiology, homeostasis and minimal part, but still some role, in the formation of our organ in morphogenesis. So basically bacteria and other microbes live on all the barrier surface in our organism. Barrier surface are those like the skin, the lung or the intestine, those are the surface in which our organism communicated with the outside environment. And in all these surfaces there are microbes, there are bacteria, but they're all quite different in the different type of the body. So the mouth, pharynx and the lung, the respiratory system, they are different bacteria. They are present on the skin or present in the digestive system, in the gastrointestinal system. And in gastrointestinal system, particularly in the lower small intestine and in the column is where the larger mass and incredible mass of the microbes and bacteria in particular are and they play a major role in our interaction with this commensal bacteria. So we co-evolve with these microbial partners, we really have a composite of species. We have our own human cell obviously, but we also made of bacteria, archaea, fungi, virus, bacteriophage. As I mentioned, the [inaudible] all the body surface are organism and they actually outnumber the human cells present organism by about 3-10 fold. And if we look at the gene, they are DNA, they are microbiome that's contain approximately 100 times more genes than our own human genome. So the microbiome is really integral part, not only of our body because they live in our body, but our genetical landscape and our general regulation of our physiological equilibrium these homeostasis. So if we look at ourselves in the mirror [inaudible] microscope or something, we could see that our skin is really covered with bacteria. It's not something we should worry about, it's nothing something we should try to wash out. They are actually absolutely needed. We cannot live without our own bacteria and we should really look at ourselves as a metaorganism that is composed by our cells and this microbe and with their own gene, their process, their metabolism and they work in concert. In the metaorganism both our cells and the microbial cell acts as a sensor for change in the environment, that could be change in the temperature, changing in the type of food we eat, infectious agent and they exchange--they talk each other, they exchange information and they adapt, they have response. They're adaptive or have new response to the change in the environment. And what is important to consider that if the environment change our own gene cannot change, our gene are fixed, I mean they are very constant. But a microbiome can change because the microbiome is made by a hundred or a thousand of different species and bacteria and when the environment change, they can change their number, their proportion and, therefore, their genetic change completely and they can adapt and respond to the change in the environment. Now in this commensal crosstalk, in the last few years it has been clearly showed in the metaorganism they regulate many of the functions of the organism. I mentioned to you regulate metabolism, regulate cardiovascular and muscular function, has even been shown to have a role in regulating urological behavioral and cognitive function, it definitely play a role in aging, in the formation of blood cells or hematopoiesis, regulate what is called the [inaudible], the change in the physiology of organism through the day and particularly, regulate inflammation and immunity. And through this role inflammation immunity is clearly an effect on cancer initiation, cancer progression and response to therapy. The NIH recognized about six or seven years ago the important role of microbiome. They start a major project that was really to develop new technology and to catalog basically the bacteria present in our body. So this project they found that I think approximately 10 center, 1 intramural and 9 across the nation. And they characterize different sites of the body the type of microbe they have present on the body. So where we get the microbe? When we are born the fetus is actually sterile, there are not microbes in the fetus, but then at delivery the newborn acquire a bacteria. And the type of delivery affect the type of bacteria we get. So the vaginal delivery or the C-section because the newborn is disposed to different anatomical site in the mother yet colonized with different bacteria. So there are different [inaudible] in microbiota depend on delivery. But then during early childhood there is acquisition of many different species from different source, from the environment, from other people, from the family and there is a rapid change in diversity in the microbiota. But eventually when you get into adult age that gets sort of fixed and is maintained fixed until old age. But that can change, the [inaudible] can change it, disease can change it, obesity can change it. So there can be some variation, but it tend to be rather constant through life. It definitely change in old age and probably is associated with the aging process. So what can change our microbiota, our own genetic, our own gene is clearly affecting that. I mentioned the mode of delivery affect the composition of microbiota and the age affect microbiota. There is also major difference due to geographic variation and that can be for different reason, but geographic location usually affect the lifestyle, the nutrition and the hygiene and that is going to affect the composition of the microbiota. Also we can take food supplement like probiotics, we can treat with antibiotic if we have disease, especially infection, then they can affect temporarily and often permanently the