The role of the gut microbiome

RICK WEISS: Hi, everybody, and welcome to this media briefing from SciLine. It’s great to have everybody aboard. I want to take a minute and a half or so just to introduce those of you who are not familiar with SciLine to who we are and what we do. We are a fully philanthropically funded free service for reporters. We’re supported by a handful of philanthropies to do one mission, which is to get more scientific evidence and research-based results into news stories. Philanthropies have come together to support this kind of endeavor in light of what’s been going on in the journalistic landscape. We know you all have tighter deadlines than ever. And in many cases, specialty reporters have gone away. And some of you are more generalists and could use some help with expert information and expertise to get your stories on a more factual basis and not have to stay at a surface level, at a level that you’re just sort of intuitively comfortable with but really get the details in there.

So SciLine does a variety of services to help you out this way. Our matching service, which I encourage you to check out, along with other things on our website, sciline.org, connects you on deadline to an expert who can help you with a story while you’re working on it. We produce fact sheets that are specially designed for use by reporters, which is to say if you’re in a hurry, and you just need some essentials, they are there. They’re produced in-house and vetted by outside experts, so you can trust them. We do training boot camps, all expenses paid, typically 2 1/2, three days, bring people together and get you up to speed on different topics. And we do media briefings, like this one, where we’re going to present you with a trio of experts with some deep knowledge on the topic of the day, the microbiome and its connection to health and, in particular, the gut microbiome.

So a very quick introduction to our three speakers – you can get more details on them on our website landing page. But we will hear first from Lita Proctor. Lita was a program coordinator of the Human Microbiome Project, which was a National Institutes of Health project that looked into some basics about the human microbiome and its role in health. And she’s going to talk about some of those basics and get us on a good foundational footing on the topic and tell us what that project has found so far. Then we’ll hear from Dr. Jeff Gordon, who is at Washington University, the director of the Center for Genome Sciences and Systems Biology there. And Jeff is going to talk about the use of microbiome products for therapeutics and the role of the microbiome in disease and the possible role in therapeutics and how the microbiome contributes to health. What are the targets that folks are aiming at to use these things as therapeutics? And what are some of the complications when you try to translate from animal studies to actual human clinical trials?

And last, we will hear from Anna Seekatz, who is an assistant professor in biological sciences at Clemson University. She has the – I guess the most colorful aspect of the microbiome story that a lot of us have been paying attention to lately, which is the issue of microbiota transplants as a therapeutic approach. That is moving different populations of bugs into people as an approach to treating diseases and, in particular, with a focus here on infections with Clostridium difficile, a very serious, potentially fatal infection – often pops up in hospitals and other settings – and get us up to speed on what’s going on in that field of research and what the promise is going forward of microbiota transplants. So with that, why don’t we just jump right into it? Each one will make a relatively short presentation, and then we’ll have lots of time for questions from you for the rest of the hour. So why don’t we go to you, Lita?

[0:03:54]

LITA PROCTOR: OK, great, Josh. So we got a lot of coaching from Rick, from Mohamed about how to make this really complex topic as simple and straightforward to lay the foundation for you folks. We’ve done our best. Of course, we will know by the questions that you ask us whether we’ve conveyed the information or not. So let me start with the first slide. And the question that Mohamed asked was, let’s start with asking the question, what is microbiota, and what is the microbiome? But in fact, it kind of solicited a larger issue that I’ve dealt with, that we’ve all dealt with. And that is it has been difficult for the media community, for the research community and for the lay public to get our heads around, what is the microbiome? You know, sometimes – and I’ve got a number of journals and magazine covers here – certainly, we initially thought of microbes as germs. And now we’re trying to make them good, so, sometimes, they’re called good germs. On the other hand, they play this major role in our bodies. So we try to think of it as an organ system. Sometimes, you hear many people speak of the microbiome as an organ system. Others are trying to bring in ecological ideas, how these microbial communities interact with each other and their human hosts. And so they try to throw in, like, this notion of an human ecosystem. So you can see all the different really, frankly, the struggles around trying to get our heads around this really fascinating but complex system in our bodies.

So typically, microbiota is used to describe the collection of microbes by their names in any organ system they’re found in, any epithelial surface inside or outside our bodies. And then the term microbiome has been now more recently used to really describe the genetic – genomic complement of all of the microbes that live in these – in us. So microbiota is the collection of microbes, and microbiome is their genetic complement or their kind of metabolic factors as well, next level. So I’m throwing the word around – microbes – a lot, so what are microbes? You know, we often use the word microbes to mean bacteria, but in fact, it’s much, much broader. Of course, we admit that a lot of the initial focus has been on the bacterial component of the microbiome. But in fact, it’s any kind of microscopic life form. That includes bacteria, of course, archaea. I try to give little cartoon examples of what these different subclasses of microbes are. We know them as swamp gas producers out in the environment, viruses, any kind of virus would be considered a part of the microbiome, bacteriophage, which are viruses of bacteria, fungi and protozoa.

