So, I'm thrilled to be with all of you here today, and I hope by the end of this session, you will feel as passionate about the microbiome as I do. And I hope that I can impress upon you that it is incredibly critical that we continue to grow and follow the literature for both microbiome and probiotics and other microbiome interventions to create the best opportunities to improve care for our patients. But before I start, I'd like to describe my, I'd like to call my alignments of interest rather than my conflicts of interest. I'd like to believe I'm in alignment with the NIH and the DoD and the industry groups that sponsor my research and that we're in alignment in trying to improve outcomes for all of our patients. But I think the key message I want to share today is we spend a lot of time in ICU trying to eliminate bacteria and eradicate bacteria with antibiotics, when the reality is the majority of the bacteria that live in and on our bodies as we sit here today and our patients sit in the ICUs, these are a hundred trillion friends we didn't know we had, and we didn't know our patients had, and these bacteria are friends we want to keep around. And so, I hope I can impress upon you the incredibly critical role bacteria play and the microbiome plays in who we are as humans, both in health and illness and recovery from illness. And so, I think this is becoming a much greater understood topic. There are a whole vast growing literature of data about the critical role of the microbiome. There are books about how you can use your poop to improve your health, if you want to do that at home, and we'll talk about in a minute, maybe we all should be storing our poop just in case we need it later in our freezers. And I think the day is coming, actually the day is here, when rather than writing prescriptions just for antibiotics, we're going to be writing prescriptions to give bacteria back to our patients, actually prescribing things like stool transplants, probiotics, and perhaps stool pills. And I think, of course, this story is not new, and I think one of the best examples of how we're prescribing bacteria and stool back to patients are stories like this. This is the story of Caitlin Hunter. She was a 20-year-old that was in a devastating car accident with multiple orthopedic injuries. And she recovered from those orthopedic injuries, but shortly before she was going to go home, she developed severe resistance C. diff colitis. And she went through 11 rounds of antibiotics, and her life was truly in jeopardy. She was dying of C. diff, one of the fastest growing atrogenic infections in the world. I saw a case every six months when I was a resident, now I see a case every week. And so to save her life, the physicians there gave her a stool transplant from her mother, and she immediately improved. And we'll look at the effects of stool transplant on the microbiome and what an incredible therapy it can be for this later when we're talking. So I think the reality is, of course, we need to strongly consider resodding the lawn, the bacterial lawn that lives in our guts, in our mouth, in our skin, that is devastated or blighted by antibiotics and critical illness, diseases like COVID-19 and other infectious diseases. And we need to be resodding that lawn with things like probiotics, stool transplants and poop pills. The kids at MIT will sell you their poop and poop pills and tell you that it will make you smarter. The FDA has a bit of a problem with that, but this may be the future. And why is this the future, and why is this getting so much attention? Well, it's important to remember, critically remember, that the world we live in is not a human world, but a bacterial world. The majority of organisms on the earth, and as I'll show you in our bodies, are microbes. They're not multicellular organisms. Multicellular organisms are the little group there in red that you can see everything else that exists on the earth are largely microbes and single cellular organisms. And why should you care about your microbes? Well, have you ever wondered why when you go into the forest, you get bit by all the mosquitoes and your wife or your husband or your friends do not? Well, it's not because you're sweeter. It's because the microbes that live on your skin actually attract or repel mosquitoes. And so they are the defining reason why you get bit more or less. And in fact, we're beginning to discover that microbes may do much more from us than just repel mosquitoes. They may actually determine who we have sex with and perhaps who we marry. Is it possible the microbes that live in our gut determine our sex and mating preferences? Well, we know this is true if you're a fruit fly. The gut's microbiome of a fruit fly determines their mating partners. And perhaps for better or for worse, we'll discover this may be true for humans as well. Wouldn't that be amazing and a little scary? So again, this is a critical part of who we are. And how is it that our microbes do all these things? Well, I think it gets back to the basic question. What is it that makes us human? And some people would think, or you may think, it's our cells that make us human. Well, sitting where you are today, listening to this lecture, you have 30 trillion human cells living in your body, but you have 38 trillion microbial cells. You're actually more than 50% cellularly microbes. Some of us think, well, perhaps it's my genes that make me human. Well, within your body right now, you have about 20,000 human genes and about 20 million microbial genes. So as you sit here today, you're about 1% genetically human and 99% genetically microbial. And what's truly exciting and what we'll talk a lot about today is we're poised to answer key questions about our microbial cells and how we can manipulate our microbial cells to improve health. Because for many, many years, we could only culture or look under a microscope and see about 5% of the microbes in our bodies and on the earth. But now with 16S microbiome sequencing, ribosomal RNA sequencing, we can see all the organisms. And so the NIH spent somewhere around $175 million sequencing about 250 subjects generating tons of ATGs and Cs that look like this. This doesn't mean very much. What