Short Summary: How diet shapes the gut microbiome and impacts health, with microbiologist Dr. Peter Turnbaugh breaking down the complex science.
About the guest: Peter Turnbaugh, PhD is a professor of microbiology and immunology at the University of California, San Francisco, where he leads a lab studying the gut microbiome’s role in nutrition and drug response.
Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.
Episode Summary: Nick Jikomes talks to Peter Turnbaugh about the gut microbiome’s response to dietary changes, focusing on high-fat diets, ketogenic diets, and their effects on health. They discuss the pitfalls of oversimplified diet labels in research, Turnbaugh’s studies comparing plant-based and animal-based diets in humans, and how these shifts rapidly alter gut microbes and short-chain fatty acid profiles. The conversation also covers the microbiome’s role in drug metabolism, its links to inflammation and autoimmunity (like multiple sclerosis), and the potential of ketogenic diets to modulate these processes via ketone bodies like BHB.
Key Takeaways:
The term “high-fat diet” in research is often misleading, as it can include high carbs and vary widely, complicating study comparisons.
In a 2014 study, switching humans to a plant-based (high-fiber) or animal-based (ketogenic, no-fiber) diet changed their gut microbiome within one day, showing its remarkable adaptability.
Ketogenic diets reduce Bifidobacterium in the gut, which may lower inflammation-linked immune cells (Th17), potentially aiding conditions like multiple sclerosis.
Short-chain fatty acids (e.g., butyrate) don’t just come from fiber; they persist even on zero-fiber ketogenic diets, hinting at alternative microbial pathways.
Gut microbes can activate or deactivate drugs, like antibiotics or digoxin, suggesting microbiomes may explain why drugs work differently across individuals.
Ketone bodies like BHB alone can mimic some ketogenic diet effects on the microbiome and immunity, simplifying research and hinting at therapeutic potential.
Related episode:
M&M #203: Metagenomics, Microbiome Transmission, Gut Microbiome in Health & Disease | Nicola Segata
*Not medical advice.
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Episode transcript below.
Episode Chapters:
00:00:00 Intro
00:05:34 High-Fat Diet Issues
00:11:00 Macronutrient Mapping
00:17:29 Metabolic Adaptability
00:25:59 2014 Study Design
00:34:01 Microbiome Flexibility
00:41:03 Fatty Acid Profiles
00:48:41 Bile and Gut Changes
00:55:09 Inflammation Links
01:00:11 Keto Diet Exploration
01:07:08 BHB Impact
01:14:21 Microbiome Products
01:19:35 Drug Response Research
Full AI-generated transcript below. Beware of typos & mistranslations!
Peter Turnbaugh 1:30
Sure. So I'm a professor in the department of Microbiology and Immunology at the University of California in San Francisco, and our lab is kind of broadly interested in how the gut microbiome, the trillions of microbes that are found within our GI tract, influence both nutrition and pharmacology.
Nick Jikomes 1:51
Yeah. And so you study lots of interesting stuff. There's many different directions we could take this conversation. I've covered the microbiome a lot on this podcast. I've covered diet stuff a lot on this podcast. I want to start off pretty high level and talk about, get you talking about something that doesn't necessarily have to do with your work specifically, but it's, it's sort of broader questions related to diet and nutrition and how it's studied in the literature, and it obviously ties into the work you do. But I want to talk about some of the different types of diets that are out there that are commonly studied, and some confusion and shortcomings maybe even the literature has in terms of how those things are studied and how they're talked about. So the points I want to start is, I'm going to keep it vague intentionally, one of the most common diets that you'll read, if you dig into the scientific literature that has to do with the diet, is the so called high fat diet. And maybe some of the listeners, listeners will know from from listening to me before, but this is one of my biggest frustrations in the literature, this term high fat diet, what can you tell us about the high fat diet, and what that term maybe doesn't tell us, or problems that come from labeling and using diets with that level of specificity?
Peter Turnbaugh 3:09
Yeah, that's a great question, and kind of near and dear to my heart. I don't know if you saw but we, we had a paper a few years ago where we did a meta analysis, where we were interested in, kind of comparing the microbiome profiles, mostly in mice, but also a little bit in humans. You know, across the hundreds of studies where people have fed mice some kind of form of a high fat diet compared to a control diet. And so, you know, something, we thought about a lot in that study. But you know, to your question, the the, you know, we, I guess going back to my work in grad school, we're kind of careful to use the term high fat, high sugar diet, because we thought, you know, when you especially when you think about the microbiome, it's important to keep in mind the kind of other macronutrient components and so like typically, when people model obesity and mice, they give them a diet that's not only high in fat, but also really enriched for sucrose and maltodextrin, you know, relatively simple carbohydrates that are readily digested by The host, but important, kind of stripping out a lot of the fiber or complex carbohydrate,
Nick Jikomes 4:25
but, but importantly, when they give them these diets that are high in fat and high in these other carbohydrates, they simply usually call it high fat diet, right, right?
Peter Turnbaugh 4:33
Exactly. Yeah, yeah. Typically like HFD, or like high fat diet is the acronym, which is misleading, you know, for the point you make, which is that it's actually different in terms of the types of carbohydrates. But even kind of more profoundly, you know, something that I think a lot of people don't realize is that, you know, normally, when we study lab mice, they're effectively eating whole foods. You know, given that it's. Largely soy and corn and other kind of commodity crops that are used to kind of, kind of smash together into these pellets, as opposed to your typical high fat diet, which is actually made from purified ingredients. So it's more like a processed food that you might buy in the grocery store. And so, you know, we think in terms of how the microbiome responds to these diet shows it's really important whether or not they're kind of seeing the nutrient in the context of a real food, as opposed to just, you know, a purified sugar.
Nick Jikomes 5:34
Yeah. So, so when we read high fat diet in the literature, more often than not, it's not merely a high fat diet, it's high fat plus high carbohydrate. And if you compare, there's hundreds, if not 1000s, probably 1000s, of studies that use the so called high fat diet, or that, at least they use that nomenclature. But they can vary tremendously, not just in whether or not they also have high carbohydrate or high sugar content, but also the specific types of fats they use and all sorts of different things. And so it's, it's, it's a bit confusing, because, you know, if you were to just look at the literature and say, let's just look at all the studies that use a quote, high fat diet, and see what they say, it's actually not, it's just not appropriate to to sort of like, look at the one vector of where all those studies point. Because it's really many, many different diets that are simply, we're using the same words to describe,
Peter Turnbaugh 6:23
yeah, totally. And, you know, that gets really kind of complex, especially if, like, every tiny variation matters within what you're studying. You know, in our case, the microbiome that you know, others might be interested in, you know, body weight or other his phenotypes and the you know, I think, you know, one way that we've graphed this is to you can kind of have a triangle, or, you know, one corner is a diet with 100% fat, and then the other corner is 100% protein, and then the third is 100% carb. And then that allows you to, kind of, you know, in that triangular, space and kind of plot where each diet falls, you know, in the meta analysis that we did to look at the gut microbiome, um, you know, what was really striking is, you know, kind of how variable the high fat diets were in terms of, not only like how far They push the fat intake, but also whether or not protein and carb change, yeah, and you know, that's at the simplest level, when all you care about is level of macronutrients, and we're not worrying about the type of fat or type of carbohydrate, um. And then you can even find examples where the control diet is kind of higher in fat than the M than some of the high fat diets. And so, you know, it means that, you know, it's, like, really important, you know, to take into account exactly what you're comparing when you want to, you know, see whether or not you see the same effects. Study to study. Yeah,
Nick Jikomes 7:57
yeah. So you're saying there's studies where, like, study a might use a high fat diet, and study B has a control diet, what they call a non high fat diet, and it might actually have higher fat content than the other study that says high fat diet, yeah,
Peter Turnbaugh 8:13
like you're, you know, my low fat diet might be higher in fat than your high fat Diet, right? You know? Because, like, typically, the, you know, I mean, it makes sense how we get here, because, you know, people are using these terms in the context of two diets that are in their study, right? Yeah, yeah. Like, really, they're just trying to say that one is higher and one is lower, yeah, you know. But it's kind of tempting to apply that between studies, yeah, yeah.