So even though most of our attention here in the last decade or so has been on the bacteria, the microbiome in our bodies and anywhere – microbes live everywhere – is a much richer complement of microbes. And in nature – I really want to point this out – there are a couple of very important key principles of how they live in nature, and it’s also, in some regards, hindered our ability to study them. They don’t live alone. Unlike this culture dish or the micro graphs I have here on this screen, they don’t live alone. They live in communities. And they interact in communities. So even though the classic way to isolate microbes from any environment is by trying to culture them in a flask or on a Petri dish, in fact, kind of working against their nature – so hit it one more time, Josh. There’s going to be a picture that’ll pop up. Go ahead and hit it, Josh. There you go.

You don’t see this very often, but this is how microbes live. They live in complex communities, often held together by biofilms or other kinds of microbial glues. And they communicate and talk with each other and work together to metabolize any kind of foods that they may encounter. But those are kind of principles of microbes that you should keep in mind. Next slide – slight lag here. OK, so I mentioned briefly, we tended to think of microbes as germs. And in fact, most of human history, the way we’ve interacted with microbes has been as a result of infectious disease – you know, the plague, measles, all kinds of things that are even happening now. But let’s look at the total number of known human pathogens, and that includes viruses and bacteria and fungi and so on. And hit it again, Josh. That’s against the background, frankly, of trillions, trillions of microbial cells that live in every habitat on earth. Hit it again, Josh. The reason I want to make this point – and it’s a really important point, and it probably forms the kind of conceptual foundation for the Human Microbiome Project – is the majority of these microbes that we encounter on a regular basis throughout our lifetimes or wherever travel don’t cause disease. In fact, many of them are beneficial.

But let me just give you examples. On earth – we haven’t gotten to that human yet – but on earth – hit it again, Josh. Microbes on earth, they are responsible for the vast majority of nutrient production and regeneration in any ecosystem – forest soils, the oceans, lakes, any crop, any livestock. They produce oxygen of every two breaths you take. One breath of oxygen comes from photosynthetic microbes that live in the ocean. They’re the base of all food webs. They form the food for many microbes, many organisms that live in food webs, and they form the basis of food webs in every habitat. And finally, where we want to go with this, is they, in fact, support plant, animal and human health. Let’s go to the next slide. So now we’re at the human microbiome. I’m going to lay out some kind of fundamentals about the microbiome that hopefully gives you a big, kind of – broad picture of what it is. These are microbes – again, bacteria, viruses and so on – thousands of microbial species, all of which together possess millions of genes that live with us, OK? And that’s why I’m using the word microbiome because I’m describing the genomic content known as the microbiome, and there’s a slightly more technical term you might run across called the metagenome. These – most of these microbes aren’t culturable. And remember what I said about culturability. That’s the typical way we’ve been working and studying microbes in the laboratory.

The little graphic I have for you here is just a kind of a rough estimate of total abundances. In most cases, these are of bacteria. And what I want to show you, it’s not – this is not an exhaustive list, but it’s an example of the range of densities or abundances of microbes. They are found, frankly, almost anywhere in the human body. Hit No. 3, 4 and 5 there, Josh. We acquire our first inoculum at birth. We get our first dose – that’s what an inoculum means – at birth during the birth process. But in fact, our microbes are continually replenished throughout our lifetimes through continuous exposure to all kinds of microbes in our environment. No. 4, these microbes interact as communities. You remember, I mentioned that before. They don’t live solo. They live in communities, and they leverage each other’s metabolic capabilities to detoxify pollutants in our bodies, to protect us against pathogens. They communicate with each other as well as with the host, and they actually make food for the host.

So the best example for the gut microbiome is microbes that live in our colon ferment fiber, and a major byproduct of fermentation – fermentation is like, you know, beer or wine or any of those microbial processes – but in our gut, they produce something called short-chain fatty acids. Now most of the cells in our bodies use glucose. Our gut cells use these short-chain fatty acids for energy. So that’s food. And finally, because these microbes are living in this larger thing we see in the mirror, I think it’s important to point out that the human microbiome augments, extends and frankly supports capabilities that are encoded in our human genome. And I’ve got another cute graphic. Hit it again, Josh. This came from Scientific American, and it kind of graphically shows you the total collection of genes in the human, which is 20,000 to 25,000 genes, versus just in the gut. It’s an old estimate, but still, millions of microbial genes that are like the engines in our bodies. OK, next slide. And I want to bring – I brought this in. I know that Mohammed was hoping I’d leave it out. But I think another really important point that we all want to emphasize is the microbiome is a co-evolved feature of our bodies. These microbes just didn’t fall out of the sky and grow on our bodies, OK? Like every living thing that has its own associated microbiome, we have our own associated microbiome that has been honed through millennia.

And the reason I want to bring up human milk oligosaccharides, or HMOs, is for two reasons that I think are totally cool. No. 1, if you look on the left-hand panel, there’s hundreds of different kinds of these sugars in breast milk, OK? And the question was always, well, why is there so many complex molecules? I mean, who cares? Well, it turns out – and it’s an idea that’s being rigorously tested right now – is that these sugars in breast milk are actually the food for the baby’s developing microbiome. It stimulates because all these different – it’s like a rich smorgasbord of sugars for stimulating this initial group of microbes that are colonizing baby. And at the same time, baby doesn’t have an immune system yet. It takes a few years for the baby’s immune system to develop. So the other hypothesis that has been – is being rigorously tested is that these sugars, HMOs, also act as molecular decoys. And I think of them as sort of sponges removing pathogens moving into the baby to protect the child as its own microbiome is developing. In my mind, this example of the role of human milk oligosaccharides not digested by the baby’s system, but the microbiome, is really the best example of this co-evolved system that we have. OK, next slide, please.