does all this mean and how do we think about what this data means and how do we think about the microbiome when we're looking at studies that examine this? So we need to map our microbes in order to look at this data meaningfully. And the reality is every different part of our bodies from our mouth to our gut to our skin to the vaginal canal all have a very different microbiome, a dramatically different microbiome. And when we're mapping microbiome data, you see plots like this. And this is from the NIH Microbiome Project. And each one of those dots represents an individual person's microbiome from a different part of their body. So again, all these bacteria look very similar under the microscope. But when you look at the different families and species, they actually plot out onto a map like continents would on a map. And each one of these colored dots represents a different part of the body. So these are samples in green taken from the mouth, purple taken from the vaginal canal, and then brown taken from the fecal stream or the stool. And so again, our microbiomes are dramatically different. They make up a bacteria dramatically depending on where the sample is taken from. In fact, the microbiome set or the bacteria that live in our mouth are more different than the microbiome that lives in our gut than comparing the microbiome of the poor reefs of Australia to the plains of the US. So there is more diversity, more difference in the three feet from your mouth to your intestine than there is in thousands of miles of distance on Earth. So we are incredibly diverse as humans. Our microbiomes are. And so these different areas need to be thought of very separately. How stable is the microbiome? This is really a question in health and disease, right? If we're going to treat to improve and stabilize the microbiome or restore diversity, does it stay similar in health? Well, the reality is there are researchers like Rob Knight that I do a lot of my research with and he has sampled himself and his children every day for years. And this is a graph of the fecal sample day after day after day of and all the other different areas as well. Mouth and vaginal canal and other areas. These are what happens to the microbiome day by day over years of time. And you can see that the average people, there's a few people representing each of these graphs, stays very stable and very tight within what the microbiome looks like when we're healthy. I'm going to show you that changes pretty dramatically when we're sick. And so, again, this is a very stable thing. So where else do our microbes come from? Well, if you have a dog at home, you have a different microbiome than those of you who don't have a dog at home. But fundamentally, our microbes come from our mothers at birth. And clearly, our microbes come from, for many thousands of years, from our mom's vaginal canal. So our stool, our skin, our mouth, as we're babies, all resembles mom's vaginal floor for about the first two years of life. And that's how we as humans have evolved to have our microbiome tolerate our immune system. Now, if you are born by C-section, this changes. And actually, your baby's mouth, their skin, their stool, all looks like mom's skin floor for about the first two years of life. And again, this is a very different evolution for our immune system as a human. And we know that children born by C-section have more asthma, more allergies, more obesity, more ear infections, potentially. And so I will tell you, Rob Knight, the incredible microbiome scientist I work with, when his child was born by C-section, he kicked everyone out of the delivery room, and he smeared mom's vaginal secretions all over the baby. Now, that may be the only thing that you remember from my lecture, but I would encourage all of you, if you have a baby by C-section, you should do the same, smear mom's vaginal secretions all over the baby, because you want the immune system to tolerate to mom's vaginal floor. And that's a real question. Do changes in the microbiome matter? Well, not only whether you're born by C-section or vaginal delivery matters, but if you get antibiotics in the first six months of life, it matters. We know children that get antibiotics in the first six months of life have more obesity, more allergy, more heart disease, appears to have more autoimmune disease. Again, all these things can be affected from even a single dose of antibiotics. And so, again, the microbes that live in our body really play a great, deep role in who we become as humans, both in health and disease. For instance, looking at the stool of an individual, we can tell with 90% accuracy who's obese and who's not. And maybe that's not so useful. Again, we can look at someone and see that. But if we looked at all their genetics, we could only tell with 60% accuracy who was obese and who wasn't. So our microbes make a bigger difference in obesity than our genetics do. And so that was a pretty shocking reality. And in fact, can we recapitulate human traits, human disease, by taking the microbiome from one animal or one person and giving it to another? Well, again, if they're looking at a thin and a fat rat, the stool of these animals is different. And there are many, many labs around the world, including at Duke and other places, where mice are grown in germ-free environments. And so they have no bacteria in their bodies or their intestines. And if you take these mice and if you do a fecal transplant into them from different kinds of mice, you get different results. For instance, if you take the stool of an obese mouse and give it to a germ-free mouse, the mouse becomes obese. Not only does their metabolism change, they actually eat more. It changes our brain, changes cognition. That's a different lecture for a different day. And if you take the bacteria from a thin mouse and give it to a germ-free mouse, they stay thin. Now, can we create human disease in an animal by transferring the stool or human illness? So if you take the stool from an obese human and transfer it into a mouse, the mouse becomes obese. So you can make human traits appear in animals as well by doing a stool transplant. And if you take the stool from a thin human, the same thing can