Nick Jikomes 8:40
And then like one thing. So one thing that's obviously becoming more popular and getting more attention in the research world is the ketogenic diet. So if we get a little bit more specific with how we describe these things, high fat diets may or may not be ketogenic. So a ketogenic diet is a high fat diet. But when we read high fat diet in the literature, broadly speaking, those are often not ketogenic, whether or not they have high fat, whatever that means exactly, and they also often have high carb diets. Can you talk a little bit? So is it fair to say that the majority of the time when a study says high fat diet, it's probably pretty high in both fat and carbs, and therefore not ketogenic?
Peter Turnbaugh 9:21
Yeah, yeah, definitely. And you're kind of like reliving the journey that I went through, starting in grad school and then, and then continuing today in the lab, and the, I guess, just to, um, kind of finish the thought on the on the meta analysis, the, you know, I think one, one of the kind of really, what I thought was good news pieces of data that came out of this is that, you know, even though there is this tremendous variation in the types of low fat and high fat diets that are used in the literature, when we were able to combine microbiome profiles from all of these different studies. Because we were still able to capture really reproducible effects on the gut microbiota. And so, you know, that suggests that that really, you know, the microbiota is responding, to a large extent, you know, to these general shifts in macronutrient intake, and that they don't, you know, even though, you know, maybe at a quantitative level, they can sense the type of fat, but that the kind of general trends are able to transcend the specific flavor of high fat diet. And so I think that was good news. And kind of like, you know, suggest that you might be able to translate some of this to humans. You know, where there, you know, there is no kind of single high fat diet, and in the human population, we're all eating variable diets to each other. And so hopefully, you know, we can kind of find these, these, you know, more foundational ways in which the microbiome responds to a shift in macronutrient intake. Yeah,
Nick Jikomes 11:00
if we think in terms of this, this sort of triangle you described, of macro nutrients you've got, you know, one, one corner is carbohydrates, one's fat, one's protein, a given diet is going to fall somewhere in that space. It might be high in one, low in the other two, or vice versa, or high in two and low in one, whatever. Can you give us a sense, a very, very basic sense for like, when we talk about the standard American diet, the diet that's going to be fairly representative of what the average person in the US is eating. Where would it fall in that triangle? Is it high carb and high fat, low protein? Or where exactly would we place it?
Peter Turnbaugh 11:35
Yeah, yeah. I think it varies study to study, but it's somewhere in the realm of, like, 45% you know, kilocalories from fat in the standard American diet. And you know, that was one of the things that we, I guess, continue to think a lot about with respect to mouse models. Because, you know, you know, I think one of the challenges in translating from mouse to human is that if you take your average American, they're already on, you know, at least in terms of macronutrients, the equivalent of a mouse high fat diet,
Nick Jikomes 12:12
so non ketogenic diet with high fat levels. But also probably right, yeah,
Peter Turnbaugh 12:19
and you know, because mice normally, on the standard Mestre consumes, so, you know, such tiny amounts of fat, if you want to kind of induce the same level of shift in macronutrients, you have to go, in humans, from a high fat to a ketogenic diet and and so the it kind of, you know, matters, depending on, like, what the baseline intake of the population is. And so, you know, I think in Americans, it's like, you know, we can do studies readily to either, you know, to lower fat intake, but it's difficult, kind of, with normal diets, to get higher than than what a lot of people are already eating,
Nick Jikomes 13:00
and what would be just, just to spell it out for people that aren't familiar, if we take a high fat, meaning high fat, high carb diet, we compare it to a ketogenic diet, what are the differences there, both in the composition of the diet and in terms of the kinds of metabolic shifts that would induce in an animal,
Peter Turnbaugh 13:15
yeah. So you know, the big, kind of famous shift that happens in terms of a ketogenic diet is that you're, you really, you know, have to lower carbohydrate intake dramatically. And so, you know, when the body kind of shifts from using glucose as its primary fuel to lipids, or fat that allows the release of the, what are called ketone bodies that go into general circulation and then provide fuel for different tissues. And so that requires, kind of the combination of very, you know, very, typically, very high levels of fat and then very low carbohydrate intake. You know, in in humans, it varies. And then in mice, we we typically remove all of the carbohydrates and so they're they're really only eating fat and protein.
Nick Jikomes 14:07
Do, um, is there anything? This is a topic that I don't hear covered a lot in the literature. So obviously, mice are a convenient model for all the reasons that people use mice when we think about them in sort of evolutionary and ecological context. Are there wild mice that eat truly high fat or ketogenic diets, or, I guess, another way of asking, What I'm asking is, do would we expect mice to have the same degree of kind of metabolic flexibility that a human being has in terms of its ability to adapt to very large shifts in the the fat and carbohydrate content of its diet?
Peter Turnbaugh 14:43
Yeah, that's a great question. Then it's not something we really look at in terms of kind of high fat consuming mice. But then, yeah, I mean, we've looked at we did have one study where we kind of tracked wild mice throughout the course of a year. Yeah, and this was working with Amy Peterson and her colleagues in the UK, where they, you know, in the UK, or they have these beautiful study sites where it's kind of wild, you know, fields where they've gridded off different areas to capture and release mice throughout the course of a year. And this has gone on for decades. And so you have the ability to, kind of like, follow the same mouse over time as they switch from eating, you know, different foods depending on the type of the time of the year. And kind of as expected, we did see a pretty clear shift in the microbiota these wild mice that we could kind of correlate to the change in, you know, eating seeds versus insects primarily. But you know, it's messy, right? Because, yeah, you know, just like in humans, they, you know, they still have access to different options, and so, you know, we don't see the kind of like clear transitions that you might see, you know, in a laboratory mess, yeah,
Nick Jikomes 16:02
yeah. So they will adjust in that. And
Peter Turnbaugh 16:04
then, yeah, yeah. And, you know, and I think that kind of, since then, people have reported similar kind of seasonal effects in the human microbiome. And so I think that's probably a general kind of feature of animals that are experiencing different nutrients at different times of the year. Yeah. But I The other thing that we're really interested in now is like thinking about more exotic diets that wild animals consume. And soon, for example, we've, we've done a lot of work on this drug digoxin, which is a natural product isolated from the foxglove plant. And you know, Fox globes are really toxic to most mammals, but interestingly, mice are resistant to them. And so we're doing some studies with Denise Deering and other collaborators to kind of track what happens to the microbes in the gut of mice that are that are kind of foraging on these really toxic plants that humans can't consume.
Nick Jikomes 17:09
But earlier, you said, when we give a ketogenic diet that can induce ketosis in a mouse, you typically have to pretty much just remove all of the carbohydrate. Is it does that mean that it's basically harder to get a mouse into ketosis than a human?
Peter Turnbaugh 17:29
Yeah, I definitely think that sling that's true. So yeah, not only is kind of starting the ketogenic process or ketogenesis more challenging, but, you know, also mice. I mean, this is true for a lot of things in mice that they you know, they're very lab mice, you know, even though you might expect them to be wimpy, you know, are often really resistant to a lot of the diseases that we have. And so, you know, we think this is definitely true for metabolic diseases like diabetes and obesity, as well as other diseases. I don't mean disease. You kind of have to, like, you know, this is why we have to leverage, you have to really push those models. Yeah, is that
Nick Jikomes 18:14
I I'm just guessing. So you tell me if I'm right or wrong, but I'm guessing that sort of acts. Is that just a byproduct of breeding mice to, you know, to live and survive in the lab. And as a side effect, they're, they're actually Hardy in certain ways.