composition of the microbiota. And that can bring to what is now defined as dysbiosis. That is an imbalance in the microbiota that change what is considered a normal healthy microbiota and that may often be associated with this different type of sickness or illness. So what the gut microbiota is doing, I told you metabolic function, for example they are involved in the synthesis of vitamins, the metabolism of bile acid and host hormones, fermentation of food, particularly of carbohydrates. But as I mentioned before, they are also important and resistant to infection and they can prevent by competing other organism, they can prevent colonization by pathogens or they overgrow this pathobiont, this normal microbe that overgrow can cause disease. They contribute 45 the barrier, the cells that divide, that line the gut and divide the lumen in the gut where bacteria are from [inaudible] organism that is supposed to be sterile. And they also signal to our own immune system and [inaudible] immune system for the immunity that give the resistance to the infection. So we look at the gut microbiota, I mentioned there's an effect on immunity that can be local in the mucosal immunity. It can affect the pathology, the level of the mucosa, for example the inflammatory bowel disease. It can have effect of distance, I mentioned metabolism, the gut microbiota has a major role in regulation of body mass because of obesity, metabolic syndrome, inflammatory metabolic syndrome, insulin resistant type 2 diabetes are very much connected to change in the microbiota. They also regulate systemically the immune system, developing the immune system and for example [inaudible] by the fact that the gut microbiota is needed in our lung to resist to flu virus infection. Without gut microbiota or ability in the lung to resist the infection like flu is very much decreased. ^M00:20:08 Also autoimmune disease, the disease in which the immune system attack our own organism and cause disease is in need of gut microbiota. For example, in autoimmune disease in the brain, in the joint or in the liver. What happens when we don't pay attention to the changes in the microbiota? If antibiotics are used at an early age, it's been shown to reduce dysbiosis and that may predispose to obesity, it has been clearly shown in experimental animal like mice. But then also [inaudible] data showed that infant less than six months get treated with antibiotic predispose them to an increased body mass by the time they get toddler and with increase of their weight and obesity. The other correlation is with allergic and autoimmune disease and for example there is a kid has been given certain antibiotic treatment have a significant increase in the risk of chronic colitis, inflammatory bowel disease. And if kid has been treated with more than five course of antibiotic that risk can be up to 3 fold increase, a major increase in this type of disease. And indeed inflammatory disease they affect the barrier tissue are on the raise. There is now in the states about 1.4 individuals suffer for a chronic colitis, 9 percent of the kids develop food allergy by age 5, and asthma affect 1 in 12 individuals. And so called the gene hypothesis, they think that we tend to eliminate exposure to bacteria or to use antibiotics and so on is considered one of [inaudible] change increase in this disease that is observed in US, in civilized country and less in underdeveloped country [inaudible], historical in humanity. So we really need to be careful of the way we change the microbiota and obviously antibiotic are needed, I mean we want to stop infection, disease, but they often, especially a broad spectrum antibiotic, they often kill beneficial bacteria together with a pathogen and one really have to pay attention to try to avoid that. So I told you we were going to talk about cancer. So cancer grow in our body and we are a metaorganism. So you can see that cancer is not only disease of the body, it is actually disease of all human metaorganism. And as you all know that the cancer cells have genetically modified, gene in the cancer cell are altered, there's oncogene, suppressive gene and suppressive tumor gene and this genetic change in the cancer cell is what makes the cancer cell grow faster and not being subject to certain growth--the ability to escape from growth control mechanism. However, the tumor cells will never grow in organism, never become a tumor and kill the organism unless it found the right environment, the right tumor micro environment and in this micro environment the inflammation and immunity play a major role in creating either a pro tumor or anti-tumor environment. And all of this, as I mentioned before, inflammation, immunity and the composition [inaudible] tumor micro environment, the fact that they are produced there are regulated, maybe moderately regulated by the microbiota, particularly by the [inaudible] gut microbiota. Saw today different effect of a gut microbiota mentioned before, we need now to add the effect of the gut microbiota on the tumor growth. We know there are bacteria that have been associated and been shown to be carcinogenic, the only one is actually officially accepted as carcinogenic by HHO is helicobacter pylori for stomach cancer. But other like Escherichia coli, fusobacterium has been associated and proposed to be important in the colorectal carcinoma. Infection, especially in the east country with the salmonella enterica seems to be associated immunological with the gall bladder carcinoma and there are a number, seven or more oncogenic virus or even parasite [inaudible] that can be associated with cancer and in general, about 16 or more percent