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Microbiome, Exercise, Diet, Metabolism, Circadian Rhythms, Endocannabinoids | Christoph Thaiss

Full auto-generated transcript below. Beware of typos & mistranslations!

Christoph Thaiss 5:12

I'm an assistant professor at the University of Pennsylvania, Philadelphia. And my lab is interested in finding commonalities among the four major types of human diseases, which are cancer neurodegeneration, metabolic disease in the broad sense and inflammatory disease in the broad sense. And they collectively affect the large majority of individuals living on the planet at some point during their lifespan. And what what we find interesting about all of these diseases is that they it's not very intuitive how they developed there, it's not clear what the evolutionarily beneficial counterpart is to some of them. So we don't always rationalize very well at this the state of our understanding how these diseases developed. Um, so usually, what we what we have as explanations is one of two options. One is that these are diseases of aging. So they just come up, the longer we live, and are basically byproducts of, of life and our normal functions as we live. Because, you know, waste products accumulate and don't get cleared very efficiently, or other things happen in our body. organ functions deteriorate. And that's why we get these diseases. And the other very common hypotheses is that these are diseases of environmental mismatch. And what we mean by this is that the human body has evolved in an environment that is unlike the one we currently have in the modern world. And as a result of this mismatch, our body's not prepared for the environmental factors that we currently experience, and that some of these environmental factors predispose us to these various common diseases, including what we eat in our diet, how much we exercise, or don't exercise, the kind of xenobiotics that enter our body, you know, whether we smoke or not, whether we drink alcohol, or not, how much we sleep or don't sleep, and these kind of lifestyle habits that that we know, predispose us to these different diseases. So these are the main areas of study in my lab is, on the one hand, how aging is a predisposing factor for these diseases. And on the other hand, how on a mechanistic level, these various environmental and lifestyle factors impact the development of human disease,

Nick Jikomes 7:34

I see so so um, let me try and unpack that. So if we think about some, let's just pick a neurodegenerative disease that usually comes late in life, say, like Alzheimer's disease, you know, people tend to get that when they're elderly. There are exceptions, but it's something that shows up later in life. So one way I suppose one could think about that diseases. Ah, well, we're living much longer than our hunter gatherer ancestors did. And so maybe the reason we're seeing more of a disease like that late in life is simply that we're living longer, and it's the inevitable byproduct of old age. But another way to think about that, another type of hypothesis you could formulate is, it's actually maybe not a disease of old age, per se, perhaps throughout our lives, we're just exposed to environmental factors of various kinds things in our food, things in the water, you know, and so on, and so forth. And those are actually breaking certain aspects of our biology that don't lead to the manifestation of the disease until later in life, but they're, in fact caused by a kind of mismatch between the environment we're in and the one that we evolved in is that more or less what you're talking about here?

Christoph Thaiss 8:46

That's exactly right. And most likely, elements of both theories are true. On the one hand, we have evidence that you know, age is certainly a major predisposing factor to these diseases simply by the fact that we, you know, we see the risk for Alzheimer's disease and other neurodegenerative diseases go up as we age. But on the other hand, there is a lot of evidence epidemiologically and experimental, that there is very strong heterogeneity in an individual's risk for developing Alzheimer's disease later in life. So aging by itself is not sufficient to to account for this otherwise, we would all develop these diseases at the same rate. And of course, there are many known environmental factors that predispose to the development of Alzheimer's disease and they might vary from person to person, which then manifests in a different rates or risk for developing Alzheimer's later in life. Now, unfortunately, we cannot do the one experiment that would tell us which of the two theories is true because we cannot design by definition, we cannot design a non aging control in the lab, so we cannot have lab animals or human beings that are non aging, and would allow us to directly test this hypothesis. So We have to basically deal with a compromise of saying, probably both. Both theories are true in principle.

Nick Jikomes 10:06

And you mentioned something that I think is interesting and worth dwelling on, you said something about, you know, we don't often understand the evolutionary trade off the the beneficial side of the teeter totter with respect to what predisposes us to diseases. But what exactly did you mean by that? What would be an example of of an evolutionary trade off there?

Christoph Thaiss 10:31

Yeah, that's right. So in some cases, we have a pretty good understanding how a specific disease came about in evolution, right? The most straightforward example, is infectious disease. So there, we have a very clear what's usually called the evolutionary arms race, between the human host in this case, and a microbial species that is basically just undergoing the same old evolutionary process and is trying to propagate its own genomes to the next generation. And as this happens, there is competition between the two species. And as a result of this, there are certain microbes, the small minority of microbes, I should say, but there are certain microbes that that make a human host sick. So in this case, in the case of an infectious disease, we know exactly what the evolutionary origin is for disease. But in the case of, let's say, neurodegeneration or cancer, this is much less straightforward. Because what would the evolutionary benefit be of accumulating, let's say products in the brain are accumulating cells that that divide uncontrollably uncontrollably in the periphery of the body. So they're usually we we resort to these alternative explanations, which is that they are just sort of, you know, waste products of normal function are in the case of cancer mutation accumulation that just happens over the course of our lives. And they, they happen to lead to these diseases that evolution has not selected against, potentially, because they fall outside of the reproductive period. And, you know, both neurodegeneration and cancer become a major cause of death, after the after the end of the normal reproductive period, which means that evolution did not have strong selective pressure to avoid these diseases from from developing. But for us, as physicians and scientists, we now face the problem of basically having a disease that our body did not naturally evolve to deal with. So now we basically were tasked with the with the challenge of understanding how these diseases arise in the first place, and then how we can leverage either external or internal mechanisms of the body that would help us to fight against these diseases.

Nick Jikomes 12:54

And I suppose with certain diseases as well, it's pretty clear that it's not just or not even largely a function of aging, right? So for example, something like Alzheimer's, it's very easy to think, well, hunter gatherers, our ancestors, the human beings, that lived in the environment for so long that have that we evolved in, they, they rarely live to their 70s or 80s, or 90s. So, you know, something like Alzheimer's might just be a disease of aging, it's natural to think that way. But for something like, say, diabetes, we know that we're seeing it more and more prevalent early and earlier in life. So there has to be something about the environment that doesn't just have to do or doesn't even largely have to do with the aging process. Otherwise, we wouldn't see that kind of pattern with those diseases.

Christoph Thaiss 13:41

Absolutely. And the same is even true for for certain types of cancer. One, one very prominent example is colorectal cancer. Where the incidence, we even though we know that the incidence for colorectal cancer is strongly age dependent. We know that in recent decades, the the prevalence of colorectal cancer, especially in young populations is rising much stronger than in the elderly populations. So here we have an example where most likely both factors are at play. We know that age is still a very strong risk factor for colorectal cancer. And most likely the mechanisms that we just discussed of mutation accumulation across the lifespan for children colorectal cancer as well. But at the same time, this doesn't explain why people in their 20s and 30s are now at a much higher risk of developing cancer than they were maybe 50 years ago, maybe 100 years ago. So there must be other factors. In the case of colorectal cancer, we know that diet is probably a major driver. So we know that these other factors are certainly at play in regulating an individual's risk for colorectal cancer development.

Nick Jikomes 14:45

Yeah, and that's an interesting point. So you know if you're seeing this earlier and earlier, and especially if it's something like colon cancer, a disease of an organ of the gastro intestinal system, it immediately makes you think about out the gut in general and diet. And not only is the specific composition of our diet much different today than it was for our hunter gatherer ancestors, but also the pattern, the patterns and rhythms of eating were very different, right? We were, we were going through, you know, periods of feast and famine, with a very different temporal pattern, you know, back then than we do today. And so it immediately starts to get you thinking about things like, like diet and the microbiome, which I know tie into this. So can you start to talk a little bit about, you know, what we've learned about the relationship between, you know, diet composition, and the microbiome and how it's impacting diseases of the gut are directly related to the gut?