Peter Turnbaugh 18:27
I don't know. Yeah, that's a good question. I mean, I think what, maybe one of the reasons, is like, we tend to study younger mice in the lab, you know, no one, although there's exceptions, but, you know, it's hard to study a middle aged or an older mouse, and so, you know, some of these diseases do kind of progressively get worse if you look in an older lab mouse. But yeah, I think it's an interesting question. I don't know, you know, if you look in wild mouse populations, whether or not you can find more evidence of disease. I think, like, one of the things that was really clear in the study that that we did with Amy is that the, you know, mice in the wild are really, you know, they have a very hard life, and, you know, I think before any of these chronic diseases happen, they're, they're getting infections and they're getting killed by predators, right, right? And then over the winter they, at least in the mice we were studying the there's a huge population crash, yeah. So starve, yeah. You know, I think there's a lot of other forces that kind of Ling are acting against, even being able to look for these,
Nick Jikomes 19:41
yeah, yeah. But, like, you know, one of the things I wanted people to take away from this part of the discussion is, obviously, mice aren't humans, but there's all sorts of other things that were, you know, there's, there's issues with the literature in terms of how we speak about things, how we. Up the experiments that start to lead people astray, in the sense that, you know, when we you'll often see, even with scientists sweeping claims about the high fat diet does this, and they're infrared things from rodent studies, where all the high fat diets are different from each other, and then mapping that onto humans. And it's, it's, you know, there's so many like, little jumps and assumptions that get made along the way that people often don't realize are being made. One of the things I liked about some of the work that you've done is you've started to fill in some of the blanks here. So one of the studies I wanted to talk to you about was people are interested in high fat, low fat. People are interested in animal based, plant based, high fiber, low fiber, all these different types of questions, how it affects the microbiome and so forth. You've actually done well, I'm gonna ask you about one study. There's more things I'm sure we can talk about, and I'll let you sort of steer us there. But you had this 2014 paper that that was really interesting. You actually took human beings, and you gave one a plant based diet that had high carb levels, so that's not gonna be ketogenic. One had an animal based diet that that did put people into ketosis, and you actually measured some things across these people. Can you start to talk about the setup for that study and what the motivation was for it? Sure,
Peter Turnbaugh 21:12
yeah, I think a colleague of mine called a carnival diets, or something derogatory, but yeah, I mean, I think we've kind of been alluding to the the logic that got us there. And so then, you know, we, I, when I was in grad school, like one of the, what I thought was a really exciting finding, was that we, we took lab mice and we put them on a high fat, high sugar diet, and compared their micro, the microbes in their gut to to low fat controls. And then, I don't know if you how quickly, or you probably know the answer now, but how quickly you think the microbiome would change if you go on a new diet? But
Nick Jikomes 21:59
Well, yeah, I'm spoiled, because I know the answer. But so, so this to set you up for this one question. There was, like, obviously your microbiome is going to change to your diet. But a big question was, how much and how quickly,
Peter Turnbaugh 22:11
right? Yeah, yeah. And so, you know, that was a really striking thing in the in these initial mass experiments, is that, you know, I kind of imagined it would be slower, and, you know, we might see more gradual effects.
Nick Jikomes 22:23
That takes weeks to adapt to it. It's sort of the slow roll, maybe, right?
Peter Turnbaugh 22:27
But you know, instead, what we saw was just after a single day. It's kind of like a light switch. You can see you go from one configuration of the gut microbiota to another, wow.
Nick Jikomes 22:38
So it's literally, literally in one day, yeah. And so,
Peter Turnbaugh 22:42
you know, and you know, it was a little bit of a bummer, because we spent a lot of time collecting all these other time plans, you know. I mean, it got a little stronger throughout week one, but then, you know, like, really, that all the action was in the first week, in, at least in the mouse model. And so, you know, that kind of raised the question of whether or not this could happen in humans. You know, our is our microbes actually changing every day as we decide what to eat. And it, you know, it kind of conflicts with the, you know, some of the more traditional views of the gut microbiome is that it's like, very stable throughout adulthood, yeah, there's not a lot of changes,
Nick Jikomes 23:24
yeah. And I guess, I mean, I guess one thing to unpack there is that that statement isn't coming out of nowhere. I think when you measure the microbiomes of a typical person, it will seem pretty stable, day to day, week to week, but, but that's probably an artifact of their lifestyle and their diet being relatively
Peter Turnbaugh 23:40
stable. Yeah. Yeah, that, well, I think multiple things that contribute to that. So one is that, like, you know, and then this kind of becomes semantics, but it's a, you know, it's really important how you define stability. And so, you know, like, one of the breakthroughs, kind of early on in the microbiome field, where the development of all these data diversity, like ways of comparing microbial communities to each other, and so that allows you to, like, plot microbial communities on a PC, away space, or some other dimensionality reduction method. And you know, but typically what you're comparing is multiple people. You know, you have samples of one person over time and then the second person, and if you plot them on the PC, away the I mean, typically the samples from the two people stay apart from each other, so that you kind of retain that, you know, the signal of individuality. Yeah.
Nick Jikomes 24:38
So, so they're they're different from each other. But that doesn't necessarily mean each one is static within the person, right?
Peter Turnbaugh 24:43
Exactly, yeah, yeah. Like, within each person, there can be dramatic fluctuations, but, you know, as long as you don't, as long as my bank provided doesn't become yours, yeah, you know, we're still going to end up a part on the plot and so, so, yeah, I kind of. Depends on what the measurement is. And then, yeah, they and then to your other point, I think, yeah, I guess I hadn't appreciated when we got into this stuff that, like, although maybe I should have, because my diet is pretty boring, but, um, you know, like people, people really don't change what they eat that much, you know. I mean, we do go to restaurants, so that's a source of chaos. But, yeah, but a lot of people have very routine diets. Yeah, it's
Nick Jikomes 25:24
not like, it's certainly not gonna be as drastic as what you, you did in the study. It's not like, on Monday I'm doing, I'm doing a vegan Monday, Tuesday, and then a carnival Wednesday, or a ketogenic like, it's, it's gonna be relatively stable in terms of the overall macronutrient profile and whether I'm generally more plant based or animal based, right?
Peter Turnbaugh 25:42
Yeah. And like that turns out to be true, not just for people that are on, you know, explicit diets to lose weight or for some other reason, but just because, you know, like we're habitual creatures, yeah, yeah. I know. I tend to have very similar breakfast and lunch, yeah? So
Nick Jikomes 25:59
anyways, like going back to this 2014 study, what were the two diets that you used and and why did you engineer them the way that you did?
Peter Turnbaugh 26:06
Yeah, so kind of the thinking was like, we wanted to really push the needle and, you know, try to change macronutrients in a big way. And so that kind of got us to this, this idea of, like, you know, if most of the people coming into the study are already eating a decent amount of fat. We want to get them even higher. We weren't really intending to study ketogenesis. It was just kind of a happy accident of, you know, designing a diet that would be really rich in fat, and then the on the and then, I guess, like, what we realized is that really the only way, you know, one of the you know, which is true in the kind of weight loss diet literature, the you know, if you try to the easiest way to get to high fat is to drop carb a lot. And so we thought, why don't we just go all the way and make it only meat?
Nick Jikomes 27:04
So it's basically just meat and cheese. It was an animal based ketogenic diet, right? Cheese, eggs, you
Peter Turnbaugh 27:11
know, much more extreme than what your average person on the ketogenic diet eats. But
Nick Jikomes 27:16
yeah, so it was high fat, very, very low carb, low fiber, and it's all animal based foods, yeah, yeah. And then the other group was plant based, and it was basically high carb, high fiber, you know, a mix, a mix of plant based foods. But it certainly wasn't ketogenic, and it certainly wasn't only fat,
Peter Turnbaugh 27:36
right? Exactly, yeah, yeah. Then, you know, once we kind of, like, realize this would be fun to test an animal. They say, you know, we should do the opposite. Yeah. And so, you know, the downside is, like, these two diets are so different from each other in so many different ways that, you know, it's not a great design in terms of getting a mechanism right, right? You can't. You can't see changes. You know what, what is driving it is really hard to be, yeah,
Nick Jikomes 28:01
you can't, you can't just, you can't conclude from the study, oh, the fiber did this. The protein content, that fat content did this. But it is, it is naturalistic in the sense that you were giving people Whole Foods. You were giving them diets that some people intentionally, you know, try and eat people. There's people out there trying to eat animal based ketogenic diet, people out there trying to maximize fiber content from plant based whole foods and so forth, and you saw pretty big differences in terms of what the response was in each group. Can you give us a basic survey of what happened to people eating the plant versus the animal based diet? Yeah.