of worldwide cancer are now known to be caused directly or indirectly by infectious agent, infectious microbes. In addition to that the gut is the ability to regulate the growth of tumor that are not infected, that do not contain bacteria and for example, they are [inaudible] at least in experimental animal for mammary breast carcinoma, for lymphoma, for sarcoma, for ovarian cancer in which the commensal microbiota can change. They grow the tumor and in general, someone can say that it is likely there's moderation of the gut microbiota of cancer progression, as well as on the response to immunotherapy and chemotherapy. Now all of that is because of the role that's been studied pretty much in the last 10 or 20 years, the role of inflammation and immunity in regulating the growth of cancer. And inflammation immunity really is involving the predisposing condition like obesity for example. Is involved in facilitating those genetic alteration that we see in the basis of these cancer cell transformation. But they're also involving promoting the growth of the cancer, disability to form metastasis, the type of immune response against the cancer that may have been used and also will describe you some of our study that involving regulating the way that the organism respond to cancer therapy and the way the therapy can be effective in eradicating cancer. And all of that, as I mentioned before, can moderate in different way by the commensal microbiota. So the way that we did to study the fact of the intestine microbiota cancer was to induce and grow a subcutaneous tumor in mice and then we use two type of cancer treatment. We use immunotherapy with a substance that's called a [inaudible] or chemotherapy using some of the chemotherapeutic agent that are commonly used in the clinics like the [inaudible] compound oxaliplatin, cisplatin. We treat the tumor of conventionalized mice or with mice in which we use a broad spectrum oral antibiotic to mostly completely eliminate the gut microbiota, the gut bacteria. An alternative if we use germ free mice. Germ free mice is mice that are kept from their birth in a completely sterile environment, so they are not associated, they have no bacteria, no germ that live in them. This is a type of response which we are showing here is the survival of mice with tumors. If we don't treat them in this type of tumor, I'll show you on the left for the immunotherapy, they die in about two or three weeks all of them. We treat them with this compound called CpG and we can block the tumor and save up to 70 80 percent of the mice. So this treatment is very efficient in the mice, but if we treat with CpG together with antibiotics, then we can protect only about 20 percent of the mice. And the result with chemotherapy I show you oxaliplatin is very similar, in this tumor mice die in about 10 days or less, but 80 percent of them survive when treated with oxaliplatin. But if we treat with oxaliplatin and antibiotics, then only about 20 percent of them survive. I like to try to explain you a little bit of the mechanism, I try to be as very simple as I can. This is a subcutaneous tumor under the skin that in mice that we not treated it, we treated them with CpG in a few hours or a couple of days you get this necrotic tumor, the tumor basically is all dead, it's basically almost completely just a scar. But if you do the same experiment in mice that get CpG and antibiotics, you see the treatment is ineffective you don't see this scar, this necrosis. This is due in part to the production of the substance in the body of a treated animal that's called a tumor necrosis factor because skin can induce the necrosis of the tumor and if we use mice that are genetically not able, they don't have the gene for this tumor necrosis [inaudible] in fact, these mice are resistant they do not respond to the treatment. So the mechanism that you should think when you have a tumor, as I mentioned before, is not only the tumor cells, but they are infiltrating inflammatory cells and other cells, including this famous phagocyte microphage neutrophage that I described before that really the major cell type that is interacting between the host and the microbes. So when you inject CpG in the tumor what CpG is inducing activated is phagocytic cell and induce inflammation in the tumor. ^M00:30:03 And one of the factor that is made by this phagocytic cell is the tumor necrosis factor that killed the tumor cells, it has also induced an immune response against the tumor and in most animal can completely eliminate a tumor. If we treat with antibiotic we block the ability of the animal to make TNF, block the ability of the animal to make this immune response and eventually the tumor will grow out of control, even the treated animal will not being able to control the growth of the tumor. We show you now data that we obtain when we completely eliminate the gut microbiota, but you want to know which bacteria, which species are able to affect the response of the tumor. So we sequence the gut microbiota, we correlate the presence of different species with gut bacteria and we find some that are associated with an increased response to cancer therapy and some that are associated with a decreased response. In two of them we grow them in vitro in Petri dish, these two species called Alistipes shahii and Lactobacillus fermentum and we then gave them orally to the mice before we treat them with CpG to see the effect on the tumor. And we found that one, [inaudible] was actually when given we increase the response of the therapy so the tumor is destroyed better and another one, Lactobacillus fermentum actually decrease the ability of the CpG to