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John Cryan: Microbiome-Gut-Brain Axis in Health & Disease

Full episode transcript below. Beware of typos!

Nick Jikomes

Professor John Cryan, how are you?

John Cryan 5:53

I'm good nick,

Nick Jikomes 5:55

can you tell everyone where you're calling in from and what you do scientifically?

John Cryan 6:00

Yeah, so I'm calling in today from Cork, which is the second city in Ireland, right at the very south of Ireland. And I'm a neuroscientist, of course, but I am intrigued by how the microbiome in our gut influences our brain and behavior.

Nick Jikomes 6:21

Interesting. And so is that basically what's referred to by this term microbiome gut brain axis.

John Cryan 6:27

Exactly. That's, you know, this axis is now becoming part of the mainstream aspects of physiology. Now, we always had a gut brain access. And it's in the last two decades that there's become a greater appreciation that there's another component to it, and that the microbes are actually key to how the gut brain access works.

Nick Jikomes 6:50

What, what is the gut brain access? What does it what are the physical connections mediating how the gut and the brain communicate?

John Cryan 6:57

Yeah, so I mean, this is we know a lot about this from basic, you know, physiology going back to Pavlov's time, you know, about an understanding about about how our gut is talking to our brain. And we use it in our language, you know, the gut feelings aspects of it, the main pathways of communication between our gut and our brain, our neural, so that will involve through the for example, the vagus nerve. vagus comes from the same duration, as words like vagrant and vagabond, so it means wandering. And so this is a long wandering nerve, one of the cranial nerves. And vagal signals go in two directions, to the brain and from the brain to all the organs, including the cost, we also have spinal mechanisms and the direct play, and within the gas, from a neuro perspective, we have what's called the enteric nervous system, the ens. And this is the the the the second brain as Mike Marshawn, at Columbia once wrote a book about, and we have more nerves in the second brain than we do in our spinal cord. And so So, so this is the, this enteric nervous system plays a key role in how the Gulf functions from a basic digestion physiology aspects. But also, more recently, we began to appreciate how it could be playing a role in sending signals to the brain, and modulating aspects of variety of things, including interoceptive signals, and to help us feel how we feel. And so the so that that's the large component, which is the neuro one. And then on top of neuro component, we have a hormonal component. So we have lots of cells in the gastech that release hormones into your endocrine cells. And these can either affect the neural signals, or they can out some of them can can also affect other targets to get to the brain. And so this has been very much studied in the context of feeding behavior. Because feeding is we need a system in our body to tell us when we're hungry. And so we need to understand within the gut brain access that there's hormones being released in advance of hunger, and also hormones being released to tell us to stop eating. And these are evolutionary wired. So that's what that's a second component of the gut brain axis. The third component of the gut brain axis is the immune system. Now, we've all got very familiar about our immune systems in the last two years. But immune signals, you know, with our gut is a reservoir of some of our of the highest levels of immune cells and they traffic to different places and they're able to to become activated in response to certain injury or infection or various systems and are able to get help communicate across the body and even into the Brain overall. So they're there they are the major, what I would say components of the gut brain axis. And then on top of that, we have the microbes, they, and they microbiome then can interact with each of these pathways in different ways. And complicated ways that we're still trying to really work out to influence brain and behavior.

Nick Jikomes 10:30

Interesting. So this enteric nervous system, you said that there's actually more neurons in this nervous system of the gut, then in the spinal cord, yes. And my, my gut instinct would be that they're mostly involved in moving, moving the food through causing causing the movements that actually

John Cryan 10:51

peristalsis and, and motility in general, and that's, you know, that's what they're, they're one of their main passions, the domain roles are, but it also plays a role in things like abdominal pain, when you get cramps, and you get if you have irritable bowel syndrome, which is a disorder we study, which is a very unloved disorder, no one wants to talk about, you know, the Center for irritable bowel syndrome, we don't have donors lining up to give us money to do that. But it is a very common and this abling disorder, which has the enteric nervous system at its real foundations in terms of what's going wrong, and how that pain is processed. It's processed through through all sorts of spinal mechanisms into the brain. And so everything is connected.