Christoph Thaiss 15:42

Yeah, absolutely. So everything you just said, are actually very important control elements of the microbiome. So we know that compared to the hunter gatherer times, the composition of our diet is vastly different. You know, we derive our our diets from different nutrient sources, the level of processing is, is dramatically different compared to to that time. But then, as you alluded to, also, the time of food intake is very different. Because now we basically have access to food from the moment we wake up into the moment we close our eyes. And it's up to ourselves and our individual lifestyles, how we basically, you know, divide the foods into meals over the course of a day. And of course, there is no more than a decade of evidence that limiting the time of day in which we eat is actually very strongly beneficial, or has dramatic outcomes in terms of our health, both metabolic and otherwise, which has given rise to the to this entire field of study that is looking at that time restricted eating or temporarily eating habits or, you know, intermittent fasting and so on. So let me try and approach this question from the perspective of the microbiome. So we know that the microbiome is very sensitive to the composition of our diet, the composition is probably the major driver of sorry, the composition of food is probably the major driver of the composition of the microbiome. We know this from, you know, more than a decade of animal studies, human controlled feeding studies, and many others. So there's scientifically there's absolutely no doubt that the composition of the diet is is strongly influencing the composition and function of the microbiome. Now, when it comes to the time of food intake, it actually gets very interesting. Because when I was a graduate student in a run a Linux lab at the Weitzman Institute in Israel, what we discovered was that the microbiome is not, the composition of the microbiome is not stable over the course of a day, but actually undergoes circadian oscillations. So the the composition and as a consequence of the function of the microbiome, undergo 24 hour rhythms, which we found are very strongly tied to the time of food intake. So what this basically means is that every time we introduce food into our gastrointestinal tract, not only does it lead to nutrient absorption by by the host cells by our own gut epithelial cells, but it also triggers cascades of nutrient cross feeding in the microbiome. And as a result of microbes that you know, immediately benefit from nutrient sources coming into the GI tract, they will bloom at the cost of others. So there's basically, you know, a wave of proliferation and potentially cell death going through the microbiome as we eat food. And if we do this in a strictly rhythmic fashion, basically introducing food into our gastrointestinal tract, the same hours every day, we observe very robust the original patterns in this microbial abundance and contraction in the gastrointestinal tract. And the other important thing that we found is that these microbial rhythms are associated with metabolic health. So it seems like having a robust oscillation of your gut microbiome is actually beneficial for health. We had shown this in animal studies initially, and then in small scale human validation studies. And then the group of deer color in Munich has done this. In very large cohort studies, I think over 1000 individuals, where they were they, first of all, they they also saw this rhythmic abundance patterns, or specific taxonomic members of the microbiome. And more importantly, they suggested that microbial rhythms might be an independent independent factor that predicts the propensity of these individuals to develop pre diabetes and diabetes later in life. So there seems to be beneficial function of microbial circadian rhythms and they, according to our studies, are dependent on the time of day of food intake,

Nick Jikomes 20:00

I see. So even if you're eating the exact same diet with the exact same composition, the temporal pattern with which you consume that diet, if you're having it at a time restricted in a time restricted manner, so that, you know, you've got a clear rhythmicity to when you're eating and not eating, versus eating the same exact diet, same exact calories and nutrients and everything. But if you're just sort of eating at a steady pace throughout the day, that would have consequences for the composition of your microbiome and what it's doing. And it sounds like in general, it's beneficial to have that clear rhythmicity to your eating pattern, rather than sort of a constant intake intake all day.

Christoph Thaiss 20:44

That's absolutely right. So we need to think about this as two independent variables. One is the composition of the diet, which as I said, strongly influences the composition of the microbiome and even affects its ability to be rhythmic. But the major driver of rhythmicity, regardless of the composition of the food, is the time of day in which we introduce food into our gastrointestinal tract. And now, the thing we don't know yet, and we're actively working on, is whether these these compositional rhythms, these daily oscillations in the microbiome, are actually functional mediators of the beneficial effects of time restricted eating, as we just discussed before time restricted eating is now well known. And it's widely practiced, because of its metabolic benefits. And there are so many different versions of it. Now, there's the very popular 816 hour rhythms, you know, some some people do every other day fasting. Some people do, you know, variations of the same theme of basically introducing food into into the gastrointestinal tract only once a day or twice a day. And then the the hours in which they fast, differ, but many of them have metabolic benefits. So for us a major research question in the lab is whether these dependable metabolic benefits that we derive from having these periods of fasting during the day are at least partially mediated by their effect on microbial circadian rhythms. So we can now do experiments in which we specifically manipulate microbial circadian rhythms and we see whether the beneficial effects of time restricted feeding would still be present, or if we lose some of these beneficial effects, because of their their impact on the microbiome.

Nick Jikomes 22:25

I see. And, you know, intuitively, at least for me, you know, I would expect expect there to be large effects here, because even though microbes don't have brains, and they don't have to sleep in the way that we do, they do have natural circadian rhythms, right, they have to have periods of behavioral acquiescence or rest in periods of high activity, just because like sort of intrinsically cells, whether it's the cells of our body or the, you know, the cells of a single celled bacteria, they have to go through those changes those changes between acquiescence and activity, because all of the different complicated systems within the cell can't all operate simultaneously efficiently, they have to kind of go on and off to let each other work is that more or less how we can think about it?

Christoph Thaiss 23:15

Yeah, this is a great point. This is actually when, when the field of both prokaryotic and eukaryotic circadian rhythms started. This was probably one of the major conceptual advances that was made that the circadian, the role of the circadian clock, both in prokaryotes and eukaryotes, is probably to partition energy homeostasis over the course of the day, just as you just said, not all the metabolic processes of a cell can be active at the same time, and it would also be highly wasteful in terms of energy metabolism of a cell. So basically, what the circadian clock does is it it synchronizes the activity of each individual cell and you know aggregations of cells that form tissues and organs, to environmental rhythms that are dictated by the rotation of our planet on its Earth. And as a consequence, you know, the exposure to sunlight, the exposure to nutrients, the exposure to many other environmental factors that's that fluctuate in a 24 hour rhythm. What's what's really interesting here is that the way this has been solved evolutionarily is is not by very quickly adjusting physiology to the environment, because you could imagine theoretically, that a clock works in a way that you have very good sensors for environmental factors. And then when you see sunlight comes you immediately adjust the physiology of a cell. But the way it evolved is through an anticipatory mechanism, which is basically designed by at least in the eukaryotic clock is designed by a set of transcription factors that CO regulate each other in a 24 hour cycle. So even if, if we assume that environmental fluctuations would stop for a day If the sun would not rise for whatever reason, or the sunlight is blocked by something or other environmental factors cease to oscillate for a day or multiple days, the circadian clock still keeps ticking inside our body. And that's because the these transcription factors they call regulate each other in a 24 hour rhythm, and completely autonomously continuing these cycles of CO regulating each other and also regulating a very large set of genes that are downstream to this to these transmitter block transcription factors. So the transcriptome of our cell will always be rhythmic, and will continue to be right to be rhythmic, even in the absence of outside cues for at least a couple of things. And then the second clever invention in terms of the evolutionary development of the system is that the system is not only autonomous, but it's in trainable to the environment. So basically, if you take a cell or a tissue or or an entire organism, and you move them to the other side of the world, which we do all the time by by flying across time zones, you know, that we can we can adjust ourselves to the new timezone, right, we do experience jetlag because the clock is autonomous, and it takes it a while to be adjusted to the new timezone. But it does adjust eventually. So the we call this the trainability of the system. So we basically, we know that there are outside cues, um, light is a very strong in trainer, but we know how to food is a very strong and trainer. That's basically these environmental systems, environmental factors that can influence the rhythms of the circadian clock. And it was known for decades already that that light is a very strong signal in the diet is a very strong signal in training peripheral talks. And what we added to this equation with our work is that the microbiome is essentially also in trainable, even though it doesn't have the same, you know, set of transcription factors that that media does. But it's basically a whole ecosystem fluctuation that we described there in terms of circadian oscillations of the microbiome. But even they are in trainable to, for example, food as a as an environmental signal. Just because as I described earlier, when food comes down the GI tract, it basically dictates the rhythm of these micro organisms. And as such, the microbiome basically serves as a as another entity of the body that that is rhythmic and can be entrained to food.

Nick Jikomes 27:28

I see. Yeah, I, I went to Europe a few months ago. And it took me a few days to adjust not only in terms of my sleep wake cycle, but also in terms of my GI system. And I suspect, you know, I suspected that not only was my diet composition changing, but because I tend to regularly eat in a time restricted manner. For for a certain chunk of the day for certain, a few hours of the day. When I went to Portugal in this case, I was eight hours off of my normal rhythm. And one hypothesis I had was that perhaps you know, even though I was eating in the same basic rhythm each part of the day, because I was in a different timezone, perhaps I was giving my my food and my GI system food to digest my when my microbiome and my GI system food to digest when they were effectively sleeping. And so that was probably throwing things off.

