 I'm delighted today to welcome Stacey Kahn as our speaker. Stacey is an assistant professor in the GI section in GI Hepatology and Nutrition in the Department of Pediatrics. Stacey is a graduate of New York University School of Medicine and then she did her residency and fellowship here at the University of Chicago. She specializes in diagnosing and treating digestive diseases in children, especially inflammatory bowel disease and celiac disease. In addition to seeing children in her pediatric GI clinics, Stacey heads the transitional IBD clinic. That's a unique program that provides multidisciplinary specialty care for teenagers and young adults who have inflammatory bowel disease. Stacey has written greatly about pediatric astroenterology as well as the role of therapies concerning the microbiome. Today, Stacey will talk to us about the following topic. Is your stool or the microbiome an organ? Exploring the ethical and practical issues in fecal. I'm not going to get this right, Stacey. Microbiota transplantation. It's a delight to welcome Stacey to our seminar series. Please join me in welcoming her. Thank you all and thank you all for coming over to this other room. Hopefully you enjoy your personal view of the slides up close on your computer screens. I also want to apologize that I'm talking about this while you all are eating your lunch. Hopefully it won't turn off too many people. Unfortunately, as a gastroenterologist, I get very comfortable talking about bodily habits at all times and during all activities during the day. So it doesn't bother me. So let's go ahead and get started. So I have no relevant financial disclosures, but I do want to point out that fecal microbiota transplantation, or FMT, is not an improved therapy. And the use of FMT for clinical or research purposes requires FDA approval and an investigational new drug, IND application. So it's all off-label. So today we're going to go over some definitions and concepts. A lot of the language that we'll use today both from microbiology as well as from the field of FMT might be new to some of you. We'll review the microbiome as well as microbiome-based research. We'll talk about the role of the microbiome in both health and disease and a term that you guys are going to hopefully know well by the end of this talk, which is dysbiosis. Dysbiosis is a state of altered bacterial balance, and the prototypical disease, my disease specialty of interest, is inflammatory bowel disease. So we'll talk about dysbiosis and IBD, and then we'll talk about fecal microbiota transplantations, what it is, the ethical concerns, the social issues, regulatory issues, and hopefully have plenty of time for questions if you guys still have an appetite left to talk at the end of the talk. So I just wanted to start off by talking about is it an organ or is it a tissue? This whole seminar series for this year has been absolutely outstanding and really addressed some of the key points of solid organ transplantation, tissue transplantation. Well, what about the microbiome? Is it an organ? Can you transplant it? And actually I'm going to argue today that yes, the organ, the microbiome is in fact an organ. Organ comes from the Greek and the Latin, meaning a tool or an implement. It's a differentiated structure. It's arranged in a definite pattern and has an organization. We obviously all know that the heart and the kidney are organs, but many people know that we've argued that other tissues, maybe you're not really tissues at all or body parts. What about your face as Dr. Semenov eloquently argued at her presentation at the Fall McLean Center conference that the face is in fact perhaps an organ and should be considered an organ. So not just the conventional bodily structures that we think about are an organ. And this is in contrast to a tissue, which is an aggregate of cells. Usually those of a particular kind that are together with their intercellular substance form one kind of structural material that supports a plant or an animal. And good examples of these might be connective tissue, epithelium or muscle tissue. So as I said, I'd like to argue that your microbiome, which is contained in part in your stool, is an organ. It consists of cells performing specific specialized functions, which we're going to talk about today. As many of you may know after hearing about it, it's necessary for maintaining health. And when it's disrupted, you enter into a disease state or dysbiotic state. Although it may not fit the traditional definition of a differentiated structure because you can't take out a part of the body that contains all of the microbiome. Some of it's contained in your stool, but as you'll learn today, part of it is in your GU tract, your oral cavity, on your skin. There's lots of areas that contain your microbiome. I would argue that it can be identified and distinguished from other human cells and tissues. And as we're also going to talk about, it can be transplanted to treat or cure specific diseases. So let's start off with some basic definitions. As I said, this is a really in-depth field and there's a lot of language, but we do need to have some basic understanding. So microbes are ubiquitous microscopic organisms. They're found throughout the environment. They're in and on our bodies. They're in the buildings that we live in. In fact, some of you have may heard that the new CCD has a hospital microbiome project to identify the microbes within the hospital. Samples taken before and after will be analyzed. And these include bacteria, viruses, fungi, progezoa, and they can be helpful or harmful. Just calling it a microbe doesn't tell you what its job is in life. The microbiota refers to a group of organisms that are localized to a specific location usually within the body or an environment. Sometimes you'll hear the term microflora used interchangeably, and this refers to microbes associated with a plant. So although people use it interchangeably, it's not technically correct when referring to human microbiota. Commensal bacteria is a term used to describe bacteria that are associated with a given host in a community and are typically present within that individual. They are generally helpful bacteria or non-pathogenic. As I already mentioned, dysbiosis is a term that you're going to come to learn well by the end of this talk. It refers to the disruption or imbalance of the normal commensal bacteria within a community. And microbiome is the total microbial community, including its genetic elements. So over the past five years, there's been incredible growth in microbiome-based research and publications. It even graced the cover of The Economist magazine in 2012. So the reason for this exponential growth is two-fold. One, we have new technology and molecular techniques, which I'll give you an overview of momentarily, that have really changed our ability to characterize these bacteria. And two, the NIH Microbiome Project. So in the past, we really identified bacteria in very simplistic ways. We could stain the bacteria and see what the shapes were and identify the morphology, or we could grow them out and specialize plates or anaerobic chambers. That was how we could tell what bacteria were present in a given community. If we couldn't stain it or we couldn't culture it, we didn't know if it was there. This is what's been dramatically changed over the past 10 years. We have a new tool. This tool is 16S ribosomal RNA. And it is how we will identify bacteria now, and probably at least for the foreseeable future. It's a novel marker, and what makes it such a good marker for bacteria is that it's unique to prokaryote. So it can be used to identify bacteria and RK, so it's not found in human cells. And it allows us to identify and characterize these previously undescribed and non-cultural bacteria. And this 16S ribosomal RNA forms the basis of all of this microbiome-based