be done. Starvation can also be replicated. These are studies from refugee camps in Malawi, where they've taken twins, one malnourished twin and one healthy twin. And if you take the stool from a malnourished child and you transfer it in a stool transplant to a germ-free mouse, the mouse becomes cachectic. And so again, dramatic changes in our biology and our physiology are made by the microbiomes that live in our gut and other parts of our body. And I think this is really critical, and I think we should realize as Western diet consumers and consumers of more antibiotics than we probably need, that the human microbiome project that was supposed to be normal in the U.S. actually looks nothing like what a tribe in the jungles of, say, Africa or South America that has never seen a Western environment or Western food. We have much less diversity and a very different-looking microbiome than those who have not been exposed to all of the Western environmental conditions, i.e. poor food, processed food, antibiotics, things alike. And the reality is, while antibiotics have been successful in eradicating infectious disease, at the same time, there's been an exponential rise in autoimmune disease. And there's a lot of belief and a lot of data now showing that the loss of these key microbes, whether it be because of birth by C-section, whether it be by antibiotics as a child or whatever, other poor diet, other things, this leads to a marked rise in autoimmunity. And so again, while we're defeating one problem, we're creating another. We have to be cognizant of this. And so can we change the microbiome to cure disease, particularly critical care, of course? And what's in our patients' guts? Can it help or hurt them? Well, I think it's critical to realize that when a patient becomes critically ill, they lose the diversity and the normal floor that make up what makes us human. And so we need to restore the balance, perhaps with probiotics, fecal transplants, and we need to be thinking about how to optimize and consider the best research to do this. Again, we need to be thinking about resodding this lawn. And what is the best way to do that? And what's the science? Well, this is a wonderful figure that was generated by the lab that I actually trained in when I was training, Gene Chang's lab at the University of Chicago. It's a GI research lab. John Alverde generated this data. He actually trained in that lab after I did. He was one of my attending surgeons in the ICU. He taught me ICU when I was a resident fellow. And then he went back to the lab and discovered our gut pathogens talk to each other. They sense our stress. All of you have Pseudomonas living in your guts right now that's sitting there quiescently waiting for you to get sick. And what we found out is when the body becomes stressed, when it becomes critically ill, when it sees high doses of antibiotics, repressors, or other disease-creating conditions, we lose our normal bacteria. It's a little bit like when a hurricane hits New Orleans. When a hurricane hits New Orleans and everyone evacuates, what happens next? Looters come, and they bring their looter friends, and they begin tearing up the town and doing all kinds of damage. Bacteria are the same. When they sense that the commensal healthy organisms that live in our guts go away because of illness, disease, antibiotics, they say it's time to attack. And they bring their looter friends with them, their bad bacterial friends with them, and they actually communicate with each other, which is what John Alvarez discovered. It's called quorum sensing. And they attack us. They express toxins. They grow faster. They invade our gut. They create disease. And so this is something that perhaps restoring the commensal flora that's lost may be able to treat. And so by giving back commensal flora and commensal organisms, healthy organisms will always outgrow a pathogen given the chance. This drives away the bad bacteria and also tells them to stop attacking. It's a little bit like in New Orleans. When the people that live in New Orleans come back after the evacuation, all the looters go away, and they take their looter friends with them. And so this is what we believe our goals to restore good health to our ICU patients should be as well. If we can get commensal flora back with the right food, and I'll show you how important that is in a little bit in some new data, perhaps we can restore health much more quickly and prevent further disease and promote recovery. Prebiotics seem to be very important as well. Prebiotics, when used by commensal organisms that make short chain fatty acids, are critical to our body's immune system and to how our gut is protected. When poor fiber diets are fed, especially in the presence of pathogens, the pathogens can attack us and they can eat through our mucin barrier and create disease and dysregulate our immune system. Now, I will show you that there are exceptions to that. If the pathogens get a hold of the prebiotic food, they can perhaps create issues as well if there's no commensal organisms to use it. We'll come back to that. So the reality is, of course, critical illness creates a whole host of conditions that promote aggressive bacterial behavior and loss of commensal organisms, loss of diversity. We know that, say, low FOS levels promote bad bacteria and bacteria attacking us. Norepinephrine, opiates can be sensed by bacteria in our guts. Norepinephrine can be sensed. All these things are things the pathogen of Pseudomonas, for instance, uses to sense this person's in trouble, I'm going to attack, they're vulnerable. So what happens to the microbiome of critically ill patients? And so we asked this question a number of years ago, and we joined forces with Rob Knight to answer it, because we wanted to know what happens longitudinally in the guts of our ICU patients. And so this was our first publication. And again, we saw, and as you'll hear, extreme dysbiosis in our patients who are critically ill. And so this was 115 patients across four centers in the US and Canada. You had to be mechanically ventilated for 48 hours, and you cannot be in the ICU in the US or Canada for 48 hours on a ventilator and not get antibiotics. We found