Nick Jikomes 11:43

I see. Interesting. So so the the enteric nervous systems not only moving the food through, but it's doing some kind of pre processing that then gets shuttled up to the brain. Yes, yes. Interesting. One of the things that I wanted to talk about, it's just a general area of discussion is the connection between the microbiome and this gut, brain access, and aging and immunity. And I know that that you and others have done experiments that center around something called a fecal transplant. And the basic idea is, you put a young mouse's microbiome into an old mouse, and interesting things happen. So very broadly speaking, how did these experiments work? And what are some of the high level changes that you guys observed with respect to aging and immunity?

John Cryan 12:30

Okay, no, great, great question. So I'll rewind a little bit just to give listeners a little bit more context about about why we would think about doing this in the first place. And so what my lab is really interested in doing is understanding this relationship between the microbiome and the gut, brain access, and key Windows across the lifespan. So we have programmed in early life in the perinatal period, in adolescence and all the way into into old age, and buoyed by experiments in humans, that my colleagues here Incorporated. Oh, it's almost a decade ago now where they showed in a project called elder match that elderly individuals who tended to live in nursing homes and assisted living, that their microbiomes had a reduction in diversity, as they aged, and this Carl frailty and other health outcomes. So the people who lived in the community then who had very much diverse, more, more diverse microbiomes had less frailty, and so So, and they went one step further to show that it was driven by diet. So the people with the more diverse diets had the more had the most diverse microbiome then and we're less likely to be frail. Now. So that was kind of interesting. But I'm a neuroscientist. So I was a bit disappointed. There was not a lot the one a lot of neuroscience in that study, even though it was in nature, but it was, it didn't have a wasn't driven from a cognitive or neuro immunology perspective, there was a peripheral immune measures. But we were kind of excited about it. And it reminded us of Elie Metchnikoff 's work at the turn of the last century. Now, I don't know if you've heard of Elie Metchnikoff. Nick. Okay. And Elie Metchnikoff is, you know, it's kind of time where he was a Ukrainian, Russian working in Paris, who won the Nobel Prize in 1908, for discovering the process of what we call phagocytosis. So the gobbling up the immune, immune cells do have foreign bodies. And so and so he was he was a brilliant father immunology, you know, brilliant guy. And maybe as happens, some are actually quite a lot of great scientists later on in their careers, they can start to come up with crazy ideas. And match the calf was really full of crazy ideas. Most of them complete nonsense. But one of the things that he when he turned 50, which at the turn of the last century was, you were getting old, he got started to get worried about aging, and he started getting worried about his own his own mortality. And he really was getting, you know, wondering why, how can I do something about this. And so he started looking around in populations where people seem to live longer and healthier. And this brought him to parts of what's now rural Bulgaria. And what he found was that people who live there ate, that live longer, ate a lot of fermented foods containing lactic acid bacteria. So he put forward the idea over 100 years ago, that it was healthy aging could be driven by lactic acid bacteria. And it's really the father of probiotics. And you know, if you go to Korea, you can get a yogurt drink with MasterCards picture on it. So, you know, it must have that Nobel sign of approval, and must be good for you. But anyway,