Peter Turnbaugh 28:36
So I think the most exciting thing for us kind of gets back to what we were talking about in these these early high fat mass experiments, is that, you know, we gave people food coloring in along with their their special diets for five days. And, yeah, the design was that we, we had daily sampling from people for a few days before each diet and then after each diet, and then the diet, each diet arm was given for five days. And so along with that, we gave food coloring, and that allowed us to kind of track when the first sample of the new diet came out of the gut. And using that, we could kind of estimate that the that actually we could see differences, especially on the animal based diet in kind of overall structure of the microbiome, just within a single day. Wow, of being on the diet. So yeah, you give people each of
Nick Jikomes 29:30
these soaps. So half the people get a plant based diet for five days. Half get an animal based diet for five days. You've also got five days of measurement before that shift, and then after that shift, when they're going back and forth to to their normal diet, and you're saying that in that five days, you see drastic changes in the microbiome, and you can actually start to pick them up within just
Peter Turnbaugh 29:49
one day, right? Yeah, exactly, yeah. And really, like most, the strongest effect was going from kind of, you know, their standard starting diet. On to the animal based diet, although we also, did, you know, see some differences in response to the plant based diet,
Nick Jikomes 30:06
yeah. So you see differences in both groups. Obviously, they're going to be different, differences in the place of the animal group, but overall, sort of the magnitude of the shift was probably stronger for the animal based diet,
Peter Turnbaugh 30:16
yeah, yeah. And I think one thing we kind of speculated that I that I still think is true, is that the, you know, like, oftentimes, the study design, you know, if you think about fiber, for example, you know, we take people that are on a standard American diet and then try to ramp up fiber intake. Yeah, here's the far yeah. It's far rare that we do the opposite, yeah? And, you know, so this is a diet where you're really depleting, you know, dramatically depleting the carbohydrates that a lot of bacteria in the gut, yeah,
Nick Jikomes 30:50
after Yeah. So the people on plant based diet are increasing their fiber content. So they start at some baseline. And it's certainly not zero. Maybe it's, you know, some people might argue it was higher, it was low, but it was some fiber content, as most people would eat at baseline, that goes up in the plant based group, and then the animal based group, they're really getting no fiber. There's essentially zero dietary fiber. And what would you know before you looked at your results, what would the prediction there be on how increasing fiber versus taking it down to zero would affect people, yeah,
Peter Turnbaugh 31:22
yeah. So, yeah. The other thing I wanted to mention is that the, you know, so that one of them really, actually the first study I worked on when I was in the Gordon lab as a graduate student, you know, I was a brand new rotation student assigned to work with Ruth lay, who had come from norm paces lab, and, you know, was experienced with a lot of these tools for microbial ecology. Um, and Ruth, before I got there, had gone to the San Francisco Zoo and collected a bunch of poop from different animals. And so the idea was, you know, now that we have the ability to sequence microbes in the gut, we could kind of compare which microbes were in the zebra versus a giraffe versus a lion. You
Nick Jikomes 32:05
could, you could get a sense for what a carnivore microbiome looks like versus a herbivore microbiome, exactly.
Peter Turnbaugh 32:12
And so, you know, kind of, one of the takeaways from that study is that you could see these correlations between, you know, the as you might expect, the carnivores and the omnivores and herbivores all group separately. Humans kind of looked like weird, regular omnivores at the time. It was just a handful of people, but you could kind of like, you know, group animals by diet, just based on microbes in their gut. Yeah,
Nick Jikomes 32:39
makes intuitive sense, right? Yeah.
Peter Turnbaugh 32:42
And then, you know, after that, Brian Maggi, another graduate student in the lab, did metagenomic sequencing of those same samples to kind of compare the levels of different genes in the gut of carnivores and herbivores. And you know, kind of, as you might predict the you know, microbes are really flexible and what they can metabolize. And so when you know, in the gut of your typical herbivore, you see a lot of genes that are involved in breaking down plant polysaccharides, these complex carbs that are in plant products. Yeah. And then, as you when you look in the carnivores, there is an enrichment for genes that are involved in breaking down proteins and amino acids and using those for kind of alternative types of bacterial fermentation. And so there is kind of, you know, a nice kind of genetic signature of, you know, what types of pathways might be useful to a microbe on a car in a carnivore versus an herbivore. And so that was kind of what we were thinking leading into the Newman study. And you know, in many ways, kind of played out, especially when we started to look at the expression of genes in the community, we could see some of these kind of signatures of switching from plant fermentation to protein fermentation.
Nick Jikomes 34:01
Yeah, so, so basically, you had a sense from prior work. You guys literally went to the zoo. You literally looked at the gut microbiome of herbivores like zebras, Coronavirus, like other animals. You lit, you collected the waste from animals at the zoo. And you had a notion that certain animals on certain diets had certain microbiomes. This involved microbes metabolism that that made sense, right? If it's a plant eater, it's got metabolic genes turned on, and microbes present that break down plant sugars and plant fiber and things like that. And then if it's a carnivore microbiome, you've got stuff that's involved in breaking down the amino acids, proteins and and stuff like that. So you had a sense for what like the carnivore, herbivore spectrum of the microbiome looked like. And when you gave people these diets, broadly speaking, they conform to that directionally speaking,
Peter Turnbaugh 34:51
right? Exactly, yeah. And I think it's, you know, the more you think about it, it's kind of wild that you can, you can become a carnivore, you know?
Nick Jikomes 34:59
Well, I mean, I. I, you know, it is kind of wild, but at the same time, I I've learned a lot about this last year or so, and to mention just one podcast that was really interesting. I have these two guys on they're basically paleoanthropologists by training. And long story short, they studied ancient DNA and ancient tissue samples from the COVID peoples of North America during the last ice age, and they basically showed that these people were eating the same diet that Saber Tooth cats were eating, which was probably a mega fauna meat, rich, ketogenic diet. Interesting. So people in history, some of them, have eaten that type of diet,
Peter Turnbaugh 35:36
right? Yeah, yeah. And I think what our data suggests is that you can your microbes are really plastic, and they can adapt to these changes rapidly. And so, you know, it raises a lot of interesting kind of evolutionary questions that we're not really working so much on in our lab. But Rachel Carmody, a former postdoc from a lab, thinks a lot about, yeah, when you look at, I mean, the potential for microbes to kind of open up new new access to nutrients as they adapt to Yeah. Humans are trying, yeah. I mean,
Nick Jikomes 36:07
look, one of the things your study clearly shows is, as you said, you see big changes in the gut microbiome composition to both types of diets in different directions in five days. You start to see it within one day, and that fits with the idea that humans are just very metabolically flexible. And when you start to think about it, like holistically, when you look at the variety of diets out there today, the variety of cultures and cuisines out there today, and you know, the stuff I mentioned before, and other stuff from from the Paleo literature, you know, humans have eaten all sorts of different diets, and that's enabled us to go into, you know, basically every corner of the globe. So it makes perfect sense that a feature of our species would be metabolic flexibility and and that would imply gut microbiome adaptability as well.