every patient got antibiotics. And so here again is one of those plots. The dots in red are normal volunteers that send their stool in to Rob Knight's, and they pay him, they pay his lab to send back their microbiome results. Remember I told you it cost $174 million for the NIH microbiome project to sequence about 250 people? Rob Knight has sequenced thousands of people and made millions of dollars for his science in the process. He's one of the premier crowdfunded scientists I've ever met. So these are seemingly healthy people that have donated their stool in the American gut group there in red. Now you can see the ICU patients in blue are dramatically different, and these are at both admission and for the days after admission. And there is a dramatic change in the fecal microbiome. And in fact, you can see the loss of the health-promoting, the normal habits in New Orleans, the normal healthy bacteria are lost. Those big dots there are ICU patients. And when they are white, that shows that the Firmicutes family, which are a key healthy bacteria that lives in our guts, they are almost at zero. They've completely gone away. White means very low levels. And you can see in the red, the small dots, the healthy people, most people have a very high abundance of these health-promoting, short chain fatty acid making in some cases, bacteria. So again, we lose lots of the healthy commensals that protect us against illness and disease versus a healthy subject. The other thing that's challenging, you can see the big dots there are the ICU patients. And if you'll notice, they're beginning to come together from the mouth, the stool, and the skin. So our mouths and our stool and our skin begin to look the same, which is disturbing, versus the normal, that's the NIH Microbiome Project healthy volunteers behind there. And so you can see we lose barrier function and our bacteria begin to look the same all over different parts of our bodies. And so that's a bit disturbing. And in fact, we could really see this. The top two graphs there show the admission and discharge ICU plots, the microbiome makeups, and those red lines each represent a patient. Those are the pathogens. You don't want red in your microbiome. Those are the pathogens that cause disease. And you can see on the bottom graph there in the healthy patients, there's very little red. There's predominantly green and blue, which are the healthy commensal bacterial families, the health-promoting bacteria that we want. So we specifically found some targets. One of the purposes of this project was to find targets we could study, perhaps with NIH funding or other funding. Fecalibacterium presenutii is a major short chain fatty acid producer. This was massively depleted in ICU patients. It's also depleted in inflammatory bowel disease. And so this could be a key target for future treatments. We saw in the stool as well, Staph aureus and Proteus and other things that are pathogens that show up in the blood of our patients when they're sick, grow up very rapidly in the guts of our patients in the ICU. This is true in the mouth as well. Healthy species are lost and Staph and Mycoplasma grow up very quickly. Pneumonia-causing organisms seem to be very quick to grow up in the mouth. And I think this is a major cause of malignant or associated pneumonia. It's not so much the gut, but the mouth. And you can see here, looking at all different species, you can see pathogens are significantly increased very rapidly in the guts of ICU patients. And health-promoting bacteria like Fecalibacterium, go back to that, are actually lost and depleted in great amounts. Diversity is also lost. You can see the red lines there are the ICU patients. And the flatter your graph is, the less diverse you are. The healthy patients there in black, they're more diverse. And if we found hunter and gatherers from tribes that had not seen Western food and Western medicine, they would be almost a straight line up. So again, normal is not necessarily normal for what our bodies have evolved as. Last thing I'll mention is that ICU admission, typically the most abundant organism family in the gut, makes up about 25% of all the bacteria. By the second day, we saw quite a few patients where one organism made up 95% of all bacteria in the gut. It's often Enterococcus or Acinetobacter. Just takes over the gut, everybody else is gone. Like all the other people, no one's just left. And all that's left is looters. And we see this crash in microbiome diversity, which we were shocked by. We've never seen this in any other condition. So this is, again, something that's happening in our patients commonly. So what were some of our results and outcomes? Well, we noticed there were some correlations with death. Increases in skin klebsiella, interesting, led to a correlation to patient dying. Oral mycoplasma led to more occurrence of bacteremia. That association, it's an association, existed. And ARDS seemed to have associations to the fecal microbiome as well. So the question then becomes, is it the antibiotics or is it the critical illness that's causing the loss of diversity? Which is causing the change, the illness or our drug treatment? So we used an antibiotic pressure score to look at the antibiotics the patients in this study were getting. And this is published in Lancet Infectious Disease. And we adapted this, obviously, for the kind of antibiotics we use in the ICU. And what we found was the loss of bacterial diversity in the oral samples was significantly related to the amount of antibiotic pressure, sort of how broad spectrum, how many days they got, the more pressure there was, the more derangement there was in the mouth, but that was not true in the gut. The fecal microbiome seemed to be more affected by something else, perhaps critical illness itself, than by the antibiotics we were giving the patient. So again, some parts of the body are effective antibiotics more than others it appears in ICU patients. So clearly it is interesting that this may be due to the state the critical illness creates. What about role of diversity in outcome? We found that patients that had more diverse microbiomes persistently had shorter lengths of stay than those who had less