Christoph Thaiss 28:27

Yeah, this is a very interesting point. This is actually interesting in two different ways. First of all, is as you know, being from Germany, myself and working in the USA, I can relate to the, to the troubles that come with flying back and forth between Europe and the US and the timeshift that comes with it. And the thing that I've been asking myself, after we we had these discoveries in the lab is whether it might actually be beneficial, at least for short term trips to continue your eating habits from home. And basically to temporarily uncouple the times of day in which you consume the meals that you normally consume from environmental sunlight, basically, it's not always compatible with life because you cannot, you know, have a have a big meal in the middle of the night. In at least if it's not available, but but, you know, there are some practical restrictions, but at least conceptually, this is what what we think could be beneficial in terms of keeping your microbiome rhythms going even if you're in a timezone that that now basically produces environmental light at a different time of day. The other thing that's very interesting about this is that there is a epidemiologically speaking there is a very strong association between disruption of the circadian clock and conditions like diabetes and obesity. We know this from for example from shift workers who are at the higher risk of developing diabetes and obesity. If they engage in in for long periods of shift work. So one one hypothesis, we have basically, as you just alluded to, when from your trip to Portugal is that some of this risk might be determined by a mismatch between microbiome rhythms and the types of food intake. Because when we have regular microbiome rhythms that are entrained by the rhythms of when we eat these, these microbiome rhythms might help us to digest food in the optimal way simply because that's what they are they evolved to they they evolved to break down nutrients for their for their own metabolism, basically, and we benefit from it. But if there is no sudden mismatch, if someone ship goes from a morning shift to a night shift, for example, and they would now consume food when they would normally be asleep, most likely the microbiome is out of sync as well, at least for the first few days until it has a chance to adjust. So we're hypothesizing that some of this mismatch between the time of food intake and these sort of anticipatory microbiome oscillations to nutrient metabolism, some of these desynchronization might be a factor that predisposes us to the loss of glycemic control, which is the first step in developing pre diabetes.

Nick Jikomes 31:13

I see. Yeah, so a lot of it just boils down to not adhering to behaviors that keep the body that keep the body on a very rhythmic schedule, that is ultimately going to be be very much tied to just the daily rhythms of the physical environment, the sun coming up and down.

Christoph Thaiss 31:33

That's right. That's right. And, you know, again, going back to the evolutionary argument, that's probably you know, for for the large majority of human evolution of changing your timezone was was not Not, not an option was not possible. And was it was not a question. Same for shift work, this is all these are all very recent inventions, in terms of human evolution. So you know, the body, evolutionarily speaking, did not have to deal with this problem.

Nick Jikomes 31:59

And so, you know, I know that a lot of your work, you know, you can sort of think of it in terms of, you're studying sensory systems of the body, that are detecting, you know, what's present in the environment, on or in the body. And normally, when we think about sensory systems, we think about the nervous system, right? We our eyes, or ears, or nose, and so forth. But the nervous system isn't the only system of the body that's, that's in the business of sensing things outside of us. So can you talk a little bit about sensation and sensory systems in the body besides the nervous system, including things like the gut and the immune system? And sort of just just conceptually, in what sense? Are they sensing things?

Christoph Thaiss 32:43

Right, so the reason why we're so interested in these sensory events is basically, because of what we talked about earlier, where there is one of the major hypotheses of the major human disease underlying the major human diseases is this mismatch between environmental factors and, and what our bodies have to deal with. So all of these environmental factors need to be sensed. And in a way, no, one might argue that that sensation of the environment is the core survival skill or the course of the function of the human body. And basically, the the way we perceive the environment is traditionally called extra reception. It's basically our ability to, you know, sense, whatever the human body has evolved to send in the environment. With specialized sensors, most of them, as you alluded to, are part of the nervous system. But there are others as well, that we'll discuss in just a second. And then to integrate these sensory events, for the most part in the brain. Right? This is actually where the, I guess the namesake of your podcast is coming from the body mind dichotomy. And actually, when when I've been shooting a row, this very famous essay on the body mind duality, I actually think he called it a mind and matter. So this is probably exactly the namesake of her podcast. But But when when he wrote this essay, he basically started by saying something like, the essence of the of the human body is the perception and integration of, of environmental signals. So now that the interesting question is how, how is this actualized in terms of the anatomy and the cellular function in the human body? So usually, when we when we talk about extra reception, in the classical sense, we're talking about the classical senses of the human body, like smell and vision and touch sensation and auditory sensation, so on. And, and this is, there's a very stereotypical, very interesting pattern of how this has been actualized it's always there's a sensory cell, which is always an epithelial cell, not a neuron, right? It can be a retinal ganglion cell or it can be a touch Center. To the cell in the skin, and then just underneath it is usually a neuron. So there is a sensing event that happens with a specialized epithelial cell that has very specific receptors for what it's supposed to send can be taste, can be, can be a mechanical event like touch, can be wavelength of light. And then the signal is transduced, to the neuron that is underneath it. And the neuron then basically connects the sensory event to the brain. So this seems to be the sort of the the anatomical blueprint or the design principle by this by which this was actualized. And then historically speaking, there is a second branch of perception, which we call interoception. And this is basically opposed to extra perception, which is sensing the outside world. interoception is sensing the inside world. So this is sensing everything that's going on in the body. And then in a similar way, reporting to the brain. And here, it's actually much less clear how this sensing occurs, what the major sensory elements are, and what is being sensed. But we know that at least, some of the anatomical actualization looks very similar, like an extra reception. For example, in the gut, there are specialized epithelial cells that also have sensory functional nutrients in the lumen, or molecules coming from the microbiome, or dietary components that are being sensed. And then at least some of them are able to transduce signals to an atomically proximal neuron, which then projects the brain. So at least some some of the principles seem to be the same. But now what gets very interesting is that we know that these epithelial cells are not the only things that talk to the sensory neurons. But there are probably other sensory entities in the human body. Because we know that these these neurons, they can also receive signals from immune cells. So immune cells are basically a second major branch or major system in the human body that has evolved to sense things. They also immune cells also have very stereotypical receptors, many of them detect microbial molecules, but some of these immune cell receptors to take the other molecules. And we may speculate that there are other sensory systems in the human body that we we don't know exactly what they perceive, because we don't know the entire range of things that is being sensed in the human body. And we also don't know how they might talk to the sensory neurons that then project to the brain and inform the brain and multi sensory events. But at least, but at least in the broad sense, this is how the human body perceives both both the outside world and the inside world.

Nick Jikomes 37:51

I see. And I suppose like on on the piece of this connected to the immune system, when you think about sort of their role in sensation and surveillance, and their connection, and cooperation with things like sensory neurons, you know, one big advantage that immune cells have over nervous systems in one respect is they can move around. And so can you talk a little bit about that and how it ties into the concept of immune surveillance and what that's all about?

Christoph Thaiss 38:19

Yeah, this is extremely interesting. So as you just mentioned, most of these sensory systems that I just talked about, they're stationary, right? epithelial cells cannot move within the context of, of their tissue. They're also very frequently renewed, so many, many epithelial cells only have a lifespan of a few days. And then they're being replaced by by cells coming from stem cells in the tissue, neurons cannot move for the most part. Very long. On the one hand, on the other hand, they don't have the ability to move around the body, but the immune cells do immune cells are very mobile and actually some of their main function is to continuously enter tissues and then go back to the circulation, then they come back, they basically scan the entire body in a way they come through the lymphatic drainage of tissues, they reach lymph nodes, they reach the spleen, which is the major secondary lymphoid organ, the systemic circulation. So, they constantly scan the environment for microbial ligands or for for peptide antigens that they recognize from our own body and foreign foreign peptides that enter the human body. So, so, we can think about immune cells as basically sentinels that scan the entire body and then report to a specific partner cells if they had a sensory event, right usually, they would, in the case of T cells, they recognize antigens presented by antigen presenting cells. So they basically form what in, in analogy to synapses that are formed between neurons they form immunological synapses with for example, antigen presenting cells like dendritic cells, and then they, when they recognize their antigen, they get activated and they send signals to the neighboring cells, including the dendritic cells and other cells. Now, the interesting question is, and there's actually, literature by now to support is whether immune cells like T cells, or even cells of the innate immune system like like macrophages and other myeloid cells, whether they can also talk to neurons directly, and basically send signals to neurons that innervate a specific tissue, and thereby inform the brain about these immune sensory events in the periphery. It's, this is a very recent area of exploration, both in my lab and in other labs in the field. And we don't have a very good conceptual framework yet of how to think about this. But we, we definitely know that there's a lot of crosstalk between neurons and immune cells, we know that many of them are relevant for inflammatory responses. And we also know that the brain integrates information from, from these sensory events in the periphery, there was actually, recently there was a very interesting study out of osteoporosis Lab, which basically identified an area of the brain in the insular cortex. That's response to inflammatory events in the GI tract. So what they discovered is that neurons get activated in the brain in response to an inflammatory insult in the GI tract. And what was really interesting there is that what they proposed was that these neurons form basically the equivalent of a memory and gram. So usually, when a memory is stored in the brain, the way it is stored, conceptually speaking, is by forming an anagram of neurons that get co activated. So this is typically studied in the hippocampus, when the when basically the hippocampus gets activated by a peripheral stimulus, it will form a network of neurons that get co activated. And then the recall of this network or the recall of this Engram produces a memory experience, right. So for example, if I'm now producing sound, you will hear the sound. And your basically, your auditory system will relay this information to the brain and in the hippocampus, for example, or in other areas of the brain, there will be a network formed in response to this. And now if, you know, many days from now, someone else will clap their hands, the same neurons will get activated. And you said, Okay, that's what the that's what the guy on the podcast did. It's the same sound, you know, it's it's the, it's basically reactivating the same end room. Now, what's really interesting is that, based on the work I just mentioned, from from osteoporosis lab, there is a possibility that immune sensation events or inflammatory events in the periphery, provoked the formation of these engrams in the brain. And because what they showed is that if they selectively reactivate these neurons in the insular cortex that that got activated by this immune stimulation, they basically produced just by activating these neurons, without the context of any gut perturbation, they produced an inflammatory response in the gut. So possibly, what the brain does is not only integrate information from this exteroceptive systems that we just discussed of, you know, vision and sound, and taste, and smell, and touch, and so on. But maybe there are memories being formed in response to interoceptive signals as well, the ones that are coming from the body through the sensory neurons, and then when you reactivate them, because you produce the same insult again, now, the blood in the brain actually potentiate, the response to this peripheral sensation. So in the case of gut inflammation, if there is reactivation of the same neurons, these might actually produce a stronger inflammatory response the second time around. So it's very early, early days in this kind of research, but at least it would suggest sort of a merger of this, of this concept of extra reception and interception because the body, the you know, the body signals, all these different signals to the brain, and the brain doesn't necessarily distinguish between where the signal is coming from and is able to form memories even for interoceptive signal.