kill the tumor. So really showing that not only the microbiome is needed for the response, but we can modulate that and try to modulate the type of therapy response that we get. The oxaliplatin mechanism is a little bit more complicated. Is that based on the fact that antibiotic treated mice do not produce chemicals that are known as reactive oxygen species when the mice are treated with oxaliplatin. So we have again the phagocytic cells that I've been talking to now. When they're activated they produce reactive oxygen species like superoxide or hydrogen peroxide or hydroxyl radical and that's a very important function in phagocytic cell because that's one of the mechanism, the phagocytic cell used to kill the bacteria they engulf. But there's hydroxyl radical and ROS are also toxic and they can actually induce DNA damage in damaged cells. Now in the case of the oxaliplatin, what oxaliplatin is doing is binding platinum to the DNA or the tumor cells and in this way alter the DNA confirmation. But it also introduce the information of ROS, activate the phagocytic cell to form ROS and in order for oxaliplatin to kill the target cell that is affected by damage the DNA of the tumor cells, both this platinum bind to the DNA and the ROS production is needed. So what happens when you treat a mass with antibiotics? So we been measuring, in the experiment I show you on the right, measure the production of this reactive oxygen species by the ability of inducing a substance with the mice that emit light with Chemiluminescence when ROS is produced. So if we give oxaliplatin to the tumor bearing animal you can see that we get this light where the tumor is showing that ROS is produced, that [inaudible] are produced in the tumor. But when the mice has been treated in the same time with antibiotics to reduce the microbiota, then there's no production of ROS. So if that is blocked this production of ROS, even platinum still bind to the DNA, there is no DNA damages, no tumor toxicity and the chemotherapy is not efficient any longer. So what I've been showing to you is that the gut microbiota and other microbiota, but particularly the gut affect the phagocytic cell, the myeloid cell that are infiltrating the tumor and CpG through the production of this factor that is the tumor necrosis factor, oxaliplatin regulating the production of ROS. But it is now known there are many other tumor therapy that are affected by the microbiota with similar mechanism involving the phagocyte. And this include two type of tumor therapies that have been very much in the news recently. The adoptive T cell transfer and the immune checkpoint inhibitor therapy. And the reason it's been in the news in the last two or three years because this two type of therapy are the only in history for the first time treatment has been shown at least in a significant proportion of patients to be able to really induce complete tumor aggression and long-term survival in patients, for example in melanoma patients, in renal cell carcinoma patients and in bladder carcinoma patients. And that was the reason why Science Magazine last year recognized cancer immunotherapy as the breakthrough of the year, the scientific breakthrough of the year. And of interest, the runner-up breakthrough is actually the effect of the microbe on the health, including the effect of the microbe on the cancer therapy that was published in 2013. And I would say that a major contribution of this access, of scientific [inaudible] provided by NCI Intramural Research Program, as well as largely by NCI funded laboratories across the nation. So NCI really a major role in supporting directly or indirectly this scientific and medical medicine progress. So how can we change the microbiotas? Can we change or reverse dysbiosis? Well we can use antibiotic. Antibiotics are a problem because they can induce dysbiosis, but if we are careful the way we use them, we use more selective antibiotics, we may affect and change and try to reconstitute in healthy microbiota. We can use probiotic, they are live microorganism and may not be constituent of the host microbiota, but they may change and may change equilibrium microbiota and might [inaudible] have benefit. And the other way is use what they're called probiotics, these are basically nondigestable food component like fiber they find in many different type of food and they favor the growth or beneficial member of the gut microbial community and try to fix dysbiosis. But the other thing that received much interest in the last few years is the fecal microbiota transplant. Now this is a very empirical type of medical treatment when basically when there is dysbiosis or disease associated with change in the microbiota, one can try to get the microbiota from a healthy individual and this is basically fecal microbiota gets cleaned and filtered and then is delivered either by colonoscopy endoscopy in the lower intestine and in the colon of the patient. So this is based obviously on the idea that if the person is healthy the person's microbiota is healthy, but unless we know exactly who has healthy microbiota this is a very empirical approach. Still receive much of interest it was used in some type of infection and was described back to the clostridium difficile, as well as attempted to use for chronic colitis for inflammatory bowel disease, Crohn's disease. Obviously, it is an empirical measure with some risk, sometimes can induce more inflammation instead of less inflammation. Is actually regulated as a drug by FDA. But I want to talk about clostridium difficile because this [inaudible] concept, the clinic approval concept how this approach change the microbiota may be