Peter Turnbaugh 36:51
Yeah. And I think that the kind of diversity of the gut microbiota allows, you know, and not only kind of this, like flexibility, where microbes that are really well adapted to different types of diets can bloom or decrease in abundance. But also, nice work from Justin Sonnenberg and others have shown that even within a single species, you can, you know, microbes, bacteria, can kind of turn on and on, on and off different pathways and so, yeah, yeah, you know, they have the ability to kind of change what they're eating depending on what we
Nick Jikomes 37:25
Yeah. So it's not just that our microbiome can shift in terms of which species are present. The actual even you could have the same microbiome and same exact composition, it could switch which genes are turned on and off, and therefore it's metabolic properties,
Peter Turnbaugh 37:40
right? Exactly one of the
Nick Jikomes 37:43
things I wanted to ask you about in this study. So So to recap, plant based diet, high fiber, animal based ketogenic diet, basically no fiber. One of the most common things I see in the literature about fiber. And I want to ask you about this because I've been thinking about it basically, if I'm going to caricature what I see in literature with respect to dietary fiber, it's dietary fiber is good because it supports good gut health, because we have gut microbes that can digest what is otherwise undigestible, plant fiber for us, and they digest it into short chain fatty acids, and that's Good for our gut epithelial cells. Baked into that statement, and we can critique it in a moment, but baked into that statement is the only way to get these short chain fatty acids like butyrate, is from bacterial fermentation of that dietary fiber. How did this short chain fatty acid profile from the animal and the plant based diets compare in the study that you
Peter Turnbaugh 38:39
did? Yeah, so we definitely saw differences that are consistent with that general thinking. So we, you know, there's certain short chain fatty acid products like isobutyrate and isovalerate that are thought to mainly come from protein fermentation and so, yeah, I guess, like, one thing for those that aren't like deep into this is that there's actually many short chain fatty acids, and they can come from many different sources, including there's bacteria that can take hydrogen and CO two and produce a short chain fatty acid. And so you don't even need to come from a macro nutrient. You can come from waste, basically, like gas waste, and so, you know, it's a lot more complicated than, like, this kind of simple model that people typically mention with, you know, which is obviously true that fiber gets fermented and then that gives you butyrate. But, you know, butyrate is kind of one of many different compounds that's
Nick Jikomes 39:41
produced. Yeah, so there's, there's multiple short chain fatty acids, not just butyrate. But the other thing that I thought was interesting here is so the so, the thing that was expected is you would expect the plant based high fiber diet to give you more butyrate, and indeed, that diet had higher butyrate levels those people did than the ones on the ketogenic animal diet. But what I thought was interesting is the. Rate levels for people on the animal based diet did not go to zero. Was that surprising to
Peter Turnbaugh 40:07
you? Yeah, definitely, yeah. And I guess it's trying to think of it a specific example offhand, but yeah, not only in the human data, but like, you know, also, like, I'm always surprised when you see data from, you know, for like, germ free mice, or, you know, diets that are really low in fiber, that you can still detect butyrate and so, yeah, it definitely raises the question of Ling. What the sources are? You know, as I mentioned, like, you can get acetate, you know, if you just have hydrogen and CO two, you can create acetate with a with bacteria, and then from there, there's microbes that actually interconvert acetate to butyrate. And so, you know, there are, there are kind of like, fiber free ways to get to butyrate, yeah, yeah. But yeah. I think, I think it's an open question, kind of like, where are these? What actually the source of these compounds is,
Nick Jikomes 41:03
yeah, yeah. I mean, the other thing that I thought was a good takeaway here is, a lot of times the discussions I read about or hear with respect to dietary fiber, it's just, it's the simplistic story of fiber goes to butyrate via bacterial fermentation, goes to good health outcomes. Really, when you shift a diet in the ways that you did, going from plant going to either a plant diet or to an animal based ketogenic diet with no fiber, you see the whole profile of short chain fatty acids both groups. It's just, you know, the mix of them is different, but, but they're all there in both groups.
Peter Turnbaugh 41:38
Yeah, yeah. And I think you know what part of what's happened over the last like, decade or so is that the, um, you know, I guess when I got into this, then, you know, was very much, at least, we were thinking along the lines of energetic so it's, you know, butyrate fuels the enterocyte. Another, you know, probably the most abundant church inside the acid, typically is acetate. And you know, acetate is interesting in that we know it can get absorbed out of the gut and then incorporated into adipose tissue, and then later, papers have looked at like acetate trafficking to the brain and all sorts of other tissues. So, you know, but that, but primarily we were thinking about these as fuel, you know, but you know, as you may know, we now know that the short term fatty acids can also be signaling compounds. And so, yeah, butyrate, for example, is an H act inhibitor. They also have effects on immune cells. And yeah, something Wendy Garrett and others discovered is in the T regulatory cells that kind of provide a check on inflammation are induced by short chain fatty acids. And so, you know, it's not as simple as just the like model of, you know, providing more calories to gut
Nick Jikomes 43:01
cells. Yeah, these things aren't nearly fuel to be, to be used for fuel, right? Yeah.
Peter Turnbaugh 43:07
And then, you know, that's not, you know, something that's really been ignored is, like, what they do to the microbes you know we because, presumably, like, if you drive fermentation towards butyrate, you know, butyrate, you know, could potentially affect other bacteria in the community. And so you can have those kind of ripple effect,
Nick Jikomes 43:25
yeah, yeah. So, so either a plant based diet iron fiber or a ketogenic animal based diet can rapidly reconfigure the gut microbiome. You see, you see shifts in the short chain fatty acid profile in each diet, and when you take them off the diet, do you also see, like a rapid reversion right back to where they were before? Or are there sort of lingering effects that prevent it from going back to what it was?
Peter Turnbaugh 43:49
Yeah, we did for the most part. Things went back to as they were, and that was really a big relief, you know? But yeah, it's definitely something I worry about more generally, in human studies, you know, that's not always the case. You know, for example, in studies of antibiotics, David Romans lab has really nicely shown that you can have really persistent effects of antibiotic exposure. Yeah, you know that can go out weeks to months after the initial you know, after taking the drug, yeah. And so, you know, you always worry that, you know, you don't want, we don't want to do human studies if we're kind of permanently changing your microbiome, yeah?
Nick Jikomes 44:32
And like, where my mind starts to go is, yeah, if you use, like, heavy doses of broad, broad spectrum antibiotics, it's not difficult to imagine you could completely wipe out at least certain species of bacteria from the gut of an animal when you saw these diet induced shifts in the study we were just talking about, were you just were the population shifting? Or did you completely erase certain species with one diet or add brand new ones that weren't there before? Yeah,
Peter Turnbaugh 44:58
that's typically how I think about. Of those that you know, at least, when you think about macronutrient shifts in diet that like, it's, it's basically like moving the knob, you know, and so, yeah, it's rare that we see what you know, microbes that actually, like drop below the limit of detection and are never seen again in the study. You know, we've looked at that kind of explicit explicitly. We had a paper a while back where we had a really patient undergrad who switched the diet of mice from low fat to high fat every three days. Oh, wow. And so, you know, relatively short intervention, but we were looking for cases of microbes that you know showed a kind of hysteresis or memory of past diet, and we could find some examples, but that they were rare. But you know that there is data from other labs, like around Elena, for example, has shown that like if you keep mice on a high fat diet, long enough that then when you return them to a low fat diet, some of the microbes look like they're gone. They're not able to recover, I see. And so it might be kind of a an effect of, you know, how extreme, you know, how strong is the dietary pressure? And then also, like, how long? How
Nick Jikomes 46:19
long does it last? Yeah, interesting, yeah. So you can get permanent changes with with drastic interventions, whether that's using antibiotics, which are obviously an unnatural stimulus, or these sort of, you know, artificially long dietary shifts, right? I mean, my mind immediately goes to thinking like, well, obviously the wild animals in most places, including mice, as you mentioned before, they're seasonal, right? There's, there's four seasons in the year food is naturally going to shift. Maybe the body is sort of expecting, or adapted, in some evolutionary sense, to shifts that happen on that seasonal time scale, but not ones that are lasting, you know, longer than that,
Peter Turnbaugh 46:57
right? Yeah, exactly. Yeah. And I think it's harder to kind of maintain these, like, long term pressures, yeah. And, you know, the other thing that I think is really, you know, maybe this is good news for humans with the, you know, we're also, like, we have constant exposure to microbes from other people, yeah. And so, you know, I think it's harder to kind of maintain permanent disruption in the microbiome, because we're constantly being receded. Yeah, and you know, that's been nicely studied in mice, where you, you know, if you treat a mouse with broad spectrum antibiotics and keep it alone in a cage, versus in a cage with a, you know, an untreated cage mate. You know, the kind of CO housing allows you to, you know, allows the microbiome to recover really quickly after a threat. Yeah.
Nick Jikomes 47:49
So bottom line, based on all the stuff you've mentioned so far, the microbiome, even when it's depleted, it can be regenerated. And it's very plastic and very responsive. It can shift very quickly in response to lifestyle changes, such as dietary shifts.