Nick Jikomes 44:19

Yeah, it's, I mean, it's fundamentally the same process. And I mean, that would make sense. I mean, when we know, when we, we don't necessarily normally talk talk this way in everyday speech, but you know, a memory is really just the brain, re instigating a certain constellation of sensory events that happened to us before. So you know, if you remember what happened to you at a party that you were at last weekend, you remembering at least certain aspects of what you saw, what you smelled what you heard, and your brain is holding on to those sensations in some sense, so that they can be, you know, relived, even in the absence of that environment being the one that you're in. And I think what you're saying is that the same kind of process seems to be at work when it comes to internal sensations. So interoception. So if you've got some inflammatory event in the gut say, that was caused by some bug getting into your gut down there, the immune system detects that the nervous system eventually detects that. And just, it sounds like what you were just describing was a result where, you know, just like we could have a memory and gram encoding what happened at the party, including, you know, what we saw on what we heard at the party, we can also have memory engrams that encode a memory of an inflammatory event in one part of the gut. And not only does it encode a memory of that, but perhaps the purpose of that memory is so that the next time the same bug is sensed down there, the inflammatory response can happen quicker and or more strongly. And that can only happen if there's a memory in there that sort of prepares prepares the body to to do that, is that more or less what you're saying?

Christoph Thaiss 45:57

That's exactly right, in that now, if you think about the consequences of this, if this is true, now, there are two very important consequences. On the one hand, maybe this is a potential avenue for future treatments, because in certain contexts, like like gut inflammation, or maybe metabolic diseases, or maybe other diseases, we don't want this exaggerated secondary response, right, maybe this is a way to potentially interfere with the brain's influence on peripheral inflammatory processes by inhibiting this, this enhancing secondary effects. The other thing, conceptually speaking, that that might be a very interesting consequence of this theory is that we know and I can relate to this personally as, as a father of two young kids, is that usually when, when a child learns, and later on when adults learn to, we know that memories are formed more efficiently when they're in the context of multiple sensory events, right, that's usually what we're taught early on, it's much easier to memorize something if you also see if it comes with a secondary and tertiary stimulus, and so on. So maybe what happens in the brain there is no information is much stronger, if there are multiple sensory inputs, both exteroceptive inputs and interoceptive inputs. So so this would mean that the body's ability to form these engrams and to remember things are the brain's ability to perform and grumps and to remember things, is a function of the number and quantity of the sensory inputs. And if that's true, of course, that's something that we can leverage in terms of optimizing the formation of memories that we want to form, and maybe suppress the formation of memories that we don't want to form, including painful memories and so on. interested this is, this is a little bit of, you know, this is pretty far into speculation territory at this stage.

Nick Jikomes 47:56

So I want to bring it back to the idea of Zeno biotics, and I want to talk about antibiotics. But before we talk about the effect of antibiotics on the microbiome and some other stuff, can you just define that term for people's, you know, biotics, it's not used that much outside the literature?

Christoph Thaiss 48:14

Yeah, as you know, biotics is basically a term that just refers to four foreign molecules that enter the body, it's, but it's really just an umbrella term for Xena, which means meats for and so it's basically a, you know, a term that describes these foreign elements in the human body. And these are actually things that we expose ourselves to all the time. You know, people who smoke cigarettes are full of xenobiotics antibiotics, as you just mentioned, is an example of xenobiotics drugs are examples of xenobiotics that we consume on a daily basis. So so the human body is typically full of xenobiotics, we just don't often call them this way.

Nick Jikomes 48:54

And so, you know, antibiotics are obviously, one of the crowning jewels of medicine, they've been highly effective at doing what we know that they do, which is killed micro organisms. And we also know, at this point that that, you know, they've probably been overused. And that can drive the evolution of antibiotic resistance, for example. But the other thing that I think we've come to appreciate, you know, in the last decade or two that we didn't deeper into history, is that the antibiotics aren't selectively killing just the bad microbes that cause us problems. They're also killing all of the micro, many of the microbiome components, the good bacteria that that we want to be there. And so with respect to the microbiome, if someone's taking a broad spectrum antibiotic, you know, how, how depleted will the microbiome become? Is it you know, 50% of the species is going to be affected? Is it 100%? How affected will the microbiome be? And what are some of the sort of the major overarching concepts quinces have that depletion.

Christoph Thaiss 50:03

Right. So as you as you just mentioned, the, the picture that we usually use in the field is is the one that is drawing comparisons between antibiotics usage and chemotherapy. In the case of cancer, we use chemotherapeutics, in order to make the cancer go away, but at the same time, it strongly affects healthy cells of the body as well. And the same is true for antibiotics, we usually use it to target pathogenic bacteria, but at the same time, we affect the, you know, the resident commensals, as well. And in both cases, I should say that, you know, their uses, their usage is is absolutely beneficial for the, for human health in general. In the case of chemotherapy, we needed to, to eradicate cancer and to survive, or at least improve survival in the case of two tumor growth in the body. And in the case of antibiotics, we need it. As you just said, it's basically, probably one of the biggest medical achievements of the last 100 100 years is that we don't succumb to simply infections anymore because of the availability of antibiotics. So with that being said, Now, you're asking what are the consequences of strong use and broad spectrum use of antibiotics? It's very hard to quantify how much the microbiome is exactly affected, because it very strongly depends on the type of antibiotics you use. For example, vancomycin, if you take Michael Meissen against an infection, it will target gram positive anaerobes. So these are the ones that are most strongly affected. If you take ampicillin for an infection or derivatives of the ampicillin, it will target a completely different part of the microbiome. So it's it's very hard to generalize what the effect of antibiotics usage is on the microbiome. But it's wise to say that we we know that it's not specific for an individual taxonomic unit of bacteria. So we know that that bacteria are more broadly affected. And now the question is, what's the consequence of this? And there's actually there's, by now, there's a lot of literature on what we what we might be causing by eradicating beneficial bacteria. One of the very early studies, way before the microbiome was was a research field as it is today. People have have basically reported on antibiotics usage. In the US Army, there are some very interesting papers from you know, as early as the 60s when antibiotics were really just getting started in terms of their wide usage. But these papers, what what some of them have done is basically to, to give prophylactic antibiotics to soldiers that were enrolled in the marine, for example. And, of course, these studies, they, you know, they would be extremely unethical to do from today's perspective, given all the knowledge that we have, but back then it was thought, If antibiotics just prevent infection, why don't we give them to people prophylactically to prevent infection, and actually, these papers, they say, We haven't prevented infection, because of course, many of the infections were a viral infection, and giving antibiotics will do nothing to prevent the viral infection. But then what these papers also report on is, usually it's mentioned as a side note, they say, by the way, the part of the you know, the part of the soldiers who got these antibiotics gained weight. And then, you know, they report on basically the percentage of people who gained weight on antibiotics, and it's actually quite significant. And in a way, that's what's what's done, you know, still it in many parts of the world. And, at least in the US, it was there in our efforts to reduce antibiotic usage, but it's still used widely in livestock, right, and we see exactly the same effect, that antibiotics usage, which is used to prevent infection, and basically causes simultaneous weight gain. And

Nick Jikomes 54:15

in that case, I guess that might be even though they didn't probably set out to do it for that reason, they they were using it to control infection rates. That might be a beneficial side effect in terms of what the goal of livestock raisers actually is, which is to fatten up the animals as quickly as possible.

