Gut Microbiome Plasticity | Peter Turnbaugh | 214

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 Intro00:05:34 High-Fat Diet Issues00:11:00 Macronutrient Mapping00:17:29 Metabolic Adaptability00:25:59 2014 Study Design00:34:01 Microbiome Flexibility00:41:03 Fatty Acid Profiles00:48:41 Bile and Gut Changes00:55:09 Inflammation Links01:00:11 Keto Diet Exploration01:07:08 BHB Impact01:14:21 Microbiome Products01:19:35 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 y