research that we're talking about today, and the NIH Human Microbiome Project. So getting into 16S RNA is obviously beyond the scope of this talk, but I just wanted to give you a sense of how powerful this technology is and some of the information we're leaning from it. So using this, we can identify where the microbes are. We can study their function and look at different proteins or metabolites. And we can also try to understand the genetic potential. As I said, the other feature that has led to this exponential growth in the microbiome-based research and publications is the Human Microbiome Project. Similar to the Human Genome Project, it's a multi-site NIH initiative with several hundred million dollars dedicated to characterizing the microbiome in humans. The objectives were to identify its role in health and disease and to determine if individuals share a core microbiome. They were also looking for investigators to develop new technology and tools using the microbiome. And of particular interest to this group as well as to me personally is to explore the ethical, legal, and social implications of microbiome-based research and technology. So what have we learned about the Human Microbiome thus far? So as I showed you, there have been this remarkable outpouring of research and publications. And just to give you an idea, we now know that there are trillions of bacteria in an individual. In fact, your bacteria outnumber your human cells by 10 to 1. And an adult probably constitute about 500 grams of weight. And as we'll talk about shortly, the microbiome has its own physiology. The figure here on the right demonstrates a summary of some of the microbial species and genes that have been identified through the Human Microbiome Project Consortium. The numbers in red show the total number of microbial species identified from each area sampled. And the blue, which totals over 200,000, is the number of microbial genes that have been identified to date. So really we're talking about an impressive amount of cells, an impressive number of bacteria, species, and genes all really impacting how we live, how healthy we are, and the diseases that affect us. So how does the microbiome develop? Well actually it's very important in pediatrics because its development begins at birth. The fetal newborn gut is sterile and rapid colonization begins after birth. There's been a great deal of interest in the microbiome in preterm infidels, particularly here in the lab of, in multiple labs have been studying the colonization of infants. They've found that preterm infants have delayed colonization and then full term infants have more abundant bacterial species which we now know the more you have and the more diverse your bacteria the healthier you're going to be. We've also found that there are differences between breastfed infants and formula fed infants and we know that the microbiota of these infants changes a lot in the first couple of years but by the age of two or three you've more or less acquired your stable lifetime microbiome pattern. Of course environmental factors, diet, changes in environment, changes in geography, all of these things antibiotics may influence your microbiome but these are small shifts and most of the research shows that these small shifts occur transiently and most individuals who then return to their baseline health. So as I mentioned the microbiome has its own physiologic activities which is part of why I argue that it can be considered an organ. It's essential for normal immune development. In fact studies in animals and germ free mice who don't get exposed to the microbiome have abnormal immune development. We know that these microbes are really important for protecting against epithelial cell injury which we'll talk about a little bit more when we talk about the role of the microbiome in inflammatory bowel disease. As many of you may not know but are experiencing right now microbes are helping you digest and absorb the food that you're eating for lunch. They stimulate intestinal angiogenesis. They protect you against the colonization of pathogenic bacteria and they've also been shown to play an important role in the production of protective short chain fatty acids. So clearly the microbiome regardless of whether you might agree with me or not that it can be considered an organ really is essential for maintaining health. The question remains if it's so important for help what happens when it becomes altered and can it cause disease? So as I mentioned before we're going to spend a little bit of time talking about dysbiosis. Dysbiosis is a term that reflects the disruption in this normal balance of healthy bacteria that we all have. And as you can see in this figure on the top panel this is a diagram to represent the intestinal epithelium. You can see there are lots of different color dots and those are supposed to represent both the diverse and abundant microbiota within the intestinal tract and their representatives from major bacterial groups. They have a healthy level of short chain fatty acid production. You have an intact mucosal barrier which is one of your first lines of defense against disease and you can see there's no overt inflammation. However, when you look down at the lower panel what you can see is in states of dysbiosis. So for example, pseudomembranous colitis which is associated with C. diff, inflammatory bowel disease, neck, all of these conditions lead to or associated with a dysbiosis. And in these cases you get a very marked reduction in the diversity of the microbiota. You get an increase in the pathogenic bacteria that exists within the gut, a skewing of the short chain fatty acid production, the mucosal barrier is broken down and becomes leaky or disrupted and you get an escalation of the host inflammatory response. There are a number of different therapeutic techniques to correct this dysbiosis and where a lot of studies are ongoing to understand this. Some are proposed that antibiotics may create this, although some studies show that actually antibiotics may perpetuate these states of dysbiosis. We have probiotics which are the healthy bacteria you often find in yogurt or other foods. Dietary interventions have been shown to be quite helpful and our topic for today, fecal transplantation. So there have been a remarkable number of diseases already that have been associated with dysbiosis. Studies have shown that aging and the frailty associated with aging may be associated with dysbiosis. Clearly, many of us have experienced patients who've had antibiotic associated diarrhea which is clearly related to dysbiosis, but there are also conditions that involve other systems in the body. Asthma, atopic dermatitis, celiac disease, clostridium difficile, which we'll be discussing today, colorectal cancer, inflammatory bowel disease, irritable bowel syndrome, heart disease, kidney stones, metabolic disease, neck obesity, periodontic psoriasis, and actually I see one of my colleagues, Tiffany Patton, who's studying the microbiome in Yacinophilicosavagitis, would also say that that may be a condition that's also associated with dysbiosis. So as you can see, dysbiosis probably plays a fundamental role in a lot of the disease states that many of the people in this room are studying. So I wanted to take a little bit of time to give you a little more background about inflammatory bowel disease as an example of a disease that clearly has associated dysbiosis. So inflammatory bowel disease is an umbrella term. It includes two main conditions, Crohn's disease and ulcerative colitis. The remaining 5% to 10% are probably intermittent colitis or patients who can't be differentiated. Crohn's disease can affect anywhere along the digestive tract from the mouth to the anus, and ulcerative colitis by definition primarily affects the colon. Both of these conditions are chronic idiopathic