So Rick mentioned that I was overseeing this massive activity called the Human Microbiome Project. This came about because the early, early foundational work on the microbiome – the microbiome field wasn’t born out of the HMP. It existed before the HMP ever came along. But the approach was quite different. The approach in the early foundational field was looking at individual microbes and how they interact with the human immune system. So it was a real critical part of the field. But then, you know, like in any field, when new tools come along, there’s an opportunity to kind of change the focus or the way that you approach the work. So the interest was in developing tools to help the research community start looking at this large, complex microbial community in our gut, on our skin, in our mouth and so on.

So the HMP, the entire job of the HMP was to build out this massive research toolbox and get it out there as fast as possible in order to allow people to begin to now look at the microbiome from this community-level kind of analysis. This also – this logo of logos also probably shows you that we were able to kick-start a very large research community as a result of this large network of research that came together to help build out these tools. I had one more comment here I wanted to make. Oh, and the type of community focus that we really wanted to do was not only being able to characterize the complexity of microbes in any one microbiome, but to figure out what are they doing. So it’s sort of who’s there, and what are they doing might be the quick take-homes for the 10-year program in the HMP. And let’s go to the last slide. We had published a paper – I guess it was this year – on a 10-year analysis of how much microbiome work was going on at the NIH. And I want to use this slide to show you. First of all, the red is the HMP funding each year, and the blue is all the other microbiome research at the NIH that was not at all related to the HMP. So No. 1, I think I can, probably just by using this graph, argue that we really did kick-start the field because there was this explosion of research at the NIH on this larger topic.

At the top, IC stands for institutes and centers. It’s the equivalent of, like, departments at the NIH. So we went from just a very few departments to then more than 20 departments. There’s a total of 27, so the vast majority are funding this area. And at the bottom, it says PIs was a way for me to characterize how quickly the research community grew. So No. 1, we helped kick-start this new approach to the field. We really helped build out the research community. There is now over a hundred different diseases that are being studied and trying to understand the role of the microbiome. And maybe the fourth outcome of the HMP is I think one of the topics that Jeff wants to address; we’re not so much only focused on disease. We want to understand, what is the healthy microbiome? And the kind of tools that the HMP help develop and kick-start will help answer the question as to what is a healthy microbiome.

[0:18:44]

RICK WEISS: Great segue. Thank you very much. Jeff, why don’t you pick it up from there?

JEFF GORDON: I want to try to give everybody enough time to ask questions, so I’ll try to go through the 250 slides that I have relatively quickly.

LITA PROCTOR: You are very disciplined.

JEFF GORDON: I – as you are reading reports related to understanding the link between microbial communities and health, I wonder if I could give you a mantra to incorporate into your thinking about these types of reports and how the field is moving forward to, not only as Lita said, understand the operations of microbial communities and health, but how those communities are perturbed. So here’s the mantra. First slide, please. A multi-step journey – I don’t see the slide in front of me. I don’t know if it’s popped up yet or not.

[0:19:51]

RICK WEISS: Yes.

LITA PROCTOR: The journey. Is that the one you want, Jeff?

JEFF GORDON: Yeah.

LITA PROCTOR: It’s up.

JEFF GORDON: OK, so the definition of normal for a microbial community of interest – in this case, we’re talking about the gut microbial community in a given human population. So if the question, for instance, is – what is the path for assembly of a microbial community in infants and children in those that possess healthy growth, normal rates of weight gain and gain of height? – you would do an analysis sampling the communities from a group of individuals. Each individual is sampled multiple times to arrive at a definition of shared features of these communities in that particular population – again, in healthy individuals. The second step in the journey would be to take that definition of normal in one population and ask whether it generalizes to other human populations, so infants and children, for instance, living at other sites in the world with different or shared cultural traditions and anthropological features. So does the definition of normal generalize to other populations? And then the third step is to develop tools that allow measurements of deviations from normal. If you have what normal is, then you would like to determine how far from normal a particular microbial community is in individuals that have perturbed health. So is the severity of deviations from normal correlating significantly with a disease or diseases? Next.

A test of causality – what do I mean by that? If there is a perturbation in the microbial community associated with disease, and if the perturbation is more severe as the disease is more severe, is that an effect of the disease or a cause? Next slide, please. So a test of causality that you’ll often read about involves the following – take from healthy individuals representing a particular population their gut microbial community, freeze those communities in time, and then resurrect the microbial community in the guts of mice that have been reared under sterile conditions. These are called germ-free animals. So transplant a microbial community from healthy individuals into mice that are reared germ-free. And feed the mice diets representative of human diets. Same type of experiments are done in parallel with microbial communities from individuals with diseases of interest. And the question that can be asked in these sorts of transfer experiments is how much of the properties of individual with disease compared to those that are healthy can be transmitted to the recipient mice? If there is transmission, for instance, of reduced rates of weight gain or impaired bone growth or defective immunity or perturbed metabolism when you transfer a microbial community from an individual who has those features – disease – to the mice, that’s a positive test of causality, that those differences between that individual’s microbial community and a healthy individuals aren’t simply an effect but rather are our cause.