as I say, most of what he talked about was nonsense. And so he was ignored. The Moses was ignored for 80 years. But you can read about he wrote a book about it about the, you know, optimistic studies on aging. And, you know, it's quite interesting because sometimes in science, we we, you know, are just reinventing wheels that have been turned already. We're inventing them and technologies now that can advance that. So much of that is a father of lactic acid, bacteria, probiotics, and so he's well known if you're an immunologist, or microbiologist, I never heard of him until I started reading these studies as a neuroscientist, but it wide by the studies from my colleagues here in Cork on the people in the nursing homes. And with this metric of idea, we started revisit what I wrote a paper called revisiting matching the Gulf, which was really about looking at using aged animals mice in this case, we looked at what's going on in their brains what's going on in their, their behavior, and how is that linked to what's going on their microbiome, and we found quite a number of what I would correlations, but it's just correlations. So it matches kind of what we're seeing in the human studies, that the microbiome seems to correlate with some of the behavioral changes. And with some of the some of the brain changes, but we needed to go one step further. And so in a study that we follow that up with, we say, could we target the microbiome, in aging and through diet would be the best way? And can we slow down some of the effects of aging, and so we used a diet that was enriched in insulin. Now, insulin is a fiber, present in lots of vegetables, chicory, leeks, artichokes, etc. And what I'm for these studies, and I turned to middle aged mice, because I started getting very interested in the middle aged brain myself, for obvious reasons. And they're already in middle aged mice, you start to see neuro inflammation happening in the brain as an harbinger of later, perhaps, degeneration. And so what we found was when we fed the animals, this emulation, enriched diet, that they didn't have this neuro inflammation in their brains. And that was really cool, because now we see that by feeding microbes, we could actually slow down the effects of aging. Boss, we It wasn't definitive, in terms of the diet could be having direct effects on the brain, independent of the microbiome. How do you know how did I know? And, you know, I was asked this question many times, how do you know it's the microbes? So that led to the study that you're alluding to, which was this kind of killer study that we wanted to do, which was kind of a proof of concept? Well, what if we took the microbes from young animals and gave them to older animals, which have a different microbiome? Could we reverse now, this was the real killer part because we went to old animals, 22 month old animals could reverse the effects of aging on brain behavior and immunity. And that was really, you know, an experiment that I told the postdoc, this is not going to work, you know, we have to do it. And so we took advantage of fecal transplants approach which you alluded to, which is exactly what it says on the tin. It means taking something some other individual's poop, and transplanting it. In this case, it's from one mouse to another. And I'll just stall and just explain to your listeners what fecal transplants have gotten some attention in the press over the years. And they're seen as something quite new but they go back to ancient China and the way they were used in the treaty treatment of I have all sorts of ailments that was called a yellow soup in Chinese medicine, and they've been revolutionary in modern medicine in treating certain forms of infection, most notably Clostridium difficile C. diff kills people, and it's antibiotic induced infection. And what studies from the Netherlands almost 10 years ago again, show that there was a 95% success rate in individuals that are being given a fecal transplant for this an infection. And so I'm, you know, I work in a medical school, there aren't that many areas of medicine where you can say there's 95% success rate for anything. So that brought fecal transplants back into the mainstream in humans, which so now,

Nick Jikomes 20:53

I just want to make sure I'm understanding. So I've been asked this before, and I don't know the answer. So I have to ask, how are these transplants physically conducted? Oh, yeah, sure. And then you're saying that in this particular example, there was some sort of antibiotic effect.

John Cryan 21:10

So so no, I mean, so So the, in the initial and the human studies, what happens there used to treat predominantly Clostridium difficile, which is, which is an antibiotic, it's caused by overuse of antibiotics, it's an infection that becomes resistant to antibiotics. And so your antibiotics don't work. So it's basically will kill you. And it's basically a hospital acquired infection that when people die, all over the world, people died today from it in western world. And because it's caused by antibiotics, and you try and treat it with antibiotic that you reach a stage where you know, something has to change. And what you do, then what they studied with the fecal transplants do is, well, what if we can get rid of the microbes and put new microbes back and when will that work? And so in terms of the physical purposes of doing it, there's really only two ways you can get to the colon, you can go either go down in a nasal gastric tube, or you can go up in an enema. And that's what people are how people deliver this overall, and, but the success rate was was just dramatic. And now it's been tried and all types of different illnesses. There's ongoing programs in depression and anxiety, also in obesity, in inflammatory bowel disease and irritable bowel syndrome. mixed effects, you know, it's not going to be the cure all, what a lot of people are also looking at is, well, could we come up with a more innovative way of delivering this disruptive medicine? So there's a product like crap tools, which are basically, you know, poo that's been put into pill formats. And this is gaining a lot of attention from an innovation perspective.