inflammatory conditions that have no known cure from medical therapy and cause a lifetime of debilitation and medical attention needs. There are approximately 1.5 million cases in the United States, and of course my primary concern is children, and you can see that this is a stark number of children with 15 to 25% being affected. And actually recent studies have shown that there's actually an increase in the number of children who are experiencing IBD, in fact at very, very young ages. I wanted to just show you some images from what it looks like on the inside of the gut when you have inflammatory bowel disease because I think it helps connect the dots between the inflammation and the dysbiosis. So the image on the top is a normal colon. You can see the mucosa, the lining is pale pink and smooth. You can see the blood vessels. The image on the left is an image from a patient with ulcerative colitis. It's red, it's inflamed, it's friable. And on the right we have the patient with Crohn's disease where we have deep ulcerating fissures, pus, inflammation, cobblestone. It's not hard to imagine that the bacteria in these patients with ulcerative colitis and Crohn's disease has got to be markedly different than the person who had the colonoscopy from the image on the top. So what causes inflammatory bowel disease? Well, it's a multifactorial disease that occurs in genetically susceptible individuals with actually several hundred specific genes identified as potential risk factors for Crohn's disease. We also know that individuals with IBD have immune dysfunction or dysregulation. There are environmental factors that may cause IBD or predispose to IBD including medicines. There's theories about the hygiene hypothesis and where you live in the geography. Others have proposed that things like breastfeeding may be protective, although that's not been borne out. Exposure to NSAIDs and smoking are also maybe risk factors. But the pace I want to focus on today is the role of the microbes and microbes clearly contribute to the development of this disease. So early evidence from the role of the microbiome in IBD comes from studies in animals. And these studies showed that germ-free animals did not develop intestinal inflammation when they were susceptible to do so. However, if you exposed these germ-free animals to bacteria, they would develop rapid, progressive, severe inflammation of the intestinal tract, showing that the presence of the bacteria really had an impact on these animals who were otherwise sterile. Also interesting to note was that when these animals were exposed to different bacteria, they had different clinical phenotypes, meaning they had different symptoms. They had variations in their immune response and activation, and that they actually had activation of different pro-inflammatory molecules. So this is really a complicated process showing that the bacteria may play different roles in different hosts, but also the type of bacteria that you're exposed to may mean different things for different people. We've moved on to do more clinical studies looking at the microbiome in individuals with IBD, and we've had really some dramatic findings showing that the individuals with inflammatory bowel disease have significant alterations in their microbiota. This was a nice study by Bibleone at all that looked at 20 individuals with Crohn's disease and 15 with ulcerative colitis and compared them to healthy controls, and they took multiple endoscopic biopsies from the sites, and these sites were identified as non-inflamed areas or inflamed areas, and as you can see from the figure on the right, an eye is non-inflamed and an eye is inflamed, and you can see that within each group, CDNI versus CDI, so Crohn's disease non-inflamed versus inflamed, there were marked differences, and overall what you can see is that patients with ulcerative colitis had more bacteria than healthy controls or patients with Crohn's disease and that there were differences within each individual group. Furthermore, they showed that patients who had biopsies taken from inflamed tissue had more bacteria present than those who had non-inflamed tissue samples taken. Other studies have gone on to show that healthy controls compared to patients with IBD have more stability in their microbiota as time passes. As you recall, I said that most of us have a more or less stable microbiome than by the time we're three, with little perturbations here and there. However, when you enter a dysbiotic state, such as inflammatory bowel disease, you're going to have a lot more instability over time. Interestingly, they also demonstrated that relapse or flares of inflammatory bowel disease are associated with decreased diversity and richness of the microbes and that this decrease was associated with a loss of the normal commensal or protective bacteria within individuals. So this is some striking evidence that shows that not only are we dealing with the genes, not only are we dealing with the immune dysregulation, but there are fundamental changes occurring in our microbiome organ in individuals with IBD that may be a target of therapy. So what are our concerns with our current therapies? Why are patients so interested with fecal microbiota transplantation, particularly if they have IBD? And one of the reasons is if patients were really happy with their therapies or had a cure, they probably wouldn't be looking for new therapies. So here are some of the concerns that both clinicians as well as patients have identified. So there's risk of developing cancer, risk of infection, the risks associated with immune suppression, obviously cost and convenience are of super importance to patients and families. We think about the duration. And as I mentioned before, these therapies, although they may provide long-term remission for some patients, do not provide a cure. We also know that a lot of our patients are interested in safer therapies and therapies with fewer side effects. And in IBD in particular, we have about a 40 to 50% rate of complementary or alternative therapies within our patient population. Patients who are looking for new ways to treat this condition. So what are our emerging treatment strategies for IBD? So one of the things we're doing is we're doing more aggressive treatment following complications or surgery to prevent recurrence. As many in lots of fields are working towards, we're working towards personalized medicine, which means tailoring the treatment plans to individuals and stratifying them based on prognosis and disease features. We can now measure medication levels for many of our medications as well as antibody levels. And as many have proposed and we're going to talk about shortly is can we correct this dysbiosis and is FMT a reasonable approach to do so? So I think probably most people who've read the newspaper in the past 12 to 24 months have heard of fecal transplants. It's been all over the press. It's been in TV, show hospital dramas. It's been in comedy news shows featured at night. Obviously it's the source of a lot of humor and jokes, but the truth is that patients and clinicians are very interested in this potential therapy. I wanted to point out that although we're calling this a fecal transplant, a lot of people say is this really a transplant. And I just wanted to show you that there has been a long history of transplants, many of which have been covered in this year's seminar series. You can see skin, the first skin transplant in 1869. We have kidney donors, organ donors from brain dead donors. We have U.S. heart transplants, liver transplants, split livers, combined organs, face transplants. And some of you might think that fecal transplant is relatively new, but actually the first reports of FMT actually date back to the fourth century China when people were using it to treat food poisoning via diarrhea. So we'd like to think that we're