important. Clostridium difficile is a bacterium is really a pathobiont that cause symptoms range from diarrhea to life threatening inflammation of the colon. And illness from C. difficile infection affect usually older adult in hospital or in community and typically if they use antibiotic medication or proton-pump inhibitor for reducing stomach acidity. And it's quite a serious disease as there are about 3 million new cases in the United States every year, it's a chronic disease, it's difficult to eradicate and cause about 15 30,000 deaths every year. Now the fecal transplant, even this very empirical process actually cure and within one or two days more than 95 percent of the patients. And if we look at what I show you on this slide, each bacterium species present in this tool is indicated by different color, you don't need to know what it is. But this is a patient and this is the healthy donor for the fecal transplant. You can see that their composition are quite different and if we look after the transplant, two weeks and a month after the transplant you see that there's a real [inaudible] change. The fecal microbiota in the patient is much more similar to the one of the donor, that the original microbiota of the patient. As I said, this is really within one two days completely block the infection with C. difficile. Now this is very empirical we really don't want to do that for our regular treatment in large number of people. ^M00:40:01 We might not know if we are really using a healthy microbiota or not, but important study are the one that really start to attempt to try to identify, like I showed before for cancer which species are involved in this regulation and blocking the infection with clostridium difficile. So what I'm showing here is a recent work by Eric Palmer [inaudible], New York. And he found out that in the normal microbiota there is an equilibrium between different species, competition between different species. And another clostridium, the clostridium scindens is actually metabolizing bile acid in the intestine of the patient, of the individual and this block the growth of clostridium difficile. If you use broad spectrum antibiotics you reduce the diversity of the microbiota, you eliminate the clostridium scindens and then the clostridium difficile can grow and cause the disease and even death. And Dr. Palmer has actually been able to show at least at the moment in mice that you can very efficiently by just giving one bag the clostridium scindens can cure most mice and even better if this is bagged together with three or four other bacteria species. So trying to give an equilibrate mixture of bacteria, but still only by itself the clostridium scindens is enough to block the infection, clostridium difficile. Now clostridium difficile is really an example of antibiotic-resistant or partially resistant drug. What do they call this super bug that represent major problem, especially in the hospital setting in antibiotic treated patients and some of them they are very common in hospital setting, some of them you know very well. Very famous, for example the MRCA the medicine resistance to [inaudible]. And we have four years ago a very typical case of that in actually NIH Clinical Center in 2011, 12 patients die of hospital acquired infection with the antibiotic resistant Klebsiella pneumonia. And that was studied, I showed you with the genomic sequence matter that really now we can study the microbiota and the NIH team that is different institute that have studied this infection and [inaudible] stop it, identify the source and stop the infection was [inaudible] Palmer and Anderson, was recognized with Service to American Medal as the first ever used this precision medicine, genomic medicine to stop a hospital acquired infection. And we are obviously trying to do at National Cancer Institute a similar type of approach. We established a new facility for both sequencing and bioinformatics study and we want to screen the microbiota of cancer patient that undergo either chemotherapy or immunotherapy. Identify strains that would favor or decrease the antitumor response and see if we can either predict the type of response we'll get through therapy or even try to change the microbiota and make the response to therapy and, in particular to immune therapy the most efficient one. So if you think about an infection disease or a cancer growing organism, it's really no different from an invasive [inaudible] that's growing [inaudible] and is eventually suffocating and destroy the wood. So how we cure that? Well the typical medicine, especially in oncology has been the war on cancer that is medicine is the battlefield strategy, the human body is a battle ground. This is every efficient, you kill the invasive, but you also kill the good when you do that. The other is medicine is park management. The human we should have a target removal invasive, we need to eliminate the pathogen, we need to eliminate the cancer cells, but really pay attention to restoration, promotion of native species. And what it is, is in a cancer patient infection is really a thing which is immunotherapy and maybe it's a microbiota study are pointing to. We need to make sure when we cure a patient, we eliminate the tumor or eliminate infection, we keep a healthy immune system, we limit inflammation and we try to correct the composition of microbiota in general, the physiology [inaudible] is the organism and the really healthy organism and the organism will not be debilitated by that type of therapy. And this is really what has been part of it has been announced recently by President Obama and by the NIH as the new effort in precision