Christoph Thaiss 54:32

Absolutely. So in the in the livestock industry, this was a nice side effect, basically, and probably maybe not the official motivation, but at least a secondary motivation to keep this going. So now, the question is, are we seeing some of the same consequences in the broad human population of maybe early life antibiotics usage much more than we would have used decades ago? And the answer is probably yes. There is. There's a lot of experimental evidence in practice. I'm playing in lab mice and in other lab animals. But there is also increasing epidemiological evidence in humans, that antibiotics use it, especially early life antibiotics usage is predisposing us to the development of diseases later in life, including metabolic diseases like obesity and diabetes, but also immune mediated disease like allergic diseases and asthma, for example. So I think by now we can we can safely say that there, there has been a pretty dramatic effect on disease propensity in the human population by by this usage of broad spectrum antibiotics.

Nick Jikomes 55:37

Yeah, and there's all sorts of places we can go with this. But it's, you know, it's very interesting that there's this relationship between weight gain and antibiotic use. And when we think about depleting the microbiome, it's natural to first think about the effects being related to digestion and what our bodies doing with food, or our propensity to infection, or whether or not sort of bad bacteria populations have room to move in when we kill off the good ones and things like that. But I know that your lab in particular has also looked at behavioral effects. And we wouldn't necessarily think of these first, right, I take an antibiotic, I deplete my microbiome, and now my motivation to behave in certain ways is going to be changed. But that does appear to be what you found. So can you explain for people what you guys have been looking at in terms of how antibiotics affect animal behavior?

Christoph Thaiss 56:30

Yeah, so So, before we get into our specific study, I'll just mentioned that this is probably one of the most surprising aspects of the microbiome that we wouldn't have predicted 1015 years ago. But we now know that there is a very strong effects of the microbiome on the function of the brain. And going back to our discussion of interoceptive systems, this is most likely how these effects are mediated because we know that molecules from the microbiome are being sensed by, by sensor epithelial cells, by immune cells and by the nervous system. And as we just discussed, these sensory signals are relayed to the brain. So basically, by perturbing these peripheral sensing systems, by microbiome depletion, or microbiome manipulation, will affect the functioning of the brain. And people have first observed this, when they studied germ free mice, which are my students are born in sterile isolators. And they don't have any microbiome. And they founded these germ free mice, they have various neurodevelopmental abnormalities as a consequence of this. They have altered levels of sociability, anxiety, and other other aspects of brain function. The way we got interested in this area was by focusing on exercise, and the reason why we are so interested in exercise is because, as I told you, in the beginning, we were basically interested in identifying commonalities among the major human diseases, including cancer, neuro degeneration, metabolic diseases, and so on. And epidemiologically speaking, the one magic bullet we have currently, against all of these diseases is exercise. Because there's so much evidence that exercise is probably the one single most most powerful and also most accessible element in our daily lives that we can use to greatly decrease our individual propensity for all of these diseases. It's actually not completely understood how exercise has always beneficial effect. This is something we're very interested in, in finding out in my own lab, but there are many known beneficial effects of exercise that protect us from all these different disease. And, and yet, even though we know about all these beneficial effects, at least on the level of the global population, we are very far away from leveraging these beneficial effects. The wh o actually recommends 150 minutes of at least moderate level intensity exercise per week, in order to reach these beneficial effects. And I think the last time I checked, I think the global average was around 50 minutes of at least moderate level intensity exercise a week. So this just goes to show that that we're very far away from, you know, as a global population, we're not leveraging these beneficial effects of exercise at all. So the question is, why, why? Why is it so hard to get people to exercise? And of course, you know, there are there are many obvious constraints. We're doing things like sitting around and recording podcasts and are not exercising in the meantime. But But even you know, leaving time constraints aside, exercise is very, very demanding on the human body in terms of Cardiovascular fitness that needs to needs to meet the requirements for exercise, respiratory fitness, muscular skeletal fitness, and so on. But but also the, you know, the state of the brain needs to needs to be a such that it gets us up in the morning, early in the morning and gets us out into the rain, if necessary to do a five mile one everything. So, so basically, we need to the body needs to meet all these requirements in terms of different tissues of the body, including the motivational state of the brain that needs to be met in order to, you know, get these benefits from regular exercise. So, so when we started this project, we wanted to identify the bottlenecks, we wanted to find out what needs to be overcome, or what needs to be improved, in order to leverage the benefit, benefit, beneficial effects of exercise. And the way we did this. And when I say weeds, it's basically one one very talented PhD student in the lab, Blanca Danilova. And her collaborators in the lab, what what we set out to do is to take a very large cohort of genetically diverse mice. So we wanted to recapitulate some of the genetic diversity in the human population in mice. And as a result of this, we had a dramatic variability in exercise performance. So we took these mice and we, we basically profile their exercise capacity on running weeds and on treadmills. And we saw that there were massive differences between the individual mice, just like we have in the human population. If you take two random people from the planet, and you put them on a treadmill, of course, their their performance will be vastly different. And that's what we saw in these mice as well. So now we had an option to basically use the system of these genetically diverse mice, and try and identify what limits their ability to exercise. So we looked at various different aspects of their physiology, we looked at their metabolism, of course, we looked at, you know, metabolites that swim in their blood. We looked at into their microbiome, we looked into various aspects of their body function. And then we trained machine learning algorithm to tell us what are the most important features that that would predict or determine an individual animals performance on a treadmill or running wheel. And to our big surprise, we found that the microbiome was a major determinant. So this is basically what got us started into trying to identify functionally how the microbiome may influence and animals ability and willingness to exercise.

Nick Jikomes 1:02:53

So the microbiome was an important factor here. So you measured the physical exercise capacity of a bunch of mice, you'd let them run on running wheels, and you sort of see how much they run and stuff. Many things influence how well they perform and how much running they do. And the microbiome is important for that. So then that would suggest that if you gave animals broad spectrum antibiotics to deplete the microbiome, you would also therefore see an impact on their exercise capacity.

Christoph Thaiss 1:03:23

Yeah, that's exactly right. So that's once we had this finding that basically, our algorithm predicted certain elements of the microbiome to be important features in controlling exercise. The question was, how can we verify this right? So one, one option would be to do the experiment I've just suggested, which is to deplete the microbiome using antibiotics. And the alternative is to use germ free mice, which we discussed before these mice that's that basically grew up with all their microbiome of their own. And we did both of these, and we found dramatically reduced exercise performance in the absence of the microbiome. What's actually really interesting here is that if you if if you think about the strong variability we found in these genetically diverse mice, when we took these exact same mice, and we treated them with antibiotics, the variability in exercise performance was much reduced. Not only was the overall level of exercise performance reduced, but the spread that we found across the different minds was reduced as well.

Nick Jikomes 1:04:21

They all started, it seems like did they all start doing as poorly as the poor performance poor performers did originally?

Christoph Thaiss 1:04:29

Yeah, in a way they did. So so the average level plummeted after we depleted the microbiome. But it seems like the microbiome also had a role in basically controlling the phenotypic spread of exercise. So once we took out the microbiome, there was very little phenotypic spread left and it was on the level of the poor performers previously. So they suggested to us that there must be elements in the microbiome. That's the drive exercise capacity and then we performed on The individual inoculation experiments because what a germ free system allows us to do is we can not only reconstitute the mouse's microbiome, but we can also introduce individual species into this jumpiness, and then basically test their function one by one.

Nick Jikomes 1:05:14

So you, you deplete the microbiome, and get rid of all the bacteria more or less, the animals are performing much, much more poorly in terms of exercise, and then you can start adding back in individual bacteria to see if any individual species have are doing most of the work here in terms of where this exercise differences coming from. Before we get to that, can you just very quickly describe how big of a difference in exercise performance are we talking about here? Are the mice running 50% less than they did previously? How what's the magnitude we're talking about?

Christoph Thaiss 1:05:45

Yeah, that's about the magnitude we observed, we we actually pretty consistently saw that, both on treadmills and on running wheels. So basically, both with endurance exercise and voluntary exercise, we see that the performance is only half as good in the absence of the microbiome. So it looks like the magnitude of the contribution of the microbiome to exercise performance is about 50%, which is pretty dramatic. Given that, we know that other systems that are known to control exercise performance have a much smaller effect size in terms of controlling exercise phenotypes in mice, I see.