inventing the wheel here, but actually this treatment goes back quite a long time. So let's get into fecal microbiota transplantation. Hopefully most of you are done with your lunch now. So this therapy also known as a human probiotic infusion, fecal bacteria therapy, or stool transfer is the delivery of an entire microbial community, or microbiome, from an individual who is healthy to an individual with disease. It involves identification of a healthy donor who goes through extensive medical and social screening. They are also screened for infections in the blood and in the stool. The fecal matter is then collected and prepared and it can be delivered by a number of different ways to the intestinal tract through enema, colonoscopy, upper endoscopy, or nasogastric tube. What is the underlying theory behind FMT? The theory is that FMT will correct the dysbiosis. So a number of applications have been proposed for fecal microbiota transplantation. It is thought to restore the normal healthy commensal bacteria. As I will show you shortly, it's been shown to be highly effective in recurrent infectious colitis caused by crostridium difficile, the superbug that's everywhere. And it may be useful in the treatment of a number or other conditions, a few which we'll talk about today, including inflammatory bowel disease, metabolic syndrome, irritable bowel syndrome, and constipation, just to name a few. And I can tell you that the patient interest in this is tremendous and people are coming out of the woodwork. We probably get about five emails a week with patients who have conditions from, ranging from dermatomyositis to autism to nonspecific GI complaints who are all very interested in this. So I think this field is in its early infancy still. So let's talk a little bit about fecal microbiota transplantation for C. difficile or crostridium difficile. This is the condition or disease for which there is the most evidence and the best evidence. The first reported use in the literature is from 1958. And there were four patients who had severe pseudomembranous colitis, which is an inflammatory complication from the C. diff infection that can be rapidly progressive, lead to toxic megacolon sepsis, and even be fatal. These patients were all treated with fecal enemas and had resolution of their symptoms within 48 hours. Since that time, there have been dozens of studies reporting the use of FMT via any delivery, various delivery methods, showing that FMT appears to be both safe in adults and children and has a primary cure rate of C. diff of over 90%. That means one treatment and you're cured. In those patients who do not have a primary cure rate, it appears to have about a 98 to 100% cure rate if they get a second treatment from a different donor. So this is a highly effective therapy. Think about the patients you take care of in the hospital who have C. diff. Think about the patients in your clinic who have had months and months and months. This therapy seems to be very safe and effective and it's even been shown to be safe in patients with megacolon and overwhelming sepsis or organ failure thought to be associated with the C. diff. In 2012, we had the opportunity to participate and actually provide the first colonoscopic delivery of FMT for a child with C. diff here at the university. The child was only 18 months old, had spent over half of his short little life on antibiotics for the treatment of C. diff, which he had developed due to antibiotics exposure for bronchitis. So this is really a remarkable treatment. Mom said that within 12 hours, he was back to normal, no longer losing weight, active, playful, no more tummy aches. Really a remarkable response. In 2013, many of you have may seen that the New England Journal of Medicine published the first randomized control trial, a fecal microbiota transplantation. And it actually ended up being a somewhat smaller child because this study was terminated early after interim analysis showed the marked superiority of fecal microbiota transplantation compared to vancomycin alone or vancomycin plus bolovage. Again, with cure rates approaching 90% in the primary care rate group. And we have planned here another study of FMT for recurrency diff in children and adults pending FDA approval. For those of you who are not as interested in the C. diff IBD GI diseases, it may also be useful for metabolic syndrome. And so many of you who take care of grown-ups experience a lot of patients who have metabolic syndrome, which is associated with central obesity, high blood pressure, high triglycerides, low HDL, and insulin resistance. This study out of the Netherlands took 18 male adults with metabolic syndrome and randomized them to receive autologous, so self-donated FMT or allogenic FMT from lean donors. In the process, they also performed microbial analysis on the donors and the recipients. And they found that these adults who had metabolic syndrome not surprisingly had a decreased diversity. As you remember, I said, the more diverse your bacteria, the healthier you are. So in fact, these subjects did have dysbiosis at the pretreatment. They found that subjects who received the allogenic or the lean donor FMT had an increased peripheral insulin sensitivity and a corresponding increase in microbial diversity. This study was followed for patients about six weeks after, so more studies are clearly needed. It wasn't a miracle drug. People didn't suddenly get skinny. This is not a magic bullet, but certainly goes to show that changing the microbiome and correcting dysbiosis has huge therapeutic implications. So what about FMT for IBD? And this is where our primary interest comes in. So in 1989, a physician who actually had severe ulcerative colitis that was refractory to multi-medications along with his partner treated himself with FMT by following antibiotic clean-out and went into an 11-year remission. There have also been a number of case series, patients who've had both irritable bowel syndrome and IBD. This series reported that 20 were cured and nine had decreased symptoms. I would like to point out that these are all case series or reports. They are not randomized controlled tiles. There's variable amounts of information about the donors and follow-up and endoscopy, but it does show a trend that there is some potential here. Perhaps the most important work was from 2003, and I'll review that with you shortly, from Buruti in Australia, who had six patients with severe medically refractory ulcerative colitis who underwent FMT and all went into clinical remission and had evidence of long-term healing on colonoscopy. More recently, in particularly of interest to the pediatricians in this room, including myself, was a study by Kunday et al. out of Michigan that showed that 10 patients with moderate ulcerative colitis who received daily FMT enemas for five days had a response one month post-treatment. Seven were clinically improved and one was in remission. Again, we don't have all of the data to know what the impact on the microbiome was, but this does show that there may be some therapeutic potential here. And as I'll talk about towards the end of my talk, we are currently planning a study for 20 adults with mildly to moderately active ulcerative colitis to receive colonoscopic FMT here. And this was just a summary slide from the study in 2003 by Broody et al. And I would just like to point out that all six patients had had long-standing ulcerative colitis eight to 20 years. The donors have been identified as some relatives and in one case it was an unrelated male. It also includes the list of the medications that they had failed. And it doesn't explain why, but all of these patients were able to go off their medications for ulcerative colitis after treatment. And it's unclear if this was patient choice or physician choice. You can see the follow-up range from one to 13 years and what's