An important part of these tests are typically, whether it’s with individuals who have obesity or metabolic disorder or immune problems, that the intact community is transmitted to the recipient animal. If the test of causality is positive, then people will attempt to culture the organisms in that community and see whether the culturable component can transmit features of the disease. If that is true, that’s a voila or eureka moment because these cultured organisms can be the starting point for the development of next-generation probiotics – live microbes that, when transferred to human hosts, can provide a health benefit. Next slide, please – the important challenge of the field is to move beyond description of parts to an understanding of how those parts function. I’ll put this in a visual way, this challenge. The tools for describing the parts of microbial communities have really advanced rapidly. They’ve become more affordable, so we can describe the organisms in the genes and even some of the gene products with increasing ease. But if we took a group of fish and looked at them individually as individual parts rather than interacting parts, we would never understand the concept of schooling of fish. Or if we looked at individual parts in terms of birds in a flock and didn’t see the overall organization – how the birds interact – we wouldn’t understand the property of that complex system that we could call a flock – same thing for ants foraging. So it’s not just describing the parts. It’s determining how they interact that’s key for understanding communities in terms of their establishment, for understanding how they respond to being perturbed, how they are misfunctioning in disease.

This is the central challenge of the field. The number of possible interactions are literally astronomical. And a key effort is to try to look at these complex systems and to focus on some key features of interacting elements that can describe the overall organization and functions of the systems and also that could be therapeutic targets. So think not parts. Think interactions between parts. Next slide – so this is the last slide. I just want to emphasize, again, the elements that you might want to be thinking about as you read about scientific discoveries, particularly those that are trying to be translated into new therapeutics. So are there organisms or gene pathways that are underrepresented or underperforming in a microbial community associated with disease? What might the therapeutic targets be? If an organism is present but not at adequate levels or if certain products of that organism are not being produced at levels compatible with health, those represent therapeutic targets. And it’s really important to not only understand those therapeutic targets in terms of who they are but to define the mechanism of action by which they affect health – huge challenge.

The most important part of this field is to surmount these very complicated and formidable challenges of looking at mechanism of action. In the types of preclinical models that I alluded to where human microbes are transferred to animals and are used to determine whether those communities transmit disease but also to identify components of those communities that may be instrumental in producing disease in those models, if you have a target and develop a therapeutic, you’re going to test it in these type of animal models and then determine whether results from the animal models translate to humans. So this is a challenge that’s been faced by pharmaceutical companies, biotech companies for long periods of time. Do we have adequate representative animal models to portray the interactions of microbes with one another and their host? Find therapeutic targets. Develop therapeutic leads. When you start seeing some of these leads emerging from preclinical tests and being put into humans, it’s important for you, I believe, to think about a couple of parameters – first of all, the importance of the investigators taking a deep dive in describing the biological state of an individual prior to treatment.

One of the wonderful things about being alive at this moment in terms of the progress of biomedicine is we have these amazing toolboxes for describing the many features of a human being. This is advanced from genomic medicine. We can measure thousands of proteins in blood, many of which are not only biomarkers but are key mediators of all manner of different processes. We can study many metabolites. So what are the features of an individual with disease prior to treatment? When the treatment, which is microbiota-directed, is applied, how are these many features affected? What is the size of the effect? And are the effects shared across individuals? Because each individual has slightly different microbial communities. So is the therapeutic effective in its targeted particular microbe or pathway among many individuals? How durable is the effect? And how safe is the effect, both in the short term and long term? That’s a framework for thinking about describing normal – describing disease states in microbial communities, understanding mechanisms, delineating targets and testing them, and there are examples emerging about how results from preclinical models are translating to human studies. One such translation is occurring in the field of childhood malnutrition, which I’d be happy to talk about when you have questions. Thank you very much.

[0:30:32]

RICK WEISS: Thanks, Jeff. And those last little sub-bullets are great questions for reporters to be able to ask as well. How long did it last? Did it work against a variety of people and so on? So that’s a great reporting primer. Anna, let’s go to you on transplants for C. difficile and other purposes, and then we’ll open it up for questions. In the meanwhile, I just want to remind reporters, if you do have questions, you can go to the bottom of your screen, hover over the Q&A icon and type in your questions there for conveyance to the speakers. Anna?

[0:31:03]

ANNA SEEKATZ: Yeah, so it’s great to follow Lita and Jeff because I thought that they did an amazing job kind of describing the broad variability in issues that we sort of have in the field when we’re trying to develop these microbial therapeutics. But that said, I’m going to go a little bit more specific and talk about one particular pathogen. And so you can bring up the slides if you want right now. And so my favorite pathogen that I work on is actually very intricately tied to the gut microbiota, and that’s Clostridium difficile, or Clostridioides difficile, as they now call it, because they changed its name. For the purposes of this talk, I’ll just be referring to it as C. diff or C. diff infection or CDI. And so really, C. diff infection is mainly known as a health care-associated infection, but it’s associated with a lot of high medical care costs and serious clinical outcomes.