Nick Jikomes 1:06:20

And then maybe the other thing to mention for people here, too, is, you know, scientists who study rodents and pet owners, if you've ever had mice, or rodents or something, it's pretty well known that they enjoy running, so to speak, they choose to run quite a bit. And if you provide them with a running wheel, they will spend a good chunk of their time on it. And it leads to benefits for them in terms of of weight, and, you know, all the different measures of sort of psychological fulfillment that you can indirectly do to animals.

Christoph Thaiss 1:06:52

That's right, that's what we observe as well, if you, if you provide a mouse with a running wheel in their cage, they will they will love to run there, they, you know, as nocturnal animals, they mostly run at night, because they're inactive during the day. But we have on, you know, an automated recording system to tell us how many wheels spin they do, and many of them run for for many kilometers every night.

Nick Jikomes 1:07:15

Okay, so, so they like to run, they're sort of intrinsically motivated to run some amount, you deplete the microbiome, and it gets rid of about 50% of the running that they do. So it's a very strong effect on how much exercise they engage in. And now you're doing the experiment where you're starting to add back in individual bacteria and figure out probably what the individual molecules that might be at work here are so what did you find?

Christoph Thaiss 1:07:43

So what we found in these reconstitution experiments is that several members of the what we call the Lochness per ACA, taxonomic family of, of bacteria, they seem to restore exercise capacity when we give them in isolation. We tried other bacteria that did not have such strong effects, including E. coli, which is probably known to most of your listeners. So Ecoli did not have an effect. It's also not a very prominent member of the normal human microbiome. But some of these lackluster ACA are important members of the microbiome and did have strong effects on exercise capacity,

Nick Jikomes 1:08:19

can you see that name, the name of this type of bacteria again, slowly?

Christoph Thaiss 1:08:24

Oh, the it's called. So the family of bacteria is called lackluster racing. I apologize if my my German accent here. That's right. And specifically, the members, the specific species that we found to strongly drive exercise. In this context, were a corporate Coco species, and a eubacterium species. These are just the taxonomic details of what we found that both of them belong to the family of of blackness, per se, they should point out is that this, this experimental system is a little bit artificial, because basically, what we do here is we take individual species, like this eubacterium species, for example, we put it into a germ free mouse, and then it will colonize the entire garden mouse, which is, which is not a very physiological system, because usually, these individual species, they constitute only a tiny component of the of the natural microbiome. But now we basically allow it to expand because there are no other bacteria there will allow it to expand. And in this system of natural expansion, we observe a specific phenotype. On the one hand, this is, you know, very stringent in terms of establishing causality, because that's the only variable we change. On the other hand, it leads to these situations that are probably not representative of the natural system or natural physiology, where these individual members are just a tiny component of the microbiome.

Nick Jikomes 1:09:52

And so, in the interest of time, and we might skip some details, but what did you guys discover in terms of some of the individual type types of molecules that seem to be at work that are either coming from these bacteria or related to how they are helping change exercise performance.

Christoph Thaiss 1:10:11

Right. So once we had this discovery of individual species controlling exercise performance in mice, the question is, how does it work? Right? How do these other these bacteria and trends exercise, and the most straightforward explanation we had is they probably influence the systems of the body that are known to generate excess capacity, such as the muscle system, Heart, Lung, and respiratory system and so on. And we spent a lot of time in his area, and we didn't find any conclusive answer there. So we ended up discovering a pathway that I'll describe in detail now, which basically links the production of molecules from these bacteria to the generation of motivation in the brain. So how do we get from, from the lumen of the gastrointestinal tract to motivation in the brain? So what we discovered was that these, these bacteria, they, they harbor specific enzymes, and what these enzymes allow them to do is to perform a chemical reaction that produces fatty acid a mites. So these are these are chemicals that are basically as the name suggests, they're a combination of fatty acid and an amide residue. So then they produce fatty acid daemons. And these fatty acid amides. They naturally occur in the in the lumen of the GI tract. What these fatty acid a mites can do is they can bind to a receptor, which is called the Endocannabinoid receptor. And, you know this is a well known receptor, because it binds to, as the name suggests, it binds to endocannabinoids. The two major endocannabinoids we have in the human body are anandamide and to AG. These are the two probably most potent endogenous ligands for this endocannabinoid receptor. Just as an aside to directly to endocannabinoid receptors. Your audience might be familiar with this already, but they're basically called CB one and CB two. CB one is the one that is more widely expressed. CB two is a little bit more restricted in its expression. But the DISA endocannabinoid receptors they don't only bind to an endermite into AG, but they bind to many structurally related molecules as well including the fatty acid a mites produced by these gut bacteria. I see.

Nick Jikomes 1:12:34

So these bacteria are producing endocannabinoid like molecules which are capable of stimulating the Endocannabinoid receptors in the brain and elsewhere presumably.

Christoph Thaiss 1:12:47

Right so usually we think about endocannabinoid perception in the brain because the brain is full of endocannabinoid receptors. And of course, you know many of the of the effects of endogenous and exogenous endocannabinoids, are mediated by endocannabinoid receptors in the brain. What we found here and this is very important is that what's required for the beneficial effects of these microbes on exercise performance is endocannabinoid receptor signaling in the peripheral nervous system. So as we just discussed earlier, there are basically the peripheral nervous system includes the sensory neurons, that innovates different tissues of the body, including the gastrointestinal tract. And just to take a very small tangent here, there are actually two major systems of sensory neurons in the body. Depending on where they're where their cell body sits, part of these neurons have the cell body in what's called nodos ganglion. And these are the sensory neurons of the vagus nerve. So the vagus nerve is probably one of the longest neurons in the in the body, it basically connects with a single neuron, it connects various different tissues of the human body with the brainstem, and cell bodies of all these neurons sit in the nose and yawn. So these these vagal neurons, they express endocannabinoid receptors. And then there is a second anatomically completely different set of sensory neurons that have their cell body in the dorsal root ganglion next to the spinal cord. And they actually project onto neurons in the spinal cord and then the spinal cord neurons relate information to the brain. And what's interesting is that these spinal sensory neurons, they also express endocannabinoid receptors. So now we have two sensory neurons that innovate two types of sensory neurons that even innovate most tissues of the body, including the GI tract. And what we found is that they also respond, the sensory neurons also respond to these endocannabinoid like molecules coming from gut bacteria. And the third important aspect here is that the sensory neurons especially the ones of the spinal cord, they are strongly activated by exercise. is not too surprising because if we, you know, exercise means movement of the body, and whenever we move part of the body, the sensory neurons will detect the movement. And as a result, they will get activated. But what these molecules from the microbiome do is they essentially potentiate the activation of the sensory neurons in response to exercise.

Nick Jikomes 1:15:23

So what? So these endocannabinoid like molecules are being produced by these bacteria? It's having effects on on the vagus nerve, some of these peripheral nerve endings that connect the gut and various aspects of our organ systems up to the brain. Do we know what these bacteria are eating and metabolizing to produce these compounds?

Christoph Thaiss 1:15:48

That's a very good question. This is something we're studying right now, we don't have good answers yet. We know that in order to produce these, these molecules, these fatty acid molecules, they need to have the progenitor molecules in the form of, for example, a medium chain fatty acid and an H residue. Where exactly they get it from something that we don't fully understand yet. But of course, it's something that we're very interested in, because it would mean that we might have a dial on how much of these molecules can be produced in the in the gastrointestinal tract. But the other big question is, now that we know that these molecules influence sensory neuron activity, how is this related to the motivation for exercise. And basically, what we found here is that this, the activity of the sensory neurons affects the levels of dopamine in the brain in an area of the brain called the striatum. And especially the the, the amount of dopamine that is released in response to exercise. So the brain is actually really interesting when it comes to the response to exercise because exercise will provoke many neurochemical changes in the brain. And one of the very prominent ones, in addition to endocrine ometer. This is a strong surge in dopamine that happens, both in lab mice and in humans in response to exercise. This is sometimes associated with the runner's high feeling of, you know the pleasure and reward that we get from from exercise. And actually endocannabinoids play a major role in the runner's high as well because they, they're responsible for some of these beneficial feelings and for know for things like that reduce pain sensitivity, that you experience when when you have the runner's high. So dopamine and adequate adenoids are to two major players in the runner's high sensation. But what's really interesting here is that when we looked at least in mice a dopamine release in the striatum in response to exercise, we found that the depletion of the microbiome or the inhibition of these sensor neurons to detect molecules from the microbiome completely abrogates, this dopamine release in the striatum. So we basically need the peripheral inputs in order to produce these dopamine release in response to exercise. So the the runner's high feeling or the you know, the pleasure and reward we get from this dopamine surge in the striatum is not brain autonomous, but it actually requires this this sensory input in the brain. We're not exactly sure yet how this works mechanistically we know that the dopamine degrading enzyme monoamine oxidase is involved in this because it probably regulates the levels of postsynaptic abundance of dopamine in the striatum. But how the sensory neurons control the expression of the small amine oxidase enzyme is something that we don't know yet. But we definitely know that the microbiome to sensory neuron to brain pathway is required for the regulation of dopamine in response to access.