diversity, who had longer lengths of stay, as shown in this graph. And we found a range of different targets that were significantly depleted consistently in ICU patients, which interestingly are also targets in IBD research. And so a lot of similar characteristics are seen in inflammatory bowel disease for future research as is seen in the ICU. But overall, the magnitude of change from admission to discharge in terms of diversity and pathogen overgrowth did seem to correlate with mortality, and we're still analyzing data for this. So what's the clinical data for giving back probiotics or giving back bacteria to try to treat this dysbiosis? And of course I can't cover all of them, but I'll cover some highlights that I think are worth mentioning as we think about our patients. One is there's really robust data for probiotics preventing antibiotic-associated diarrhea. This is a large meta-analysis, 12,000 patients, many, many studies, and JAMA showed a 40% reduction in antibiotic-associated diarrhea when virtually any commensal probiotic was given. Again, the commensals will always outgrow the pathogens. Things like C. diff are weak little organisms that will not grow in the presence of normal health-promoting bacteria. It's when everything gets eradicated by our broad-spectrum antibiotics that things like C. diff and other diarrheal-causing illnesses are allowed to show up. This was a compelling trial that I think really changed our thought processes about the potential of probiotics in the ICU. This was an NIH-funded trial done by Lee Morrow. It was published in the Blue Journal where they used lactobacillus GG, and they did it uniquely in a way that I think we would all need to consider if we're going to do more trials of this. They gave one capsule to the stomach and they smeared one capsule in the mouth, where we think that is probably where a lot of the pneumonias are coming from, not the gut, but the mouth. And they found a 50% reduction in venereal associated pneumonia in the intention to treat group. So this is robust data, and they saw changes in C. diff diarrhea as well. And so this led to groups like mine doing meta-analyses showing that probiotics led to reductions in infections and venereal associated pneumonia, and the sicker you were, the more beneficial they were. And you can see the early meta-analyses here. That then led to a large randomized trial being done by Deb Cook and her group in Canada. And they looked at many, many ICUs to prevent venereal associated pneumonia. And in this case, to simplify it, they only provided the probiotic to the gut. And they enrolled 2000 patients using LGG or a placebo, but not giving the capsule to the mouth. And they found no differences in this particular instance. And so again, I think it is more complex than just giving probiotics to the gut. We also have to address, remember the microbiome, other parts of the body are very important and probably it's things in our mouth that are getting into our lungs and creating disease. And so I think we'll hear more about ARDS in lung and microbiomes of the lung and in lung disease later in these lectures and we'll learn a lot more, I'm sure. But the results were there weren't differences in venereal associated pneumonia or other outcomes. And there was a small incidence of LGG showing up in sterile sites like blood or other places. So again, these probiotics can't escape. They aren't typically disease or sepsis causing organisms, but it's key to know that in patients at risk, immune dysfunction and other things that these bacteria can escape and that has to be considered. So then a large meta-analysis was done in critical care medicine. I had the honor to review this paper. I thought it was very well done and they still showed a signal, although it was in smaller trials typically, but some larger trials too, but typically the smaller trials showed a benefit on venereal associated pneumonia. And I think the most robust trial, the one in the Blue Journal gave probiotics to the mouth and to the gut. And I think that may be critical, but again, they consistently showed signals of benefit that I think if we're wanting to explore further, we need to refine how we give probiotics. And I think we can get some signals from how other respiratory diseases have been very successful in using probiotics and probiotic-probiotic combinations. But again, there were signals of potential benefit that I think this needs more research. So again, low certainty evidence. I think there's things we can learn from these trials. And I think there's considerations that need to be made that I'll talk about in a moment. There are meta-analyses in other areas that show reduced sepsis and infection, both in elective surgery and trauma. This literature continues to grow. What about prebiotics? And I think this is really critical. In an individual who has antibiotics exposure, if they are an omnivore or a vegan and have a good fiber amount in their diets, they'll quickly recover their healthy bacteria. You can see they get their greens and their blues back very quickly if they're taking in fiber. If you're on intralutrition though, without fiber and you get antibiotics, the pathogens remain, and it's very hard to recover your normal flora. Again, so that led us to want to do a study, what is the role of prebiotic fiber in critically ill patients? So I'm going to present some new unpublished data to you that was done by Dr. Mara Subinescu, who is a critical care physician we recruited at Duke from Hopkins. And I think she's truly a rising superstar in our field. And she's unique in the world because she has been trained to analyze her own microbiome data. So typically you need a computer scientist and a very elite statistician to be able to analyze the incredible amount of data from this. She can do it on her own. She's the only critical care doctor I know in the world that can do that. So I'm excited to see what she can do. I'm honored to mentor her. So we looked at the effect of a prebiotic fiber formula. There's a lot of formulas in your ICU that probably have fiber, versus a control formula. It's the same formula without the fiber. We call it the PRE-FET trial. And this is data we're submitting for