And interestingly, in recent years, both health-care-associated and non-health-care-associated infections have been on the rise. And some of this increase can be attributed to a couple of what we think of as more virulent strains of C. diff that have been identified globally, but it’s also just as likely that some changes that have occurred in our gut environment, specifically the gut microbiome, could also be responsible for this increased incidence. And really, there’s a lot of evidence to suggest that a healthy microbiota is key to prevention of C. diff infection. Classically, most patients with C. diff infection have been exposed to antibiotics prior to disease, but like I said, recent evidence suggests that many types of changes to the gut microbiota, such as following some type of diet or certain types of medications or present in a certain patient population, could also be some important risk factors that we have to consider. And so really, when a susceptible individual comes in contact with these C. diff spores that are highly prevalent all over the environment and in hospitals, it’s really just susceptible microbiota that can promote growth of C. diff, resulting in that individual either being colonized by C. diff but also then potentially developing disease.

So a lot of research has focused on what defines a susceptible microbiome during this period, including focusing on looking at the types of bacteria – so kind of more of this description idea that Jeff talked about – but also starting to look at what types of bacterial functions or bacterial products could lead to infection. Other research to keep in mind with this is – there is a huge push for alternative treatments for C. diff, which are currently antibiotics, and that, you know, even more destroys the – can destroy the microbiota. But really, there’s a push to look at, you know – looking at treatments that would preserve the microbiota while still targeting C. diff. And I also want to point out a little bit – and feel free to ask during the Q&A – that we don’t know a lot about asymptomatic colonization by C. diff. This could be tied to that increase in non-health-care-associated infections that we see in the community, but really, that’s also sort of a burgeoning area of research in this field. And you can go on to the next slide right now. So another piece of evidence that supports the idea that a C. diff infection is reliant on a healthy microbiome has really been the success rate of one particular treatment, and that’s fecal microbiota transplantation, or FMT. And really, FMT is exactly how you think of it as. It’s the transfer of a healthy individual’s fecal material into the recipient, and this idea that fecal material could cure diarrhea has actually been around for hundreds of years. It’s been referenced in some Chinese manuals and instructions as early as the fourth century, referred to as yellow soup or golden juice for the treatment of diarrhea. And it was applied for the first time, I believe, in American hospitals in Colorado in the 1950s for the treatment of antibiotic-associated diarrhea before C. diff was even identified as the major cause of antibiotic-associated diarrhea.

And so really, for treatment of C. diff in the last couple of decades, FMT has had some crude beginnings. It’s become very popular, but initially, most hospitals that were, you know, doing this type of treatment were relying on the patient to identify a donor. And then that donor would be screened, and then that material would be blended and filtered in a very crude way and then administered to the patient via colonoscopy, endoscopy or enema. And so a lot of research labs as well as companies are now sophisticating this process. So there has been a poop bank that will harbor prescreened fecal material that you can purchase open vial, so this takes a little bit of the burden of choosing that donor away. And now a lot of companies are encapsulating fecal material or even more defined spore mixes and types of bacteria that we think might be responsible for clearing C. diff into pills that can be then ingested orally. And really, FMT has been so successful for C. diff infection that it is being considered as treatment for other disease states and, you know, being applied in a DIY manner by patients with other GI conditions or even other non-GI conditions who are rightfully desperate for a cure. But I just want to note that it’s extremely important that this procedure does not come without risks, and there are many unknowns. And so it’s possible that fecal material from some individuals could contain pathogens that we have not yet identified.

We also don’t know what the long-term consequences of transferring microbes from one individual to another is – where perhaps the recipient person’s genetic makeup or immune status isn’t quite as tolerant of those types of microbes that were present in the fecal material. And recently, the FDA, which is responsible for regulating FMTs and other microbial therapeutics, administered a warning about the use of FMT for – because a patient died after being – after receiving a fecal transplant that contained a multi-resistant drug organism. And so really, currently, the FDA only sanctions the use of FMT for the treatment of recurrent or very severe C. diff that has been shown to be refractory to treatment. And so finally, one other important note is that, you know, FMTs have been extremely successful for C. diff infection, but even for C. diff, we still don’t know exactly how it works. There has been some great work by multiple research groups identifying certain types of bacteria, such as Clostridium scindens, that can attenuate initial susceptibility, but there’s a reason why we don’t have a one bacterium or one probiotic treatment for curing a C. diff infection. And really, that’s because the microbiota is so complex with so many interactions that we have yet to identify, and as both, you know, Lita and Jeff had sort of pointed out, that these can vary across the human population.