really marked is the histologic follow-up from the colonoscopic bias shows that there was no active inflammation in any of these patients following FMT. So, moving on to the ethical issues, which clearly there are many, we need to think about as we move forward for microbiome-based trials in humans. And not just FMT, but other microbiome-based therapies. Of course, we all know the important pillars of beneficence, non-malphesence, respect for persons, justice, autonomy, shared decision-making, and resource allocation. And as I'll talk about in a little bit, what's very interesting is that there's been very little ethical analysis done into human microbiome studies or FMT in general. And if you compare it to the work done by the human genome ethical analysis, we're not even on the map. So the first thing we did to analyze some of the ethical and social concerns around FMT was we conducted a focus-group qualitative study of patients with ulcerative colitis and parents of children with ulcerative colitis. And we gave them a brief description of fecal transplant in lay words. We did not provide them with any information about its efficacy or its safety. We just simply described the process. And what was interesting is that the patients really had five main areas that they identified. They considered fecal transplant as a treatment. They really talked about the benefits and the risks. They also seemed to have some understanding of the mechanisms. And they also talked about the social concerns. Clearly one of the big things that often comes up, not just at lunchtime, is the yuck factor. But patients also had the ideas about what would make the ulcerative colitis worse, how would we screen, would this decrease the total number of medications that they needed to take. What was really interesting, however, was that patients perceived this therapy as natural. They thought that it was safer than conventional medicines and that they were really eager to have this therapy. They often preferred that family members be donors and they recognized the importance of screening all donors regardless of who they were. And I think more illustrative than the table or me summarizing it is just to give you a couple of quotes that we had from the patient groups. So one parent said, just like what I've been saying, the initial thought is the yuck factor. But you know what? I'm kind of at the stage where my colitis where I'm kind of on the last straw before removing my colon. So I'm at a point where I would try anything. I even see this fecal transplant as a more natural way of treating my disease. If I was given the option of four pills that have all these chemicals that I don't even understand or this kind of natural thing where bacteria is used to help, I would do it. So you can see that patients were really very invested in this idea. In fact, we had many patients and this study was conducted a couple years ago who said that they wished it were already available. Also interesting in this group, we had patients who had already undergone colectomy for their ulcerative colitis. So they have no treatment requirements at this point and they were still very interested in this as a potential therapy. So clearly the yuck factor is not a deterrent for patients. We followed up this qualitative study with a quantitative study. We did a survey of 95 adult patients from the adult IBD clinic and we asked them about their disease, their control of their disease, their current medications and we asked them what they thought about fecal microbiota transplantation. Again, provided no data about its safety or efficacy but simply described the process. And what we found was that 46% of the patients were willing to have FMT regardless of how severe their disease was and most of them reported very good to excellent control of their disease at this time. Patients reported wanting FMT because they already perceive it as effective. They think it's safer and many of them would like to have it to avoid surgery. Most of them would prefer to have it delivered colonoscopically or by enema, although some would accept a nasogastric tube and perhaps most interestingly to us was that the patients said that they would be equally comfortable letting the doctor decide who should donate or having a family member or spouse donate. We also asked patients about their primary concerns for fecal transplant for ulcerative colitis and as you can see patients were thoughtful. Many were concerned that it might worsen their ulcerative colitis. Many, oh I'm sorry that's missing a percentage, the cleanliness of the procedure, the unsafe delivery method, the screening for infections. But what is very marked here is the fact that 21% reported no specific concerns about FMT at all. So we have patients walk into a room, they tell us they're concerned about this medicine or that medicine and here we have something that we have no data about the long-term safety and that a lot of patients are reporting no specific concerns. So clearly we have to think about the vulnerability of this patient population and their eagerness for the therapy. So what are some of the practical problems to developing trials of fecal microbiota transplantation and IBD because this is where my primary interest lies. Who should be included? Children, adults, long-standing disease, new diagnosis, Crohn's disease, ulcerative colitis, doesn't matter where your Crohn's disease is. Should patients who have upper GI tract, excuse me upper GI tract Crohn's get upper GI tract delivery of FMT? How severe the disease is and what about other therapies? Are we going to play a role in how effective FMT is for our patients? We also need to think about the human protection of human subjects and this is regardless of whether it's our patients with IBD or other individuals but as I told you, we're getting a number of emails on a weekly basis asking for this treatment and we've really been pretty clear that desperation obviously as you all know is not an acceptable recruitment strategy for clinical trials and neither is insurance. We also have to think about the fact that this treatment substrate is readily available and it doesn't cost anything, right? And actually the technical logistical delivery of it is really quite simple because it can be done as an ANIMA and in fact there are numerous alternative practitioners on the web who will be charging upwards of $8,000 to go on a fecal retreat. There are online directions, videos and all of this is from non-medical people so there are clearly some vulnerable individuals and some people who may be taking advantage of them. So we really need to make sure that our clinical trials of FMT will require safeguards to protect our vulnerable patients with a clear understanding of the limitations and alternative selection of the appropriate patients as well as protection of the donors. About a year, a year and a half ago we actually had a research ethics consultation for FMT and the development of our FMT trial and a lot of really important initiatives were raised regarding donor protections. How are we going to select the donors? Who decides what's a healthy donor and what's not a healthy donor? Is it like organ transplantation for solid organs? One of the very interesting part that was brought out by many of the people in the group was this idea that there's no opt out. So for solid organ transplantation there is a donor advocate who will meet with a family member and if they're uncomfortable donating we can just say that there's no match. There's not a match. But what do we do in this case when there's a lot less medical risk to the patient compared to something like kidney donation or liver transplantation? What about blood transfusions? Is this more like a blood transfusion? Because it's an organ that can be readily replaced on a regular basis. And what about matching? Many people have talked