Peter Turnbaugh 48:08
Yeah, that's definitely kind of a working model, yeah, and yeah. But I definitely think it like in terms of the, you know, some really simple things that we still have yet to follow up on from that study is, you know, kind of like modeling better, what the gradient would look like if you, you know, if you're on a less extreme version of that, of the animal based diet, yeah, yeah, you know, or, or vice versa, if you extended it longer in a time, it'd be really interesting to see if these effects compound, yeah, yeah.
Nick Jikomes 48:41
One of the things I wanted to ask you about that study is so on the animal based diet, I believe you saw the microbiome shifts that you saw involved. A lot of you saw more bile tolerant organisms, because presumably the animals were secreting more bile. Can you unpack some of the basic biology there when you're eating a ketogenic or, you know, truly high fat diet like that. What? What is that bile doing and and what is sort of the basic biology there?
Peter Turnbaugh 49:12
Yeah, this is something, you know, I guess I'm always excited when we see something in a human study that that matches what some what we have seen in model organisms. And so the, you know, Suzanne Dakota, who is in Eugene Chang's lab at University of Chicago at the time, had this really beautiful paper where she kind of getting back to your earlier question too. You know, they were interested in the question of whether or not microbes in the gut care about the type of fat. And so they fed mice high fat diets that varied in the source of the fat. And I probably will butcher it if I or I think it was the milk derived saturated fat, if I remember correctly. But, you know, they found on kind of one of the high fat diets that there was this expansion in kind of. A weird microbe named balafala Once worthy I and you know this to microbiologists, it's an interesting organism because it's actually named for loving bile. It grows a lot better in the presence of bile acids, which is the opposite of most bacteria, and bile has a really strong detergent and antimicrobial effect. And so, you know, it's not to actually be one of the pressures that kind of keeps the level of microbes down in the small intestine,
Nick Jikomes 50:32
I see. So Bile is essentially acting as a detergent. And naturally, you would expect any cell based organisms probably not going to tolerate too much bile, because everything's made out of a membrane. But nonetheless, there are somehow, some way nature has evolved certain bacteria that like the bile. Basically,
Peter Turnbaugh 50:49
yeah, exactly. And they, you know, specifically what balafa does. Or one of the things that does the bile is that it, you know, our bile acids in the gut have kind of decorations that are added by our body, including taurine. And so buffalo grows on the taurine, really, you know, cut it off of the bile acid, and then use it as a substrate. And so, you know, that was kind of just like interesting from a more micro, basic side. But then I think the reason why the paper got a lot of attention is that Suzanne went on to show that this expansion in balacla actually made mass models of inflammatory bowel disease worse.
Nick Jikomes 51:35
So more having more of the bio tolerance species exacerbated inflam this inflammatory bowel disease, and mice, yeah,
Peter Turnbaugh 51:46
and I, you know, I haven't followed that literature carefully, so I don't know what the latest is in terms of them. You know whether or not that's that's still the case and or, you know how exactly that works at the time, I think there's some speculation that it had to do with hydrogen sulfide, but, um, but, yeah, we got interested in it just because when we looked at the animal based diet, we saw one of the microbes that really went up was the lafala. And so that kind of made us wonder if, you know, maybe at this elevated dietary fat intake could have kind of selected for this microbe that that axon fat or that metabolizes bile acids. And you know, the other thing we know, knew from the literature is that, you know, bile acids are controlled in that they're they're often produced in excess as we increase our fan intake, I
Nick Jikomes 52:42
see So, so bile levels tend to go up and correct me if I'm wrong. So the liver makes the bile, the gallbladder secretes and stores the bile, and the bile acts as a detergent. And basically, if you're eating a lot of fatty food, it's, it's meant to sort of emulsify and act as a detergent for to handle all of that fat.
Peter Turnbaugh 53:00
Yeah, exactly. So it's kind of, you know, it's a good thing we need the more fat we eat, we need the bile to kind of help with digestion. And so, you know that we knew, and so that kind of like prompted us to kind of look like more carefully. And yeah, we were able to, you know, kind of consistent with the mouse study, you know, show these, these increases in the level of the microbe that word associated with changes in bile acid composition. And,
Nick Jikomes 53:30
you know, you've done, you've done work. I want to talk about autoimmunity and information, especially as it relates to the cut you've you've done work in this area. And I'll let you kind of direct what work is most relevant to talk about from your lab. But before we dive into that, can you just give us a sense so but based on everyone I've talked to on the podcast and stuff I've read, basically inflammatory gut issues seem to be on the rise, and they have been, I don't know, as far as I can tell, for quite some time. To what extent is that true? What are sort of the most common inflammatory gut issues that we see today in people?
Peter Turnbaugh 54:07
Yeah, I'm definitely not a gastroenterologist. I can answer that well, but yeah, I mean, I think that you've probably seen the graphs of, you know, increased chronic disease burden that kind of like, you know, coincide to the decrease in infectious diseases that are now, at least currently being controlled, you know, with antibiotics and vaccines, but the yeah and so, you know, I think the the kind of primary diseases that people are really focused on with respect to the gut microbiome, or, you know, inflammatory bowel disease, colon, you know, as well as colon cancer, kind of linked to inflammation, yeah, yeah. And then, you know, even diseases and other tissues. We're working a lot now on multiple sclerosis, which is a. Um, you know, a disease of inflammation and the central nervous system that we think has links to microbes in the gut.
Nick Jikomes 55:09
Oh, really, yeah. I mean inflammatory bowel disease. When you think about gut microbes and food, I mean inflammatory bowel disease things like colitis, that makes sense, right? You're talking about in the gut, the food goes through the gut, the inflammation, makes sense, but you're saying you're working on multiple sclerosis. This is a C A central nervous system thing, and even that is potentially connected to gut microbiome stuff,
Peter Turnbaugh 55:30
yeah. So you know, what's interesting is that, I mean, a lot of this has been studied with respect to how microbes in the gut affect the immune system. And so, you know that is really well established within the gut. We know that if you look in a germ free mouse, for example, they lack many of the key immune cells that are typically found in the small and large intestine. And then, and you know, people have identified specific microbes that can kind of control the levels of different immune cells sometimes. But you know, the the effects of the the microbes and the gut, it doesn't stay there, because the immune cells can move, I see, and then the, you know, the other thing that happens is that microbes produce metabolites, some of which we've talked about, like these short chain fatty acids that can go into circulation and then reach other tissues. And so there's kind of this potential for microbes to remotely control immune function in many different tissues.
Nick Jikomes 56:33
Yeah. So just because the gut microbiome is, you know, microbes in your gut, they can affect things anywhere else in the body, potentially, because a the immune cells that might be in your gut at certain certain time points can literally move away. They are mobile, or the metabolites produced by the microbes can enter your bloodstream. Then, you know, get all over the place,
Peter Turnbaugh 56:53
yeah, yeah. And then, you know, there's also, although we haven't really worked on this in our lab, but a lot of interest in, you know, microbes also moving throughout the body. And so then the, you know, in certain situations, like gut inflammation, you might,
Nick Jikomes 57:10
there's some thinking that you you the microbes might actually translocate out of the gut. Oh, yeah. So, so like, if there's microbes moving throughout the body, I see So, so if there was, say, some inflammatory condition, and, say, the barrier between gut lumen and the inside of the body is compromised, then you get, you start to get creatures that are supposed to be in the gut lumen, and maybe they infiltrate and get in the body where they're not
Peter Turnbaugh 57:35
supposed to be, right? Yeah, exactly, yeah. Or, you know, another situation, if you have a lot of immune suppression, then the normal kind of mucosal defense that you have in the gut might not not be able to keep the microbes out. Yeah. So, so, yeah. So there's definitely, like, many different ways that we think microbes that are normally in the gut could affect other tissues.
Nick Jikomes 58:00
I mean, some of the work you've done recently, the last year or so, was looking at giving ketogenic diets and how that affected neuro inflammation and things like that. Can you walk us through some of that, and also what the thinking was for why you went down that route?