So as far as the use of FMT to treat other conditions, the case for FMT is a little bit less clear-cut. FMT has not been nearly as successful for treating inflammatory bowel disease, which is a serious GI condition in many patients and also patients who are more at risk for contracting C. diff. But really, these areas of research – you know, how microbe swapping is tolerated by humans, what exactly the microbes are doing to prevent or cure a particular disease – are critical to the future development of microbial therapeutics. And really, these types of therapeutics could occur in multiple different ways. You know, as Jeff has pointed out, we could put together groups of bacteria to target one particular disease. So this would be more of a probiotic approach. We could provide our microbes with certain nutrients that promote the growth of specific microbes. So this is more of a prebiotic approach. And finally, some labs are even working on reconstituting some microbial functions that we think might be important and putting these into engineered microbes or delivering that to the gut by other methods. So really, for future fecal transplants or microbial therapeutics to work, there’s still a lot of work out there for researchers and industry and the like. And it’s important for patients and media, clinicians and researchers to not blindly follow the hype that sometimes gets written up about very specific studies.

[0:40:00]

JEFF WEISS: Fantastic. Thank you, Anna – really interesting set of presentations there. Fascinating to see, in some ways, how young this field is, considering how much commercial activity there does seem to be growing in this area, so – and that is reflected in some of the questions we’re getting here. Let me just start with one from Tina Saey at Science News. How can an individual know whether they even have a healthy microbiota? Is there any kind of a test right now or a screen? And if they want to change it, the question here is, you know, can they change it? I think you’ve spoken to that a little bit, Anna, yourself. Right now it sounds like probably not in a very directed way yet, but can a person even find out if their microbiota is OK? This is not directed to anyone, so whoever wants to jump on that…

[0:40:44]

LITA PROCTOR: I’m going to just make one response to that. A while ago – maybe four years ago now – Rob Knight, who’s a scientist at the University of California San Diego, set out to basically engage the public and say, you want to know where your microbiome fits in with everybody else’s? And you send in a sample – stool sample. And I don’t remember how it worked. It was some type of – what do you call it? – GoFundMe-type structure. But the point was that it worked very well to answer that kind of question because once your microbiome was analyzed, you could see where you fit in to the American public. And then there were other criteria – you know, age, gender, a number of other properties – so you could figure out where you fit in. So it is one way to compare yourself against other people in your community and your population. And the American Gut Project – that’s what it’s called.

The American Gut Project is an example of that effort to help the public figure out where their microbiome fits into the larger scheme of things. I don’t – you know, I think Jeff was trying to make this point. There’s no, like, absolute gold standard. This is a healthy microbiome. It’s all population-dependent, age-dependent, all kinds of other things. So this community or population approach the American Gut has is probably the best way right now – I’d love to hear from the other two – the best way right now for an individual to figure out where they fit in.

[0:42:14]

ANNA SEEKATZ: Yeah. I mean, I’m definitely of the agreement that there are multiple types to the healthy. At least for the C. diff world, there are multiple types of susceptible microbiomes, as well. And that makes our job even harder because there’s not necessarily one profile that we can look at and say, well, they’re not going to get C. diff, especially when you’re talking about hospital populations where the microbiome doesn’t look like a, quote unquote, “healthy individual.” I mean, that said, we can definitely sort of tell – you know, if we’re comparing someone’s – a healthy individual’s microbiome to someone who has C. diff, you can – you should generally be able to make that type of distinction, but, you know, that distinction of the susceptible individual can be very broad, so it makes it difficult.

[0:43:03]

JEFF GORDON: Tina, I’d like to turn around your question a little bit and talk about the connection between different components of a microbial community in certain systems and subsystems in our body because the functions of the gut community extend well beyond the walls of the gut to influence many aspects of our physiology. So I mentioned the idea that if we can obtain a much more detailed description of healthy state – and some of the tools that are coming out now are proteomic tools where you can measure literally thousands of different proteins that are key markers and mediators of many of the different functions in our body at different stages of our life journey, in different cultural lifestyle settings. How to connect the parts of the microbial community with specific functions – perhaps the most informative setting for that is to take a diseased microbial community and try to repair it. That act of repair allows these connections to be examined, and those are the connections that I think are going to be most informative in determining whether, in the context of your body, the parts, the interactions between the parts and their microbial community are such that they’re sustaining health and whether they could, in a different microbial community context, also perform the same function.

We live in an era of precision medicine. The microbiota does a lot of different things. It has lots of different components that interact. So I think we need to think of it this way. In the case of childhood malnutrition, where microbial communities don’t develop normally and where these children have arrested development of the microbial communities which we think are causally related to many features of malnutrition – when we have microbiota-directed food interventions where prebiotics are given to target certain microbes that we think are growth-promoting – the reconfiguration towards a healthy state is mirrored in changes in the levels of many of these proteins that are involved in immune function and metabolism, et cetera. These are the great lessons to be learned at this moment in time. From that, you’ll understand what healthy is. I don’t think that defining healthy is just sampling, at a single time point, many, many different unrelated individuals who have many different lifestyles, including different diets. That’s an approach, but I think we’re taking a much deeper and ultimately more informative dive in the way that I just described. But thank you for that question. I think it’s a really profound one.

[0:46:00]

JEFF WEISS: Great. We have a question here actually aimed at Dr. Seekatz, asking that – I heard a while back that FDA was regulating fecal matter as organs, not tissue – so I can sort of see, given what you’re talking about, is a communal activity here – which would make transplant usage more difficult, though. It would be equivalent to an organ transplant. Is that still the case? Is FDA looking at things that way?