publication here in the next few days. And so again, this was a trauma study. These are mechanically ventilated patients with severe trauma without GI tract involvement. And they either got an EN formula with a fructooligosaccharide prebiotic or same formula without that. And so we enrolled 10 EN fiber patients. We got samples on and seven controls. And we got many, many samples. We got 60 stool samples and 90 oral samples. And we did 16S analysis of this. And as you can see, in all the patients when you put them together, things like diversity, which is measured by Shannon index, goes down over time in the ICU, much like we saw in the ICU study. So we lose diversity in trauma patients as well. And the amount of species that are existing in the mouth and the gut also is lost very quickly across the first two weeks of ICU stay. So again, very consistent signals here. And we found across the board, and these are all comber patients, that fecal pathogens begin to grow up very quickly, especially after the first five days. And this is true in the gut and in the mouth. And so pathogens very quickly, especially after the first five days, really begin to take over. And all these patients received antibiotics. Again, you can't be an evaluator and not get antibiotics. Now, again, we saw differences in diversity between the fiber group and the non-fiber group. And you might think that would be expected. The challenge is, we began to see loss of diversity in the fiber group to perhaps where it wasn't beneficial. So if you look closely over time, there was a greater loss of diversity in the Shannon index in the fiber group than in the no fiber group. And this wasn't much different, but it was somewhat different in the oral as well. So the opposite of what we expected to see, we actually wanted to make sure that patients, we had the samples correctly labeled because we were a little surprised to see less diversity in the fiber group. And in fact, what we saw was that things like healthy bacteria, like lactobacillus actually recovered more slowly or didn't recover at all in the fiber group. And the pathogens appeared to be using the prebiotic fiber to grow up quite robustly. And so in the fecal stream, things like Shigella and Bacteroides, which are real signals, I'm sorry, Shigella is a real signaling pathogen. Shigella grew up more quickly in the fiber group and beneficial organisms appeared to grow up more quickly as well. So it not only fed the pathogens, but it also fed the beneficial organisms. So again, if there is a hurricane in New Orleans and there's a lot of food in the stores, but all the regular folks that go there have gone away, the pathogens come in and take the food. So it feeds everybody. And if there's more pathogens around, they get more of the food. And in fact, you can see that helpful commensals in the oral communities actually were more benefited perhaps in the non-fiber group and the pathogens seem to benefit from the fiber more. You're beginning to see a signal here that the pathogens are taking advantage of the fact that there is food around for them in the fiber. And because there's such a loss of the commensal organisms, they're not there to compete for the food. And so I think this is a really key signal and was not what we thought we would see, but it appears we're feeding the pathogens as much or more than we're able to restore the commensals because they've been lost to such a great degree. We did a lot of neat network analysis that I won't try to explain. It's a little beyond even my understanding totally, but basically what this says is, is the pathogens interact with other species and communicate with other species, especially in the fiber fed group, and that perhaps benefits them. So again, the fiber is promoting a mutual relationship between the pathogens and the commensals. And so everybody's benefiting from the food and the pathogens perhaps are growing up even more than the commensals are. And so I think this is a signal of concern for the role of fiber. And so the conclusions in contrast to other populations where prebiotic fiber is definitely beneficial, our initial data says that the provision of fiber for ectoligosaccharides may be deleterious and enhance the expansion of pathogens as much as it does the beneficial organisms. And this may foster interactions between the pathogens and the beneficial organisms that allow the pathogens to benefit. And so again, it feeds them both. And so I think it's critical to realize that we need to understand how these bacteria communicate. And I think what it says for the future research is, I think it's critical that if we're going to give a prebiotic fiber, we need to give a probiotic commensal with it so that it can out-compete the pathogens and repopulate the gut, taking advantage of the prebiotic fiber to make sure it's through fatty acids and other beneficial things. So again, we need it to out-compete. We probably need to give symbiotics. And I'll show you there's some pretty good data for symbiotics in other areas of medicine that says this may be just as true in the ICU as in other areas of medicine. So quickly, what about probiotics and C. diff colitis? Again, this is an area where we're definitely prescribing bacteria, whether it be through probiotics or fecal transplants for C. diff and C. diff risk. And the data is robust here. This is where the data is clear for the benefit of probiotics in patients at risk for C. diff, like critically ill patients, both adults and children. And the data shows there's a 60% risk in C. diff diarrhea when you give a probiotic to an at-risk patient. And in fact, the data also shows the risk goes to a 70% reduction in risk in high-risk patients like ICU patients or patients in broad-spectrum antibiotics. So this data is even more robust in a high-risk ICU patient where it's 70% reduction. But in the whole group, it's a 60% reduction in the risk of C. diff diarrhea. And this is the same in adults and kids, in patients and outpatients, lower and higher doses, different probiotic species. And in high- and low-quality trials, pretty much all the same signal was seen. And what this means is, again, any good commensal probiotic species is going to outgrow