Peter Turnbaugh 58:16
Yeah. So we were, you know, we got really interested in that, kind of starting on to back up. We, you know, we had done the study that we've been talking a lot about, where we, we put mice on or humans on an animal based diet. And you know, we weren't really intending to study ketogenesis, but we, we did note that the subjects were in ketosis. But you know, it got me really interested in ketogenic diets, you know, just because it, you know, I guess I'm attracted to these more kind of extreme interventions. You know, we had shown previously that if you, if you kind of take a mouse from a low fat to high fat, you know, we did these gradient experiments and showed that it was a really predictable effect on the microbiota, kind of as you titrate up dietary fat, you know. But that was all within the realm of kind of standard low fat to high fat. And so whereas ketogenic diets are different in many ways. And so I wanted to more explicitly look at that, and was fortunate to get in contact with a group of obesity researchers that were designing a human a study that was really designed to look directly at ketogenic diets, and they were mainly focused on energy expenditure, but were kind enough to kind of collect stool samples from their subjects, and so we were able to look at subjects under really controlled conditions. These are all overweight and obese people given a ketogenic diet for four weeks or kept on a control diet for four weeks. Weeks while they were kind of living in a study center. And let me just
Nick Jikomes 1:00:03
ask, before you get into the results, do you know any of the details of the ketogenic diet, like the fatty acid profile, or anything like that?
Peter Turnbaugh 1:00:11
I do. Yeah, I think some of that is in I don't know if it's in our paper or it might be in the the original study paper, but, but yeah, that was one of the great things about that study is that then they, you know, at least in terms of energetics. They, you know, they measured exactly what every single person ate for every meal. And then they, they did that, not only in terms of, like, cataloging the food, but also, you know, measuring calories that remain. And so, you know, because the primary goal of the study was to kind of see whether or not energy you know, your kind of efficiency of energy extraction from the diet versus energy expenditure changed. But so we have a lot of, like, really detailed diet data from that study. We, yeah, we should probably return to that. We didn't. The analysis that we published was, was pretty straightforward. We kind of, like left it at the two arms, you know. But, you know, we didn't really do a lot of work like looking at the variation between people. I guess part of the challenge is, it was, it was a relatively small number of people. So, you know, we didn't maybe need a bigger study if we're going to start getting into, you know exactly which items people were eating. But yeah, what was interesting is that we, you know, we're able to see clear differences in the Human Microbiome on this ketogenic diet relative to control. And then that kind of prompted us to start modeling this in mice. And so we could, you know, although the results were different in many ways, one thing that kind of repeatedly kept coming out is that we saw lower levels of Bifidobacterium, a group of gut bacteria when subjects were on the ketogenic diet. And so this kind of raised the question of whether or not bifidobacteria, you know, is that a good thing or a bad thing? Yeah. And at kind of like year or two before we were thinking about this, there was a nice study from Diane Mathis lab at Harvard, where they had screened. They did a very laborious screen where the they took, you know, different groups of germ free mice and just colonized them, one of the time, with different gut bacteria, and then measured the levels of immune cells in the gut, as well as in other tissues, as a way to kind of figure out, like which microbes affect which immune cells. And one thing they saw is a Bifidobacterium in the gut can drive the expansion of T helper 17 cells, which we know are really important, both for fighting off infection as well as potentially playing a pathogenic role in autoimmune disease. So
Nick Jikomes 1:03:10
a type of white blood cell is responsive to the composition of microbiome. When you go on a ketogenic diet, this one type of bacteria goes up. This is related to type of white blood cell going up, and that could potentially be a good thing or a bad thing, depending on if, if the conditions actually
Peter Turnbaugh 1:03:28
the opposite. So the the ketogenic diet was driving the bifidos down, okay, you know. And then we confirmed what Diane had shown, which, which is a Bifido, at least some Bifido bacteria and drive the increase the level of th 17 cells. And
Nick Jikomes 1:03:45
if that happens, the idea, so, if this tie, this ties to autoimmunity, so you don't want too many of these,
Peter Turnbaugh 1:03:52
yeah, yeah. I mean, it's kind of a, you know, potentially a double edged sword with it, yeah, you know, it raises questions about, you know, if you do have this happening while you're on a ketogenic diet, does that affect your risk of infection? At least got infection, or, you know, does it potentially protect you from from diseases like on immunity?
Nick Jikomes 1:04:16
Yeah, yeah. And a lot of, I'd imagine, a lot of this stuff is sort of a Goldilocks thing, where, especially immune system, you don't want, you don't want to crank up too high. Certainly don't want it too low. It's, it's, you know, autoimmunity on one side and infection on the other. Right,
Peter Turnbaugh 1:04:29
exactly. Yeah. And we, you know, we haven't really explored the infection angle, although that, you know, that maybe is what we should have started with. You know, in the initial paper, we really just didn't get to any disease model. We were just able to show the other thing that we found, which that was really interesting, is that you can, you can drive the bifida bacterium down just by giving the ketone body. So, you know, you don't actually have to be on the diet. You can just, you know, just the. Population and the ketone body is
Nick Jikomes 1:05:01
interesting? Yeah, I wanted to ask you about that, because that is a theme that I've seen come up across organ and model systems where like for just to give one example that will tie into this completely different field, completely different organ, I was talking to a kidney biologist named Thomas wimes, and he observed some very interesting things about how a ketogenic diet had protective effects for the kidneys in mice. And long story short, they show that BHB supplementation, on its own, without going into ketosis, without having a ketogenic diet, just the BHB supplemented was able to completely recapitulate the protective effect on kidneys. And you're saying something similar is going on here, where the effect of the ketogenic diet on this white blood cell phenotype can be recapitulated by just giving them BHB, right?
Peter Turnbaugh 1:05:49
Yeah, yeah. We looked at both the the effect on immune cells, but also the changes in the gut microbiota. Actually, yeah. It's very same experiment, or similar experiment to what he did. We are using these ketone esters that are, the one we were using at the time, was beta hydroxybutyrate with kind of attached to two medium chain triglycerides, and that allows you to just spike it into the diet, you know, or take it as a drink if you're a human, yeah, yeah. And, you know, you can kind of artificially elevate ketone bodies without being on a ketogenic diet. And so, you know, that's really exciting from the standpoint, you know, both for the translational implications, but also, you know, just allows us to really simplify the experiment. And so, right, right? Because now we can take out all the complications of changing fiber, and, you know, like all of the other kind of things, baggage that comes along with a ketogenic diet, and in a mouse or human study, yeah,
Nick Jikomes 1:06:53
it's pretty wild that just supplementing with that one molecule, BHB, can recapitulate at least most of what you see by this. You know, what is it? Otherwise, a pretty drastic change, going into a ketogenic state from a dietary intervention some pretty you know, lots of things are changing, changing when that happens,
Peter Turnbaugh 1:07:08
yeah, yeah, I wouldn't say most necessary. I mean, I guess we still haven't, like, well, quantified that, but, but at least in terms of the major things, you focused on, the immune cell levels, it was very comparable. I think on the microbe side, you know, definitely qualitatively Ling directly, it had a bigger effect. So, yeah, yeah, I wouldn't say we've like, you know, I think we are missing things. And it's an open question, kind of, what part of the ketogenic diet, you know, should be added to the
Nick Jikomes 1:07:39
supplement? Yeah, yeah, okay. So, so bhp wasn't fully reproducing the effects of keg diet was just, it was partially but still pretty dramatically, yeah,
Peter Turnbaugh 1:07:48
yeah. And really specifically, we saw this link suppression of Bifido bacteria, which was very interesting. And so, you know, and we're still trying to kind of figure out why this happens, you know, I mean, so we know that bhp has, you know, all of these different signaling effects on the host. So, you know, it could be that the, you know, compound is kind of directly changing the immune cell. Um, but we all, you know, we're a microbiome lab, and so we're more interested in, you know, how, how the microbiome, you know, what is it that kind of links BHV levels to changes in the microbiome? Yeah, you know. Is that a direct effect? You know, in the initial paper we we showed in vitro that you can change bacterial growth by adding BHV and so, you know, could be that the compound itself has kind of an antimicrobial, or maybe even then could benefit some microbes. Or, alternatively, maybe the compound is kind of changing other things in the gut. Yeah, microbes care about Yeah, but yeah, that that initial study, or the that paper, kind of like, set the stage for thinking about, like, which disease model this would actually matter in. You know, we could have gone down the infectious disease route, but we, you know, Maggie Alexander, who was a really talented postdoc working in the lab, was very interested in autoimmunity, and so we opted to go for this really well studied mouse model of neuro inflammation, where you kind of like prime the immune system with a combination of this peptide mog and pertussis toxin, and that leads to kind of paralysis phenotypes that are similar to what patients with multiple sclerosis experience. Interesting,
Nick Jikomes 1:09:43
do you think you know a little bit of a speculative question here, obviously, that you just described these results where, you know, ketogenic diet or BHB supplementation can have, can modulate the activity of the immune system. It has implications for, you know, neuroinflammation, autoimmune. 30 stuff in the realm of you know, therapeutic ketogenic diets brought in that field, broadly speaking, you know, there's a lot of excitement and some new studies around using the ketogenic diet for things like bipolar disorder, other neuropsychiatric conditions. Obviously, the ketogenic diet, I think its original claim to fame is that it's been known for a very, very long time that it can treat certain forms of epilepsy. Do you think there's maybe a connection here, that, you know, ketosis, a state like that that produces high BHB levels, the bhp is just having very general effects in the body when it comes to inflammation and even nervous system function.