[0:46:26]

ANNA SEEKATZ: You know, I actually don’t know. The regulation of FMTs and other microbial therapeutics is under the Center for Biologics Evaluation and Research, and so I’m not – I know that they have multiple microbiologists in particular working on, you know, how to handle the regulation of a lot of different therapeutics coming to the market. But any type of therapeutic that is stated to be used for a specific disease needs to go through the FDA, but I have – I actually don’t know if they are regulated by tissue versus organ. I’m not sure.

[0:47:08]

JEFF GORDON: Can I have one other comment about that? I think that you’re seeing, in a number of different components of our society, two factors that are occurring coincidentally. On the one hand, the difficulty of, you know, regulating components of the microbiota – there are patent issues, but also, there are regulatory issues. It depends on the indications for which the intervention is designed. But at the same time, this community is being broken apart, and much more defined collections of microbes where we know all the genes, where these collections of microbes can be manufactured under best practices and where these defined consortia of microbes – let’s say from the gut – will be administered as a next-generation probiotic. So I think that the regulation of fecal microbiota transplants is a very intermediate step in terms of where we’re going to go.

[0:48:18]

LITA PROCTOR: Right.

JEFF GORDON: And when we think about the word probiotic now, at least within the field, we’re not talking about what many people can buy off the shelf, which are often from fermented dairy products that aren’t very carefully regulated, where the number of viable organisms in a pill isn’t always defined and even where the genome sequences aren’t defined. We’re going to have, in the 21st century medicine cabinet that we’re envisioning, these defined collection of microbes that will be administered in specific dose, and that those could be carefully monitored within reason. And not only the microbes but, as described, some of the metabolic products of the microbes will likely be therapeutic agents. So let’s think in that dimension and be alert to that as a goal.

ANNA SEEKATZ: Yeah. And apparently, the probiotics that you can get off the shelf, I believe they’re monitored for safety, but really they’re sold as dietary supplements, so they don’t require any kind of approval from the FDA.

[0:49:25]

LITA PROCTOR: Right.

ANNA SEEKATZ: But the minute you want to treat a disease such as C. diff, you do have to get approval. And it’s been very difficult to come up with an appropriate endpoint on how to measure the effectiveness of – you know, despite the clinical recovery, but really to establish, you know, is it colonization? Is it, you know, the function of the microbes? How do we measure that when we don’t quite know yet what to measure? That’s been a difficulty, I think.

[0:50:00]

RICK WEISS: Great. OK. Well, that question, I wanted to mention, was from Federer Kossakovski at PBS NewsHour. Can follow up perhaps with Anna if you want to get deeper into that. We did have a couple of questions asking about all these experts who are promoting specific diets and supplements to fix your microbiome. I think you’ve addressed that pretty nicely in the last couple of minutes here. Sounds like they’re not – certainly not closely regulated and not very carefully measured out. So we understand that. Here’s a question from freelance reporter Kathy Jean Schultz. She wants to know, with regard to fecal transplants, some stool bank donors are apparently screened for good health, such as healthy diet, weight, exercise. But could genetic factors also be relevant to your – and maybe a more effective way of screening? And would a person who lives a healthy lifestyle but has a genetic disposition to illness not be the best donor for this kind of activity?

[0:50:50]

ANNA SEEKATZ: Definitely. I think what – back in the day, when most hospitals were still kind of letting the patient choose their own donor or sort of finding their own donors, those donors get screened for diseases – you know, some viral and bacterial infections. But that was about it. So now with, you know, these poop banks popping up – although I believe OpenBiome is really the only one that’s going, that’s actively still providing fecal samples for hospitals. They go through a very extensive training process, which I believe they look at your health, long-term health, maybe even family history. And the rumor has it that it is more difficult to become a donor for OpenBiome than it is to get into Harvard.

[0:51:40]

ANNA SEEKATZ: So that’s how that is. But I believe once you’re screened and you pass their screening, you can donate multiple times, so.

RICK WEISS: That sounds like something an MIT person would say, but we won’t get there.

RICK WEISS: Here’s a question from a reporter – what are some of the – anonymous reporter, in this case. What were some of the pivotal scientific discoveries that opened the door to this improved understanding of the microbiome? In other words, what was previously keeping us from delving into understanding the microbiome and its connection to human health?

[0:52:15]

LITA PROCTOR: Well, I can contribute my point of view, and I’m sure the other two have their own. I briefly mentioned that in my introductory slides. Certainly, the field of human microbiome research has been ongoing for a long time. The early – in my opinion, the early period was really zeroing in on how specific microbes are interacting with the human immune system. But it was done as individual microbe by microbe. And there was a recognition. There was a large, diverse – my cat is in my office and crying. Sorry. But – I hope he wasn’t making too much noise. So the thing that I think the community was interested in is, how do we study this diverse, rich community of microbes? And I already mentioned that culturing them wasn’t doing the trick, that many of them weren’t culturable, or they interact with each other so much that you had to actually have cold cultures and other kinds of complex ways to get at these microbes.