Nick Jikomes 1:18:56

So this is fascinating. So if you didn't actually set out you didn't, you guys didn't predict ahead of time that the effect on exercise coming from the microbiome would primarily have to do with effect, and in effect inside of the brain, controlling motivation at that level, you probably didn't expect ahead of time that these endocannabinoid like molecules would be what you would end up focusing on. But that is what you found. And there actually is previous literature that you referred to that, that actually shows a very strong role for endocannabinoids. And controlling the so called runner's high, which which even apparently mice mice exhibit. And so we've had this interesting connection from the gut, all the way up to the motivational centers of the brain that use dopamine, among other things, connected by things like the vagus nerve and these sensory neurons that are responsible for interoception. And one thing it's worth pointing out to people here and related to a question I have is that you know, endocannabinoids and these related molecules, they they basically are fats There's sort of like a version that there are fatty molecules. And so they're probably derived from fatty components of the diet. And you know, I'm curious, my prediction would be that the fat composition of the diet is plausibly related to how much of this sort of how much of this effect that you would see in an animal how much motivation to exercise, there would be a perhaps you're doing the experiment already. But are you playing with the the ratios of things like saturated to mono unsaturated to polyunsaturated fat to see how this affects everything that you just described?

Christoph Thaiss 1:20:32

Yeah, that's exactly the types of experiments we're doing right now we're trying to, as we discussed earlier, we're trying to understand what exactly controls the ability of material to produce these signaling molecules and why they would even produce it in the first place. Right, we have some, some speculation about what the what the natural function of these molecules might be, because evolutionarily, they most likely have not evolved to control exercise behavior of the host, but there is probably some endogenous function of these molecules, and then they happen to be detected by the host, in a way that controls dopamine release in response to exercise and as a consequence, exercise performance. But why the whole pathway exists evolutionarily something we don't know yet?

Nick Jikomes 1:21:18

I see you. Go ahead. Yeah, if

Christoph Thaiss 1:21:21

if I can speculate for just one moment on what what the function of this pathway might be, we have two leading hypotheses here. One of them is probably the most straightforward explanation is that the reason why an animal would want to send these molecules in in the in the gut and coupled them to the initiation of physical activity is because physical activity is best performed, when there is sufficient nutritional supply in the GI tract, right, it doesn't make sense to engage into prolonged periods of physical activity if the nutrient stores are not full. So it might be a way for the for the animal to sense the state of microbial activity and the state of microbial metabolism in the GI tract. And basically indirectly, since the nutritional status with the GI tract and and to see whether it makes sense to initiate prolonged physical activity. The other hypothesis, and this is more of a conceptual one. And is something that was suggested to me by by my friend and colleague, Noah Pom, who was a microbiome researcher at Yale. So So what he suggested is that there is this theory that, as we briefly discussed earlier, the microbiome might be able to expand the phenotypic repertoire that can be observed in a population, because usually, the range of phenotypes is determined by the set of genes in a population, right. And that's basically what's available for evolution to select. A possible role for the microbiome. Mostly conceptual at this stage on very experimentally proven, but at least conceptually interesting is that the microbiome might expand this phenotypic range, just like we see in the case of exercise, we have a set of genetically determined ranges of exercise performance that these mice will exhibit. And then the microbiome will diversify this phenotypic range, and maybe enhance the ability for different selective niches to identify those set of genes that would be most beneficial in terms of their ability to adjust to certain environmental requirements. So that's sort of a more speculative possibility providers might have evolved. But but this is another an alternative explanation for why the microbiome might be an important regular exercise capacity,

Nick Jikomes 1:23:39

as well, one of the so when I was a graduate student, I studied feeding behavior in mice. And so I often worked with food restricted mice, mice that we gave less food than they would have chosen to eat, in order to keep them lean and motivated to learn and to work for food. And one of the curious observations that's counterintuitive to a lot of people is if you food restrict a mouse, you might naively think, Ah, okay, so the mouse is going to lose body fat, it doesn't have as many as much energy storage, because it's not eating as much. And so it might want to conserve energy and therefore move around less. But you basically observe the opposite. If you have a mouse in a cage, who's food restricted, not only will they be literally looking around for food, but they run more on those running wheels. And so I wonder if there's an ecological perspective here to think about this with which is that if you're fat, basically fat stores get below a certain level and or you are or not getting certain types of fat in the GI tract. The brain has to motivate the animal to actually get out and explore its environment, which, you know, when when an animal is exploring its own food, right? It's not exercise in the sense that you know, human beings exercise, but it is it has to actually get out and in engage with the environment more, because if it doesn't do that, and it stays where it's at, it's probably going to starve to

Christoph Thaiss 1:25:04

death. Yes, very, very interesting point. So, so we observe the same thing, when we calorically restrict our animals, they will voluntarily run more, probably for exactly the reason that you just mentioned that this is basically a, an evolutionary signal for the mouse to go and explore to seek food. And, as you also mentioned, of course, we cannot think about the exercise in the master, same way we think about exercising humans, because most likely locomotion is or that the reason why the animal engages in locomotion is because it has a natural need to do it, including trying to find food. And in fact, the the most commonly used mouse model for anorexia is to to calorically restrict animals and provide them with a running wheel, in which case the animals will basically, you know, obsessively exercise and neglect food intake, which, which, you know, has some some aspects that that can be modeling human anorexia, and in this animal system, so it's kind of counterintuitive, but But it's, it's probably evolutionarily driven by by what you just mentioned. Now, the interesting question for us is whether these fatty acid amide molecules that we discovered to control some of this pathway, whether they increase in fasting animals, so that's something we're now we're now we're exploring to see whether the levels of these molecules are actually based, basically, anti correlating with how many nutrients are coming down the GI tract and whether the bacteria will start producing fatty acid a mites during during periods of starvation. So in that sense, it could be, it could be that the nutritional coupling that I described earlier is actually working the opposite, where the body has a sensation mechanism for the nutritional status of the gut, but not in order to evaluate how many how abundant fatty acid molecules are, but how stars they are, and then respond, basically initiate local motion in physical activity in response to that. But these are completely open questions that my lab is now exploring.

Nick Jikomes 1:27:14

Interesting. And so you know, if sort of, to fully connect the dots here between the microbiome, the production of these endocannabinoid like molecules, and these changes in motivational centers of the brain, like the striatum that involved dopamine, you know, what's, what's the causal chain there? In terms of the metabolites being produced by the microbes, and the motivational effects happening up in the brain, if you if you selectively get rid of these endocannabinoid like molecules, does that completely erase the motivational impact here?

Christoph Thaiss 1:27:49

Yeah, so these are experiments that we have done, we've actually experimentally blocked the pathway. It's basically essentially every every level that we discovered, we have inhibited the production of these molecules we have inhibited pharmacologically, the sensation of these molecules by by the Endocannabinoid receptor, CB one in the periphery, we have silenced the sensory neurons that we know are responsible, and we have silenced the dopamine response in the brain. And in each case, we see that that exercise performance drops by about 50%. So we think that even though the pathway is probably more complicated than we currently think we think that there is basically more or less linear connection between the microbiome the molecules, they produce their sensation in the GI tract, the activity of the sensory neurons and the dopamine response in the striatum, we can, we can not only inhibit each stage of the pathway, but we can selectively activate each stage of the pathway. For example, what we have done is we have taken antibiotics treated mice, which we know exercise much less than their conventional counterparts. And we have selectively stimulated the sensory neurons in the periphery or we have selectively reactivated the dopamine response in the brain. And in each case, the mice basically had completely restored running capacity. So that means that there is nothing intrinsically wrong with antibiotics treated mice in terms of their exercise capacity, or there's nothing intrinsically wrong with mice that are lacking this endocannabinoid receptor on sensory neurons. We can always recover their exercise capacity if we stimulate dopamine production in the brain, because we think that this is most likely the most downstream aspect of this pathway. Yeah,

Nick Jikomes 1:29:38

so this pathway is simply needs to be turned on in those animals. So they're just lacking a signal that gives them motivation. It's not that they are physically incapacitated in some way.

Christoph Thaiss 1:29:48

That's exactly right. And that's that's what we saw when we looked at muscle functioning these animals and so on this there didn't seem to be a major disturbance in their actual ability to carry out physical activity. It seems to be a problem of dopamine release in the brain that was preventing them from doing it.