Peter Turnbaugh 1:10:41
Yeah. It's a good question that, yeah, the epilepsy. So some of the really nice work on epilepsy that I can't really do justice, but it was actually a lot of was performed by Christine Nelson, who's a postdoc in our lab right now, when she was in Elaine South lab, done in LA. But yeah, so that there's also data kind of linking the microbiome to some of the epileptic benefits of ketogenic diets. But yeah, I think it's still kind of early days. I think, you know, even in mice, we don't really have a good sense for, you know, how many situations, at least, kind of limiting to the microbiome effects of the ketogenic dietling, you know, is that always a good thing? You know? Are there diseases where the, you know, diet is changing the microbiome in a way that is actually not helpful? And then, yeah, I think that the mechanism is also difficult to unpack. You know, even though we've, like, narrowed it down to a single compound, you know, part of the benefit, as well as the challenge of setting HP, is that there it has all these different targets in the body. And so, you know, it's really hard to unpack that and to figure out, you know, how this is all working. But, yeah, but yeah. I mean, a lot to keep working
Nick Jikomes 1:12:03
has, you know, obviously, there is no user manual here. We don't, you know, even people like you in this field can't, can't tell us. You know, you should definitely do this, or not do this, to have a healthy gut microbiome. It's probably even challenging at this point to define precisely what is a healthy gut microbiome. What does that even mean for a given person, for a given context, for a given state of metabolic health, all that stuff, just broad strokes. You know, as a microbiologist who studies this stuff, has this being in this field affected your relationship with with food and antibiotics or anything like that, in a particular way.
Peter Turnbaugh 1:12:46
Yeah. I mean, I guess, like, I'm kind of the, I'm the type of person where the more I learn about something, the less I feel like I know about it. You know, not to use it as an excuse. But then, yeah, I mean, I think it's like, it's, it's hard to given the state of knowledge to, like, really convince myself that, you know, I'm always second guessing. I guess what I think the right diet is. So, I mean, it definitely makes me think a lot about what I eat, reading labels more than I used to. But yeah, I don't think it's really kind of dramatically reshaped what what my own diet is. And yeah, I, you know, wish I could say the opposite. I, you know. I hope that at some point we can get to the Get to the point where the, you know, we can really translate this information to more actionable recommendations for people,
Nick Jikomes 1:13:44
given given that, given what you just said, What do you think about so there's lots of products now that people can buy. I've had people on the podcast that work on these things. What do you think of these? You know, microbiome products, like biome and like other things. Or, you know, you could send in for a kit. You send them samples of this, that or the other, from your body, and then you get an analysis of what you're eating. And it tells you, you know, you should take more of this, you should avoid eating that are the do those things really work? Is that information likely to at least be directionally accurate, or is it, are we just not there yet?
Peter Turnbaugh 1:14:21
Yeah, I read a commentary kind of, and I don't want to target any specific companies with a couple years ago. Yeah, I guess my kind of opinion is within, you know, I think the thing that we're really good at right now is profiling. So, you know, we can definitely kind of measure which microbes are in your gut. We can, you know, look at their genes or metabolites. So we have a lot of tools in terms of characterizing your microbiome. I think, you know, it's always the challenge of, you know, what we do with that information? So, you know, you know, even in kind of best case scenario, the links we have between the microbiome and health are, are kind of at a more population or general level. And so, you know, like, you have, I mean, it's the kind of classic challenge of medicine is, like, you know, that doesn't really matter what's good in general. It matters what's good for you. And so, you know, I definitely don't think we're at the point where we can accurately tell you what the best thing to do is, you know, I do think it's exciting that, you know, if at least some of these companies are often offering, like, repeated measurements of your microbiome. And so, you know, I think there's some potential to, you know it, kind of, if you think of it more as an experiment, that you know, you start with a certain profile, maybe the you know, the company or your own, on your own initiative, you you try to do certain interventions to improve it, and then you can kind of see what's working and what's not. Working. You know, I think that kind of, like paired diagnostic and intervention is really attractive, but, but it's definitely like, I would consider it more in the R and D stage. What?
Nick Jikomes 1:16:11
What are some of the big questions or exciting things you're working on today in the lab that you're really excited about?
Peter Turnbaugh 1:16:20
Yeah, so I think the topic that we, we haven't gotten to yet, is, really, you know how and is related to what you're asking about food, is, you know how to, how do differences in the microbiome kind of control drug response? And so, you know, we got interested in this area, you know, kind of similar to why we're excited about studying BHV as opposed to ketogenic diets. I think, you know, when you think about pharmacology, you know, it kind of narrows the scope to compounds that we know are really important for the body, and it kind of allows us, you you to then ask questions about how the differences on microbiome affect either the level of those drugs, or, you know, how they're metabolized and removed from the body or so they make it to the target.
Nick Jikomes 1:17:10
Yeah, the general idea here is, if you take a pharmaceutical drug, say, the gut microbiome could be important for activating that pro drug into the active drug. Could be important for how quickly the drug is metabolized and leaves your system and all of that type of stuff.
Peter Turnbaugh 1:17:27
Yeah, it's like, you know, it's interesting to me, like the really back to the very early days of drug discovery. There were links between the microbiome and drugs, and so, for example, one of the first antibiotics that was ever developed is called process. It has what's called an azo bond, which is two nitrogens with a double bond in between of them. And those azo bonds are not readily broken down by our own body, but they but bacteria can act on them. And so, yeah. And then it turned out that the active compound in front is all is actually the metabolite. And so you need a microbe to actually create the antibiotic, even though, you know, the drug that's given is is effectively inert, yeah.
Nick Jikomes 1:18:20
So, so there could be, you know, you could imagine scenarios where, I don't know, maybe someone's doing a clinical trial. They're giving some drug to 100 people, and just, we'll just make up numbers here. Maybe it works for 50 of the people and doesn't work for 50. It could be that, you know what, what explains that is the gut microbiome, and whether or not you've got the right bacteria to, say, turn the pro drug into the active drug,
Peter Turnbaugh 1:18:42
right? Yeah, and also in the opposite direction. So, you know, we have, you know, I mentioned to Jackson earlier, that's a classic example in the textbook that is a drug that is not really thought to be metabolized very much by the host, but is metabolized by bacteria to a downstream compound called the hydro digoxin, and that metabolite is no longer active. And so you can have microbes in the gut that are both turning on and off drugs in ways that you know could change. You know what amount of drug actually makes it to whatever the target is in the body and, and, yeah, so that's something we're really actively working to try to unpack for various drugs of interest.
Nick Jikomes 1:19:35
Well, we've already covered quite a bit. Is there anything you want to reiterate or think we should cover off on from our discussion that that you want to say anything more about?
Peter Turnbaugh 1:19:47
I know. I think that's great. We talked about a lot. All
Nick Jikomes 1:19:51
right, thank you for having me. Yeah. Peter Turnbaugh, you've done a lot of really good experiments, some of the recent stuff I really liked. And also. Apologies for digging up that 2014 paper from your past that was an interesting study, I thought. Thank you very much for your time.
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