about this concept that in the future we may be able to actually do a microbial fingerprinting for each individual and identify who's missing what bacteria and find the ideal donor and deliver the appropriate bacteria back to that. And how do we screen these donors? Clearly there are a lot of infections that are communicable and transmissible but how do we decide which tests are the most appropriate? Clearly the test that we use to screen an individual for C. diff donation of FMT may be different than the patients who we screen for inflammatory bowel disease where there's a genetic component. Should family members be allowed to donate or not donate if it's a heritable condition? And who's going to pay for all of the screening tests? There are also practical problems regarding the recipient. Clearly for C. diff there's a very strong literature with thousands of patients having received this therapy and high, high cure rates and intermediate safety data. However inflammatory bowel disease is a much more complicated disease than C. diff as are most of the other diseases that we talked about associated with dysbiosis. And as I said we really need to think about the genetics, the immune dysregulation and environmental factors that may be involved. Several people and groups have also raised the potential for unroamed risks. What about infections we can't screen for? What about the possibility of transferring bacteria that predispose individuals for risk of a new immune condition? How does that affect your metabolism? In fact, one of the screening questions for stool donors is about body weight and obese or individuals with metabolic syndrome are not considered appropriate fecal donors. We have questions about allergy, the predisposition to cancer, obesity. All of these things are really important issues and until we have the clinical data right now there are theoretical ethical questions about what's the best for our patients and our donors. There have also been a number of issues related to regulation. Clearly the use of FMT in a research setting will require approval from an institutional review board and Dr. David Rubin who's my collaborator on this project and I just returned from a meeting at the NIH with the FDA where they made it very clear that despite the good data for the use of FMT and CDIF an investigational new drug application is required even when you're using this in a clinical way without research purposes. So there are really a lot of legislative and regulatory issues to work out here. Other concerns include infection control the involvement of an ethics committee as we've done here. In our case we've also been asked to involve the pharmacy and therapeutics committee. Is this something that the nurses have to do? Is this something doctors will do? Is it done in an inpatient setting and outpatient setting? How long do you need to follow these patients? This is a table from our most recent publication that will be coming out in the inflammatory bowel disease monitor talking about the ethical issues associated with fecal microbiota transplant and IBD specifically. I actually adapted this table from the human genome project because I feel like they had a very strong ELSI which is ethical legal social issue platform and a really strong base of research on these questions and what's really remarkable is there's less than half a dozen publication on the ethical legal and social issues in microbiome based therapies or FMT. So clearly more work needs to be done. Some of these issues include uncertainties talking about the potential impact in vulnerable populations privacy protection and confidentiality if we find that one donor has a microbiome that's as good as gold for curing different diseases do they own it? Do we own it? Can you patent it? Can we sell it to a company who can make it? Can we extract it and put in a pill? There are really a lot of questions about that. Fairness, justice, legal issues who's going to decide? So just to touch upon the work that we're doing here and kind of round this out I wanted to just go over with you briefly the study that we're going to hopefully be starting in the next month or two which is a prospective study for adults with ulcerative colitis and I want to highlight that this is a really unique we feel is a unique study because not only are we going to have the clinical endpoints where we establish the safety and efficacy of FMT and mild to moderate UC and not only are we going to have our microbiome endpoints where we characterize the microbiome pre and post donation but we also feel that it's really critical to continue to evaluate the ethical and safety concerns around FMT as a whole other area entirely. And I just wanted to give you a sense of some of the screening questions because I mentioned that these individuals go through quite an extensive screening many of you are familiar with the screening that you undergo when you want to donate blood this is actually more involved than the donation for blood the questionnaires that have been developed include over 50 questions that are done within a couple of weeks of donation and then another repeat questionnaire that will be given to donors on the day of donation to make sure there have been no changes, no development of GI symptoms and I'm sorry the print might be too small to read but these questions range from anything from sexual habits exposure to high risk behaviors tattoos, travel but then in addition to all of those questions you also have questions about GI habits, antibiotic exposure and other things that might impact the microbiome so hopefully the next time I speak to you I'll have the new data about this study and some of the ethical and clinical endpoints that we've established so I would just like to conclude by saying that I feel and hope that I've demonstrated to you all that the microbiome contained within our stool is an organ and as was pointed out by two microbiologists the microbiome constitutes the last human organ under active research like other organs and despite its intrinsic complexity the microbiome is readily inherited and like any other organ the microbiome has physiology pathology and the individual and collective health may be damaged when its collective population is altered and I would just like to take a minute to thank everybody in particular my mentor for this project and ongoing work David Rubin in the adult GI section Jean Chang overseeing all of the microbiome data Yun Wei Wang who helped us perform our fecal transplants as well as Mark Mush who's here Lainey who's been an outstanding mentor for all of the ethics related issues and also like to acknowledge our pediatric FMT working group who is a group of individuals across the country who are interested in advancing this treatment for children with CDIF and IBD the adult working group and then of course our invaluable research coordinators Sarah, Tom and Rubin and Allison in the OCR who helped us with our IND application which in the end after two years was over 200 pages so and of course I'd like to thank our funders the Gastrointestinal Research Foundation and of course the CTSA and with that I'd be happy to take any questions I guess even though we're in a different room we have the same process with the the microphone so that the video camera can capture it. Terrific talk we'll get to you here so is there the differentiation between organ and tissue cell is critically important from a regulatory point of view and despite your desire to be classified as an organ it appears as if the FDA has decided that in fact it is a tissue or cell because the reason I say that is that the FDA does not regulate organ transplantation and the FDA has made it clear that they do regulate tissue slash cell and that's why Larry and I and others made a big point in the early phases of what we CTA or vascularized tissue transplants really