medicine. Precision medicine is really based a lot on this new technology that are available, the same technology that I've been showing you, the genome sequencing, the really careful characterization of the patient, the immune system of the patient, of the genetic of the microbiota individual, the genetical cancer and be a real very tailor and personalized medicine to try and get the most effective response for each single patient. So I would like to thank the collaborator of this work, it's my lab that has done some of the cancer work has been showing. Amiran Dzutsev is actually in the audience. I have not been doing work yet with [inaudible] sitting over there, but [inaudible] is actually the one that he's setting up this new facility and we worked very hard on that. An important collaborator is [inaudible] the allergy infection disease, Karen Frank in the clinical center microbiology service and my clinical collaborator in the NIH clinical center Heidi Kong and Jim Gulley. Thank you very much. ^M00:46:08 [ Applause ] ^M00:46:14 >> Speaker 1: I hope I can present my question sensibly. With respect to clostridium difficile, I had read a few times that its growth is accelerated when various stomach acid reducing medications are given to the patient and I'd like your comments on that. >> Giorgio Trinchieri: Yeah, I mean it's usually associated in--the question is whether the clostridium difficile infection is favor or induced by the use of anti-acid in the patient and as I said, the major cause has usually been attributed to the use of antibiotics. But the anti-acid and particularly the proton-pump inhibitor, they clearly change the utilization of the food and they can change the microbiota. And it's been clearly shown they change microbiota and they can affect the growth of the bacterium. Also the, as was shown by the Eric Palmer study with this competition between two species of clostridium, what the clostridium is protecting is actually digesting bile acid that obviously come from the stomach and digesting to a form of process bile acid that in which the C. difficile bacterium cannot grow. Now if you get an increased amount of change in the bile acid and change in this process of this micro environment, then the clostridium difficile can grow. So that is absolutely correct about the anti-acid, especially the proton-pump inhibitor, a strong anti-acid can induce that. >> Speaker 1: So if one wanted to reduce or eradicate using the proton-pump inhibitors, what would be a less drastic approach? >> Giorgio Trinchieri: Well obviously some of the traditional anti-acid they just buffer the acidity or some of the less strong [inaudible], they clearly have been less associated with that, they are also much less efficient in reducing stomach acidity. So that's always the catch 22 situation. When sometimes we present the data on cancer in the newspaper and sometimes people were calling up and say, oh we should not give antibiotics to the cancer patient. Well cancer patient, especially during chemotherapy they are infected with very dangerous pathogen. You need to protect the life of the patient, you cannot worry about not giving antibiotics. So it's always this catch 22. Obviously, stomach acidity [inaudible] are again a disease of civilization is linked to stress and food and so on. So I mean it's very theoretical, but the way would be to change the predisposing condition and try not to treat. It's always better to prevent a disease than treat it when you treat it you have always this good and bad side of the treatment. >> Speaker 2: I want to [clears throat] excuse me, I want to, even though the room is not filled. I do want to thank you on your research into the microbiome it's been a long time and it's been an area that has not been focused on quite a bit and I think there's a lot to really appreciate in what you presented here today and what will be coming in the future. ^M00:50:07 My question has to do with what is the differences and the effects and less on cancer and more on autoimmunity and probiotics and how and if there are differences in the probiotics in changing the make-up of your microbiota. And the second half of that question is what about the biologic medicines and their treatment and have there been any relationships to their effectiveness and/or are there any side effects to using the. >> Giorgio Trinchieri: Okay. >> Speaker 2: Biologics to treat autoimmune diseases? >> Giorgio Trinchieri: Okay the question is--what is the role of the microbiota in autoimmune disease, how different probiotics may be more or less effective and what is the effect on the biological therapy affecting the microbiota and affecting the autoimmune disease. The probiotic is very not regulated field, so it's really difficult to understand. Even when we buy probiotic on the store shelf and there are so many billions of this bacterium you really don't know how careful those are analyzed, you don't know if the bacteria are alive or no alive, it's not clear how long they stay on the shelf and so on and not being FDA regulated. It's really difficult to say get this one and not get this one that's available commercially and I'm not competent to do that anyway. But they are competent, some of the probiotics that have been used that are known to have an anti-inflammatory effect and I showed the data with the Lactobacillus fermentum in cancer, but what we get in that case is Lactobacillus fermentum block the response of CpG because it decrease inflammation. So this type of bacteria has been shown in experimental animal to being able to decrease systemic inflammation and have an effect in some condition autoimmunity. But I think