the weak C. diff pathogen that it is. But again, when we lose all our bacteria in our gut and all the people leave New Orleans, looters like C. diff can proliferate. And so that's why probiotics can be so beneficial. And this is an area that I use in my ICU. And I think this is where really robust data exists for all of us to think about using these in our ICU to prevent C. diff. And again, we know stool transplants are robustly effective in C. diff. The data would say the cure rate's over 90%, even in very resistant C. diff. And so we have some exciting new data that was generated by the University of Minnesota that shows the effects of fecal transplant on the microbiome in C. diff colitis. Again, these are the normal makeup of the microbiome in the Human Microbiome Project. And I'm going to show you some stars here. These stars represent patients who have C. diff. They're fecal samples. These stars are not down where the fecal samples of a healthy patient are. Remember how in the graph I showed you from our data, the mouth, the stool, and the mouth, the gut, and the skin begin to look the same, and they begin to come together? You'll see this in the C. diff samples too. These C. diff stool samples look nothing like normal stool samples. They're beginning to look more like the mouth and the skin than they are the stool. Now, these patients in orange got a fecal transplant in red. Some of these patients got a fecal microbiome transplant while they had C. diff. And watch what happens to their microbiome. So again, this was what happened after the fecal transplant in the patients. Their stool samples immediately returned to a normal microbiome fecal appearance. And then these are daily sampling. They did day after day after day after day for many days and weeks after the sample was taken. And so their stool samples stayed the same. So this corrected their dysbiosis, and this correction was long-lasting if not permanent. So again, a fecal microbiome transplant can change this incredible dysbiosis that leads to C. diff and other diseases and correct it. It looks like long-term. And so again, this is why they're so beneficial. So again, patients to donors, very effective. Now, what can we learn from other areas of medicine where probiotics and symbiotics have been used very successfully to prevent disease, especially respiratory disease? So this is the landmark trial you have to know if you want to know about the microbiome and probiotics. This was published in Nature. It was a study of a symbiotic, a pre- and probiotic combination. It got five full pages in Nature, one of the highest impact factor journals in the world. And this was a study of healthy full-term newborns, babies in India, where they gave a lactobacillus plus the fructooligosaccharide we studied in the ICU in the slides I just showed you, given to healthy full-term infants looking at prevention of sepsis, respiratory infections, and death. And what they found was there was a massive reduction in respiratory infections, sepsis, and death in the healthy subjects who got a symbiotic with lactobacillus and a prebiotic combination. Massive effect. In fact, there was a 40% reduction in the combination of sepsis and death in the treatment arm, and there were 60% and 70% reductions in culture positive, bacterial perhaps, and culture negative, viral, sepsis, and lower respiratory tract infections. So profound effect of giving a prebiotic with a probiotic. Again, published in Nature. Really, this kind of data and the data I'm going to show you say perhaps all of us should be taking a probiotic or symbiotic because this is really compelling data. And it's been shown in many other studies as well. I think that is the premier study, but there's large meta-analyses in Cochrane showing that if everybody just took a probiotic every day, we would reduce the numbers of upper respiratory tract infections, things like influenza and other viral diseases, by 50% almost in the average individual. Again, lots of studies, thousands of patients. Probiotics significantly reduce respiratory tract infections in the average person. So I think the data is very robust that all of us should probably be taking a probiotic. And it shortened the length of the upper respiratory tract infection by about two days. So again, a profound reduction in not only getting infected, but how long you're infected. And this is true for symbiotics, where there's 10,000 patients studied in 16 trials. Pre- and probiotics reduce respiratory tract infections significantly as well, both in children and adults. And again, so the data is very compelling. And so a modeling, economic modeling group took this data from the Cochrane meta-analysis to show that if we just had everyone taking a probiotic throughout the US, we would save health care payers $373 million, avert 54 million sick days, reduce antibiotic prescriptions by 2 million courses a year, which would do wonders for many other parts of our health care economy, reduce work absences 4.2 million days a year, and save society a billion dollars. Again, this is the power of the microbiome. And again, I think this is why more and more research needs to be done in this area. It needs to be done correctly. It needs to be done thoughtfully. But I think it really shows the vast data saying perhaps all of us should be taking a probiotic every day or a symbiotic every day to benefit us and prevent us from ending up in our ICUs, perhaps with pneumonias or more severe disease. So that led us, this data, this sort of data I just showed you, led us to realize perhaps we could prevent COVID-19 with a probiotic. So in the midst of the pandemic, a group, Tony Sung, an oncologist, and myself, organized a trial to treat patients who'd had a family member diagnosed with COVID. And we were going to treat the whole family in the home, whoever lived in the home with you, children from one to adults of 99 years old. Anyone could be in it. And we treated everybody in the house with either a probiotic or a control placebo. We got an IND for this study. We got an IND for the lactobacillus GG. This is the same lactobacillus that was studied in the critical care trials we talked about before. And we randomized people for 28 