to think of it more as an organ and we're making good progress I don't think the final decision has been laid down from the regulatory but every indication is that in fact the vascularized aspects of tissue transplantation et cetera will be classified as an organ not as tissue slash cell Larry an organ right right so so it's it would be great it probably facilitate the progress of this for more rapidly if we were able to get it classified as an organ but it looks like the FDA has laid claim to this and just as we with eyelid transplantation it's classified as a cell and it goes under the FDA regulation and there's no way we can extract it from that similar for your stuff now the one question that I have and so if we kind of accept that as now decided by the FDA at least how much manipulation of the cells is there between procurement and implantation so the sample is obtained within six hours of donation of transplant it is mixed with saline and liquefied for delivery and that is all so the so the reason I asked that so the FDA and the reason I know all this is from the eyelid stuff the FDA has said that within cellular therapies if it is minimally manipulated then the level of scrutiny and oversight is far less than if it is extensively manipulated cells so the cells that we use for eyelid transplantation are extensively manipulated there obtained from an organ and then after 12 hours of processing we have a component that is utilized for transplantation versus something that is autologous and perhaps even allogeneically procured very little is done and then the level of scrutiny otherwise is very low so hopefully you're at least in that category hopefully thank you for your comments similar thing with fat and stem cells derived from fat correct that you can harvest and put it in without FDA approval but if you harvest it they manipulate it and send it back you need FDA approval so this sounds like you wouldn't need FDA approval you make an excellent point and actually when we first submitted our IRB application almost two years ago now we assumed that it would go through I had multiple discussions with members of the IRB about the requirements and what would be involved and the steps necessary to make sure that we had everything in place and it came back with a pending conditional review pending conditional approval from the FDA so we went to the FDA and we said do we need an investigational new drug application and they said yes and we said huh we didn't know that we needed this and mind you during this time multiple groups are publishing on the use of FMT both in animals but numerous studies in humans as well that clearly groups are not having an FDA application involved so we actually had an extensive conversation with the GI department including Steve Hanauer who had many discussions on our behalf with the FDA trying to determine why they felt that they needed to regulate this yes exactly so they were pretty clear that they wanted us to go through this process and this public workshop that they hosted about a week and a half ago was really to let other people know because FMT was being is and was being done across the country without any regulatory oversight for better or for worse and now that has really put a halt to the use of FMT even in clinical settings where it may be indicated and the best option for patients yes especially for CDF I think that there's a lot of debate about FMT for these other conditions and I'm hopeful that it may provide some options for my patients with IBD but I'm also realistic that it's not going to be that simple and I think that what is unfortunate is in this situation as you guys have mentioned with the FDA involvement and not allowing us to call it an organ and really designating it as a tissue and something that's a biologic substance that they want to have oversight and regulation of is that it's going to slow down individuals abilities to treat patients that would otherwise be appropriately treated with FMT on a physician basis which is when we discussed this with our IRB they said you can treat the patients how you see appropriate we don't oversee medical decision making we oversee research treatments and research protocols so it's really changing how FMT is going to be used because obviously this process is really involved and lengthy there's no standard application that all groups can use so the smaller community or non-academic centers have no foundation or support team to really help put this through so it'll be very interesting because groups have been reporting doing hundreds of them and just not publishing the results because it's shown to be effective and what's really interesting is we may not have all of the safety data there have really been very limited reports of adverse reactions and in fact the only adverse reactions have been in patients who have had CDIF and IBD may have had worsening of their underlying inflammatory bowel disease although in all of the cases they've had clearance of the CDIF so it seems that at least for CDIF even in young children even in the elderly even in those with sepsis or organ failure that it seems to be safe and when you consider the alternatives of those patients in the MICU or the PICU are really quite ill it seems like a reasonable option it strikes me the FDA is not exactly experts in your philosophy or ethics and that's the question those are the questions we want to raise here and it strikes me that your claim that it's an organ may even be distracting I'm not sure what it gets you other than maybe trying to claim credibility and equality with other sorts of things because scientifically you don't need anything more than you've got already and you don't want to raise questions about outside of commensals and symbiosis because you raise questions ontological questions about whether pilot fish which are symbiotic with sharks become an organ because they're necessary or whether the moss and lichen is an organ because the lichen is really an organism and those sorts of questions I think are just just distracting I don't even think it gets you anything in terms of the ethics of a question like ownership because I would think that probably if you begin to look at it the question of whether this is inside a person and is in a symbiotic relationship would be enough to make or not make the claim of ownership the same as if it was an organ anyway so I don't think it's going to do anything except maybe some regulatory issues you might get around but from a philosophical point of view I think it's merely a distraction and it might be best to just sort of say it has a lot of similarities to organs and then you avoid those controversies Thank you I had the same thoughts and I wanted to use the term organ envy for the concept there just one follow up on the regulatory and stuff when the FDA came down and said cellular transplants were under their purview it had a huge effect and deleterious effect on the progress for cellular transplant and in fact whereas at the time there was a lot of enthusiasm and effort and hepatocyte transplant it essentially killed it because there's not enough funding for hepatocyte transplantation versus islet transplantation that's why islet transplantation continued and hepatocyte transplantation in this country essentially died after that Very quickly Stacy is there a standard treatment protocol that people around the country are using published and reproducible or is everybody doing things differently That's an excellent question there were guidelines written and published by the FICO Microbiata Transplantation Working Group in 2011 published in the clinical gastro and hepatology that outlined the basic screening requirements I would say that since that time the screening requirements requested by the FDA have elevated what is being asked and I think it's continuing to evolve as I said I think that