this is a field that really need to be understood much better in order to really know what to take and what's working and what's not working. The biologic therapy is always something that's very close to my heart that Tomoko has been talking about I12 and anti TNF that I mentioned or anti 12 are now major drugs for autoimmunity different type. They are atomic bomb, they are really blocking substance that have a major role in our immune system, our physiology and all this biologic done to TNF, as well as anti 12, for example cannot be used in patients that may be at risk of tuberculosis, micro bacteria tuberculosis infection because they will reactivate infection. And it's because they change the way the immune system work if they are used continuously, they are very likely to change the microbiota and again, it may affect in a good or bad way what's the autoimmunity or what's disease or induce different type of disease. And as far I know there's not many study about that, but I think it would be something very important to study. >> Speaker 3: Could you talk about leaky gut and how that occurs and how that plays into this whole health and disease. >> Giorgio Trinchieri: Well the, as I mentioned before, one of the function of the--I'm sorry the question was discuss about leaky gut, the permeability of the barrier and how this may affect the disease. So as mentioned before what the healthy microbiota is doing is really protecting the integrity of the barrier, definitely in the gut. We always consider that we keep our bacteria outside, but they actually can go through the barrier and they do all time, just you don't want that to happen too much. In healthy microbiota protect the barrier directly, the barrier is made, the epithelium, the cells that cover the gut is really a single layer of cell of epithelial cell and they have what are called tight junction, they are very much touch one to the other. So not much can go through even there are mechanism which this permeability can be open and think sort of things can go through. The other thing that the microbiota is doing is in inducing production of substance that are called antimicrobial peptide that regulate the immune system, the mucosa, production of antibody for example, IGA antibody and that all work together in controlling the composition microbiota and keeping the barrier intact. When we start to have any pathology--an inflammatory pathology or a dysbiosis for example in chronic colitis or in infection like cedeficile, then this barrier is disrupted and that obvious physiological effect like the diarrhea and so on, but it also increase the permeability of bacteria can come in contact with our organisms, can actually migrate to our lymph nodes and that really dramatically change all the inflammatory environment. So that a change in barrier permeability in the digestive tract is not only affect locally, as I say for example symptoms like diarrhea, but it's also having systemic effect, so our overall health can be affected by that. >> Speaker 4: A couple of months ago I had, I know I have low vitamin D and high cholesterol because I had a blood test and my doctor for an annual physical. How can a normal person tell how your microbiota how healthy you are at a particular point in time before you have [inaudible]. >> Giorgio Trinchieri: The question is how do you know what is a healthy microbiota and how can you say you have a problem you don't have a healthy microbiota? Well actually that's a clinical problem with the microbiota, it's a clinical problem with the immunity in general. We always--when I talk about analyze the immune state of an organism, I always show a slide and say if you have heart disease there are a hundred very sophisticated tests that you can do and find out what you have. If you have--they want to know how your immune system is working, well you get the blood sample and you count how many lymphocyte and monocyte are in there and that's basically what is done. And you really by doing that, well there is a major problem you know, but you really don't know how good your immune system is. And we are in the same way with the microbiota because that was one problem with fecal transplant, they try with chronic colitis, with IBD, they say this person is healthy so his microbiota should be good and when they give the patient they actually, they get more disease, they get more inflammation because that microbiota look healthy in the donor because this mucosa was okay, but in the patient there is already inflammation that add to the inflammation. So that is exactly what we need to understand better and improve. Right now you cannot really say what is good and what is bad. The mouse it's been helping here, it's not solving this problem, it's helping because even mouse and human has different microbiota, you can actually tag the fecal microbiota, for example from fit and obese people or obese twin even, so with the same genetic. And you can transfer that to germ free mice or mice or mice that have no microbiota and basically make this mice have human microbiota. And the microbiota from a slim person you would get slim mice simplifying the experiment and the one from obese people you get fat mice. There are some correlations, some change, some species that we start to understand a little bit how they're [inaudible] with that, but the full understanding of that we will see require a lot of work. >> Tomoko Steen: This is a very good example of the transformation of medicine and please join me to thank Dr. Trinchieri. >> Giorgio Trinchieri: Thank you [applause]. >> Speaker 5: This has been a presentation of the Library of Congress. Visit us at LOC.gov.