days looking for primary outcome of developmental symptoms of COVID and also COVID diagnosis and the time to COVID diagnosis. And we also got microbiome samples from these patients. You can see this is how we did the trial. We would screen people. We screened thousands of patients at Duke that tested positive for COVID. And we used the internet to enroll as well. And we would send you overnight to enroll family, either the probiotic or the control. And we had data collections weekly online. And we got stool and nasal swab collections as well. And so this was, we just published this a few months ago. You can imagine there were a couple of groups we had to do. There was the Actual Intent to Treat group, everybody that got enrolled. There were patients who actually took the study product, who confirmed to us they took it. And then there was a group where we had patients who stated they were asymptomatic when they started because some people got COVID in the period of about 24 to 36 hours when we were enrolling them before they got the probiotic. And so interestingly, across the groups, we had statistically significant reductions of any symptoms related to COVID in all three groups, including Intention to Treat and in the patients who didn't have symptoms at start. And in fact, there were strong trends, especially in the no symptoms at start in the reported COVID diagnosis that just missed its real significance. And so again, if you look at the time curves, you can see there is a significant reduction in reported symptoms of COVID over time. This was quite statistically significant when you received a probiotic. And in fact, there was a statistically significant reduction in the time to COVID diagnosis. So the number of people who were diagnosed with COVID over time was reduced by taking a probiotic when you're exposed to someone with COVID. So again, we found this data to be very compelling. We measured LGG and the fecal samples that were sent to us and we saw the patients did appear to be taking the probiotic. This is the way you can actually sort of monitor how well they're taking the probiotics and if they're complying. And in fact, we saw significant changes in patients' microbiomes who had COVID and those who didn't, and those treated with probiotics and those who weren't. These were quite significant and are behind the scope of this lecture, but we're still digging into this data. So again, we found that a probiotic, just like it can in other respiratory infections, can reduce the symptoms you develop from COVID and reduce your chance of developing COVID over time. And again, I think larger trials would be warranted in these patients. And we continue to explore this. And again, we found some interesting microbiome findings. LGG was able to persist in the gut. It did colonize the gut. It did show up in the fecal microbiome. And again, we saw many changes in the microbiome from COVID and from our probiotic treatment of COVID. So again, I think probiotics have this true potential to reduce viral and bacterial respiratory infections, especially in, say, our high-risk patients or for any of us who sort of live the stressful lives we do. And I think the data is strong enough to say it's worthwhile that all of us should be considering taking a probiotic. So in closing, what have we learned so far? Clearly, a healthy gut is a diverse gut. And critical illness and a Western diet lead to loss of diversity, which is associated with more illness, more autoimmunity, and poor outcomes in our ICU patients. And we need to study and find the best ways to correct this. And it's likely for most of us, we should probably be correcting as part of our daily lives. And this shows us that the reality, we can change the world of both ourselves and our patients. The microbial world that we live in by not eradicating bacteria with antibiotics, perhaps, but with using the power of poop and the ability to write prescriptions for healthy bacteria to re-sod the lawn that our antibiotics and a critical illness and COVID eradicate and allowing for the right bacteria to grow back up in our guts and in our mouth and our skin, allow the inhabitants of New Orleans to come back and end the looting and restore balance. And of course, the amazing thing is now with the incredibly reduced costs and incredible growth in the science of the microbiome, we can do this research and make it so easy even a child can do it and understand it. And so with that, I'd like to thank my partner Rob Knight and his group. I would like to make a plug. If any of you'd like to learn more about clinical nutrition in general, we know that 75% of medical schools don't teach any clinical nutrition. We have started an online clinical nutrition fellowship where you get to interact with the very best professors around the world in nutrition topics, including the microbiome and probiotics. And we run a course every year. There's a module every week and you get to have a Zoom meeting and actually meet other students from around the world. We have 37 fellows right now from 13 countries on four continents. And so this is a really wonderful interaction. And in fact, we have a clinical nutrition research training certificate for those in should we accept dietitians, physicians, APPs, pharmacists. And in fact, we even have funding to help train and mentor a few young people to do specific projects. So with that, I think we're left just to do it. I encourage all of you to follow me on social media. I post lots of new data, including many studies we have coming out for the microbiome on prebiotics and the ICU and on cognition. We have a lot of new data coming out on cognition and the microbiome. Follow on Instagram and Twitter to keep up with the latest literature. And I'm happy to share these slides with anyone or if you want to see how these papers or receive anything, I'm happy you can use my email and I'll send any and all of this to you. So I look forward to the lectures and to your questions and it's been wonderful to spend this time with you here today. Thank you.

microbiome

probiotics

interventions

diversity

bacteria

antibiotics

fecal transplants

symbiotics

human health

critical care settings

respiratory infections