this is relatively early in the field and I think as we start to understand more and changed our criteria and our protocols but there are these screening guidelines and there are the protocols that are available online By the way I think you could have an opt out you could screen someone's stool and say it's just not ideal just like we would screen a kidney or liver donor and say it's not the ideal scenario if you wanted to have an opt out scenario for the donor The question is would then they have already incurred the cost of screening and would they be willing to donate because some of the individuals may have the yuck factor and they may not want to donate I have two comments one in ownership it seems to me that something so long as in your body you may claim ownership but once you discard something you no longer once you discard something you have no ownership once you discard something you have no ownership and more you know you could have a most beautiful painting and you put it in a garbage you no longer own it if you feel it is owner then you have to take responsibility make sure it's not a public news the second comment we don't know entirely it is harmless do we no so why shouldn't then FDA have any participation in it if we don't know that it is entirely you even people want to say lemonade outside they may have to have some kind of you know supervision to make sure that it is not harming people the water and so we give something from someone's body to another one which we not entirely sure it is harmless and then we would like to have FDA have no participation in it I'm not arguing that the FDA shouldn't participate and thank you for your comment Shavad I think that what we're troubled by is the regulatory process that seems as others have pointed out not necessarily based in the individuals who have the most experience or expertise so there have probably been several thousand patients with recurrent or refractory C. diff who have received FMT at least a thousand of those reported in the literature with no adverse information about it now that's over maybe a ten year time period so we don't have longitudinal data twenty fifty years out but there have been many drugs and devices and therapies that have been approved by the FDA with a lot less regulation and supervision and in this case this may be a life-saving treatment for many individuals so if the FDA can create a process that is streamlined and easy enough for most people to lead in a reasonable time frame to tell you it took three of us two years to do it is not reasonable for most people it's not reasonable for me I think finding a way for them to maintain their regulation and certainly for conditions other than C. diff is important one of the things that was suggested at the public workshop was the creation of a registry so that all patients across the country will be put into this database so we can have long term safety data so then the question becomes who's going to fund it who's going to maintain it so these are some very important issues that we still have to grapple with so this is a I'll get to you in a second it's a very sticky area and part of the regulation for this kind of thing also comes back probably a decade plus ago there was a lot of enthusiasm for doing stem cell transplant for patients with heart attacks and there were a proliferation of centers similar to this just went and did it without any oversight without any IRB control trials or anything so the FDA became increasingly sensitized to this area re-emphasized their control over cellular therapies and probably somewhat the reason they've taken such a hard line is in your talk you mentioned that there are places out there that are just doing it and that's the kind of thing that the FDA doesn't like there's lots of things that we do in transplantation that harm people and have the potential of harming people that the FDA has no control over so just because this has the potential of doing harm that the FDA has regulatory oversight so it's a very complex avenue and field that we're in and I would just like to point out that the medications the standard antibiotics that we use to treat clostridium difficile in children metronidazole as well as vancomycin are not FDA indicated for the use of C. diff in children so the current therapies and quote standard of care as well as many of other antibiotics used to treat C. diff in children have no FDA approval or oversight and at the cost of thousands and thousands of dollars as well as the questions of whether the long term safety of those medications are so it's hard for me to believe that this isn't going to move forward so I'm thinking of it mostly as a regulatory, political strategy, tactics perseverance, patience kind of an issue but I think the interesting to me more interesting issue is kind of this ownership and maybe profit thing and so my question to you is what do you think would be an ethical way to distribute or share the profits that come out of this because I imagine there being profits once it goes forward well the academic institutions that are conducting research on the microbiome many of which are NIH funded and it all goes into public domain so nobody owns the information about the microbiome just like nobody owns the data from the genome project and so well no okay well they're not supposed to right it's supposed to be available and right that's true I stand corrected right that's true so I think those raised some excellent questions there are certainly a number of industry groups that are trying to develop versions of microbiota transplants that are derived from individuals with no renumeration to those individuals who donated the samples there are individuals trying to create synthetic stool just like groups have tried to create synthetic blood and it's unclear clearly my interest in this are academic and I'm not and I think many of the individuals who I collaborate with and participate in this aren't interested but I think you raise a really good question of who's going to own it I mean it'd be nice if there are anything that profits that get generated that they get put back into the research to further the field because these are expensive studies the microbiome based studies are incredibly costly the procedures are not covered by insurance in most cases so it'd be nice to either have those go on to perpetuate the projects clinically or research wise you didn't mention the donor maybe I'm missing something but what I don't understand is the rationale for what seems to me a pretty important distinction between the therapy for C. diff which has really been demonstrated to be usually more effective than the alternatives and much less expensive and the areas which are relatively experimental because we don't have that data what kind of rationale can you give for not at least making that distinction oh I completely look at you understand do they have any kind of rationale they being the FDA because evidently they're the ones that are not making the distinction correct so they saw this public workshop as the door to a discussion and they appreciated all of the comments that we made many of which are similar to the comments that have been made in this room many people raised the issue that they wanted a clarification about what additional evidence would be needed to accept FMT as a standard treatment either for recurrent or refractory C. diff and they really were not able to provide us with any answers so we're hopeful that they are back at the NIH and we'll talk about this and providing some clarification about what the distinction is between FMT for something that's been established to be safe and effective and what's the difference and it's used for other conditions where it may be more experimental and what is the process for moving the research forward in both of those conditions well join me please thank you