And then out of another field, human genome research, came this vast improvement, advancement in sequencing technologies. And sequencing something without culturing it was a big boom because you just sort of try to jump over that step and just go right to the environment, whether it’s a human body or the ocean, extract the DNA and infer the community based on what your sequence analysis told you. Now, that was initially applied in environmental fields. The ecologists working in terrestrial systems and oceans and so on was utilizing this DNA analysis approach to get at characterizing communities. So at least from the NIH perspective, when I came on board, it was quite clear that the jump-start was coming from being able to adopt sequencing technologies that had been developed for the Human Genome Project but also being used by environmental scientists and ecologists, but now applying it to trying to characterize microbes in the human body. So that’s one thing that helped kick-start this new era or a second phase of human microbiome research.

[0:54:33]

RICK WEISS: Wonderful. Question here from Jill Draper, who’s based in Kansas City. Can fecal transplants be used to correct lactose intolerance or other food sensitivities?

ANNA SEEKATZ: Well, I mean, for something as specific as that, I wouldn’t necessarily want to go the fecal transplant route, right? What you’re probably looking for is the recovery of a specific function in this case. So, you know, lactose intolerance – so, potentially, you could either engineer a microbe or apply a microbe probiotic to sort of reconstitute that function in your gut.

RICK WEISS: Right.

ANNA SEEKATZ: Yeah. But, I mean, I guess – yeah, I don’t think it would – I don’t think there has been any evidence that fecal transplant has reversed someone’s lactose intolerance. But it’s a good idea. And perhaps someone has a business out there looking at that. So…

[0:55:30]

RICK WEISS: That’s actually a great segue to another question here. We just have a couple minutes left. But a reporter is asking here, how will pharmaceutical companies get involved here? Who’s going to make money off of fecal transplants? And are there ethical implications? Are we heading to an area – an era when we have to think about whether Big Poop is somehow taking advantage of us?

[0:55:54]

ANNA SEEKATZ: Yeah. I mean, to a certain extent, I do think that there’s already some turmoil in the field. I think Jeff mentioned, you know, how does one patent a living organism? So that’s definitely something that’s been a little bit interesting going along. I do believe that people patent organisms for specific uses and functions. So that’s definitely, you know, applicable. But just patenting the existence of a microbe – that’s a little difficult. And then there’s the other idea that, you know, even if you put this microbe – this secret microbe or microbial mix or poop on the market, you know, anyone could probably just come in and isolate it. You know, I don’t know how that’s going to work. So…

[0:56:41]

JEFF GORDON: I’d like to make two comments quickly ’cause I know we’re running out of time. More and more work is being done to determine how an individual’s microbial community – remember, there are literally hundreds of thousands of genes in a given individual’s gut microbiome – how some of those genes may determine the metabolism of drugs that are orally administered and why differences between individuals, in terms of the response to different drugs, may be ascribable to differences in their microbial community – point one. Point two, microbes are master chemists. And they’ve devised ways to produce products that affect the features of their human hosts. And oftentimes, new pathways or specifically new ways of manipulating pathways that are important to health or that are perturbed in diseases may be revealed by some of these microbial products. And I think when we’re mining the microbiomes of humans, from a chemical perspective, I think that there’s a tremendous amount of opportunity to understand how this intersection between microbes and us regulates our health status. So those are two motivations for the pharmaceutical industry.

[0:58:00]

RICK WEISS: Great. Lita, any last thought from you as we close here?

LITA PROCTOR: No. I’m really delighted that you organized this panel. And I think all of us are very happy to answer any questions that maybe come up later as the reporters are digesting the information that we shared – certainly available.

RICK WEISS: Thank you all.

JEFF GORDON: I think the field…

RICK WEISS: Yeah, go ahead.

JEFF GORDON: One last thing. I think the field is important in giving everyone a more holistic view of what constitutes a human being…

LITA PROCTOR: Exactly.

[0:58:36]

JEFF GORDON: …And improves the definition of health to appreciate what the interactions are between our microbial communities and ourselves. I think that’s going to have a huge impact on preventative medicine and also trying to understand recovery from disease and risks or relapse. So I think terra incognita is becoming more cognita – that is to say we’re exploring the wilderness in the gut. Lots of people are focused on the fecal microbiota. But there is 8 or 10 meters of small intestine that’s populated with… (Inaudible) …In the future. The story is unfolding.

[0:59:20]

RICK WEISS: You folks are explorers in a really interesting way. I want to thank you all for helping out on this media briefing. I want to remind all the reporters who are tuned in right now of a couple quick things. First of all, the transcript – video and transcript of this media briefing will be up on the SciLine website probably by Friday, maybe Monday. So we encourage you to be able to look back at that and pull out parts that are of most interest to you. I want you all, of course, to be following SciLine at @RealSciLine to keep up on all the offerings and free services that we have. And last, you will see as you shut down, you reporters, at the end of this briefing a quick message asking you to answer three short questions. I know we’re all tired of the surveys that come to us from every place that we shop and visit. But it would really be helpful to us for you to take the half a minute it’ll take for you to answer those three questions so that we can keep these media briefings as useful and interesting to you as possible. So thank you in advance for doing that. Last, thanks again for our guests, Jeff Gordon, Anna Seekatz, Lita Proctor. Thank you so much. And we look forward to seeing you reporters again on our next media briefing. So long.