Nick Jikomes 1:30:05

Interesting. I mean, given, given that study, and just everything that you study generally, how do you how do you feel about like prebiotics and probiotics for humans? Is that something that you use? Is that something that can work? You know, because there's a lot of products out there. And, you know, you could imagine it could have very large beneficial effects. But also, I know that, you know, a lot of times the supplements and stuff that actually get production alized and marketed to people aren't actually efficacious in the way that one would hope they are.

Christoph Thaiss 1:30:40

Yeah, so I think we have to make a distinction here, because prebiotics, which are basically food elements, that that would control the composition of the microbiome, I think they there is a very strong scientific reason to assume that they will be effective. Because as we just discussed earlier on during our conversation, the basically the composition of the food is a major driver of what can establish itself in our GI tract. So prebiotics, I think, or food components are very effective and very accessible way to influence our composition of the microbiome. When it comes to probiotics, I'm much more hesitant. And there are multiple reasons why I'm much more hesitant. On the one hand, we know that probably the evolutionary evolutionarily, most powerful function of the microbiome is to provide colonization resistance, which means that the microbiome has evolved to keep out foreign microbial elements, basically, when we consume a probiotic, that's what we do. Right, we introduced we tried to introduce a foreign microbial element into the GI tract. And we know empirically, it doesn't not work very well. There were actually studies done in the lab of my my PhD mentor, Ron Elina, and many other labs that have looked at how well probiotics that we consume orally established themselves in the GI tract. And the unfortunate answer is they don't establish themselves very well at all, we mostly end up finding them in the toilet, basically. So what this means is that this colonization resistance property of the microbiome is very powerful in the context of pathogenic infection, but it's also very powerful in the context of probiotics. So we need to take this with a grain of salt. And, of course, most probably most probiotics are offered as food supplements are not FDA approved. So they haven't undergone the same rigorous study that that we would otherwise expect from from FDA approved drugs. So probiotics might be useful in certain contexts, but I think I cannot, at least from the scientific perspective, I cannot support unrestricted usage of probiotics across the board.

Nick Jikomes 1:32:47

I see. So what I'm taking from what you just said, is that probiotics are probably typically not going to be an effective way to change the composition of your microbiome, at least not in the gut. And the best way to do that, or a effective way to do that is actually just to change the composition of your diet and or the pattern of eating that you're adhering to.

Christoph Thaiss 1:33:10

That's exactly right. I think from you know, from the first 20 years now, we're sort of microbiome research. In the modern era of microbiome research. That's, that's probably a major conclusion that we can draw that can be generalized, that if you want to change the composition of your microbiome, diet is the way to go. There might be certain disease contexts or certain other contexts in which probiotics are very powerful, but it's probably not the most general solution.

Nick Jikomes 1:33:37

And, again, I'm gonna ask you another question about yourself, given what you study and everything that you know. When do you when do you eat? Do you do time restricted feeding? Is that something that you think is it going to be effective for most people? And how, how easy is it to do?

Christoph Thaiss 1:33:58

So I think that the easiest and most accessible version of time restricted eating is basically what's called intermittent fasting, because it doesn't limit the amount of calories that you can consume. But it just, you know, limits the hours of the day during which you consume your calories. And something that that most people find. To be compatible with daily lives is basically to limit the window of food consumption to eight hours during the day. Which basically means in simple terms means skipping other breakfast or dinner, but eating two meals a day that are not more than eight hours apart. And we know from animal studies, including the ones done in my own lab, that this already has pretty dramatic metabolic benefits. It also has various effects on the brain that seems to be beneficial, but there are certainly metabolic benefits. So that's something from you know, from the scientific perspective as well as anecdotal evidence from my personal life I can I can definitely I recommend to people, of course, in the end, it comes down to people, you know, trying out their own protocol and seeing what what works best in terms of their own body. But I think if there was a generalizable scientific solution, I think intermittent fasting is definitely an important component.

Nick Jikomes 1:35:18

Yeah, interesting. Do you have you know, this is just popping into my head, but then we don't have that much time left. But, you know, across many different animal species, a key aspect of diet that's sort of being aimed at or that's been baked into animal systems by evolution has to do with things like it has to do with basically the protein to fat to carb ratios of foods. And animals will naturally sort of balance these things in particular ways that are really interesting. And so my question for you is, if you take a fasted mouse, and you give it, is it known if you give it the option of choosing diets with different fat composition? Is it known what they will spontaneously choose? And if so, does that sort of tie into what we think might happen in terms of the connection between the fat composition of the diet and the whole chain leading up to the motivational systems that you described?

Christoph Thaiss 1:36:22

Yeah, that's a super interesting question. This is, this is also a very recent field of exploration in my own lab and in the field in general. And we're trying to understand what controls the preference of an animal, a human being or a mouse, for different types of macronutrients. What's really interesting here is that there is so there, there are two interesting components that I want to mention. One is that there's something which is called the protein leverage hypothesis, that your listeners might be familiar with this, but it's basically a concept that that hypothesizes that there is something like a rheostat for protein content in the body, and that basically, the protein content of the diet determines how much we will eat overall, because there were experiments done in primarily in mice, where basically, mice were exposed to diets with different protein contents. And what was observed is that the mice always ate up to a specific amount of protein consumption. So for example, in the high protein content diet, they stopped eating after a certain amount of food. And in the low protein content diets, they ate a lot more. Basically, they ate as much as they needed to match the protein content of the high protein content diet. And what this means is that low protein consumption comes with excess calorie consumption, because then the calories come from carbohydrates and fats. And if the animal eats until it meets a certain amount of proteins, then it will have consumed other, you know, other macronutrients and is predisposed to to metabolic disease. So that's one very interesting aspect of it. The other one, which is also a very recent development, scientifically, is we're starting to understand where macronutrient preferences are coming from. Because for a long time, we thought that it's all mediated by tastes, right, because that's basically the first step when when an animal or human being ingests food, we basically immediately we can tell the composition of the diet by by how it tastes. And we have taste receptors in the tongue that would tell our brain relatively quickly what the composition of the food might be. And of course, we have warning signals that if the food might be contaminated, we don't proceed with ingestion. But but then the experiments were done on animals that were lacking specific taste receptors. And they were given a choice between different macronutrients or, for example, between sugar and a non caloric artificial sweetener, for example. And the animals were still able to tell the two apart even in the absence of the taste receptor that would allow them to distinguish between the two. So there must be a mechanism that allows to establish macronutrient preference, even the absence of taste in the tongue. And it looks like where this preference is coming from is again from the gastrointestinal tract. And from these specialized epithelial sensory cells that we talked about earlier, that sit in the in the epithelial lining of the gut lumen, and can send some of the same nutrients and will then send a signal to the brain, which influences dopamine release, again in the striatum, and basically the preference for different nutrients. So I think there is a lot to be learned about the pathways that control food preference, but they might end up being very, very powerful in terms of how we can potentially therapeutically intervene with people's food preference and the consequences for metabolic health.

Nick Jikomes 1:40:01

Interesting. Well, Christoph, I, we've been talking for almost two hours, we covered a lot of fascinating stuff. I think I think your lab is really doing interesting things. Is there anything else that you want to say? Or maybe something you want to reiterate from what we discussed to tie it together?

Christoph Thaiss 1:40:17

No, I just think that the theme that really connects all of what we just discussed is sort of a conceptual merger between extra reception into reception. I think if, if there was one thing that people will remember from this conversation is that not only is there sort of the, you know, a merger of the, of the mind and matter of body and brain duality, but there is definitely a merger between the extra reception and interoception concepts that have been around for quite a while, because now we understand that many of these, of these sensory systems rely on the same anatomical principles. And maybe in the, in the future, we will be able to leverage some of these pathways for much more effective ways to control brain function from the periphery. Because if you think about it, the brain is kind of mysterious and very inaccessible, because it's anatomically secluded from the rest of the body, right, we cannot easily access it with drugs, we cannot easily access it with therapeutics, like we can't for the rest of the body. But now that we start to understand these how these sensory systems influence brain function, we can basically approach it in a completely different way we can we can look at influencing brain function as a pharmacological problem from the periphery or a lifestyle problem from the periphery. So I think now we're starting to, you know, enter into an area of scientific research where we understand these pathways, you know, on a very detailed cellular molecular level. And what we're trying with what our long term vision is in the lab is to try and see whether we can leverage some of these these principles of post environment interaction, to basically influence brain function from the periphery, which would open a completely new world of how we understand and treat the brain in terms of the scientific and medical perspectives that we have.

Nick Jikomes 1:42:09

All right, Dr. Christoph Thaiss, thank you for your time.

Christoph Thaiss 1:42:15

Thanks for having me. It was a pleasure.


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