Nick Jikomes 22:53

But is it just is it like a purified preparation of some of the bacteria,

John Cryan 22:57

though, why do you think you can do that, and some groups are doing that? So there's a group in Arizona that are doing that with with the conservative but 100 bacteria? What what people are really looking at is just from from donor from, you know, fresh. It's remarkable.

Nick Jikomes 23:14

Interesting. So the idea is just you're putting in other bacteria that then out compete, the one that you don't want there.

John Cryan 23:20

Yeah, yeah, exactly. Exactly. And they can grow over and they can, you know, whatever else, and so, and so in the CDF world, and Clostridium difficile work, it works. And, and outside of that, the, you know, the, it's more equivocal, shall we say, yes, but we need more studies. But with that knowledge of clinical medicine, and how this is working, that fecal transplants are moving into the mainstream in such a way that almost all Western hospitals nowadays will be performing fecal transplants regularly, then it becomes a more viable approach to use in our animal models, as well, because it has a translational potential overall. So that led us then to Seagull could we do this in our aging animal? Could we take the microbes from young animals and give it to the age animals and reverse the effects of aging? And quite remarkably, and to my surprise, many of the effects we had seen were were changed at the level of the gods at the level of the immune system at the level of the metabolism. So that's the chemical makeup of the region, the brain called the hippocampus, which is involved in learning and memory. And we were able to reverse some of the age associated behaviors. And so we published that in nature aging, we got on the Steve Colbert show, joking about it, he made he made jokes about our studies at the time, it was kind of one of these papers that you know, had got a life of its own in it. It was really important to show, you know, the next steps from our earlier work where we could go. But it asks so many questions. And before your listeners all try and rush out now and start stealing the poo from infants, that is not what I'm saying. And that's not where this research is really advocating. Really, what we're, what it tells us is that it gives us some really good evidence, at least in a mouse, that the microbiome needs to be looked after, as we age for to engender healthy aging, to engender our brains for healthy aging. And, you know, we need to look at ways of doing that. And so that's kind of, we know where you know where it's at, rather than the fecal transplant was, was a proof of concept.

Nick Jikomes 25:45

Another way I could have imagined, exploring the necessity of the microbiome for some of these diet induced effects would have been to give the mice what you mentioned earlier in terms of diet, but sort of nuke the microbiome with antibiotics first, has anyone ever done something like that?

John Cryan 26:03

So, so yeah, not not the same way in age animals that I'm aware of? That we were thinking of doing that, but we were a bit worried that age animals are very expensive. They may not respond to the toddler, antibiotics are quite a, you know that there's a tolerance effect. So yeah, so that needs to be done. And that would have been the cool experiments, that we were still on our list of things that we should do. But it's going to be, there's going to be other collateral effects of antibiotics in the gut in terms of energy absorption and food, you know, that's going to complicate things that could be give you indirect effects. So the way we did it, I think was probably the most indicative that that it is actually the microbe because the only two differences between these two old animals is that one has got the microbes from a young animal, and we gave the other the microbes from an old and I'm, you know, from an old animal, so so we were able to, you know, control for the transplant itself.

Nick Jikomes 27:07

And so when you do this, the old mice have brains that start to look younger, in effect. And so what does that actually mean? What are some of the markers that differentiate the younger looking versus the older looking brain?

John Cryan 27:20

Yeah, so we looked at a variety of different ones. So the really intriguing one for me was the metabolism in the hippocampus. So the so this is using mass spectrometry, you know, to look at what are the chemicals in the, in the brain that are being formed. And, you know, there are hundreds and hundreds of chemicals. And we were able to use this approach, then to see you which ones were changed with aging, and then which ones were reversed. And there were quite a lot that were that were sensitive to the fecal transplant. And so that was kind of really cool, because some of these may originate in the Gospel, because one of the things about the gut microbiome is that it's like a little factory, producing all kinds of weird and wonderful chemicals that our bodies wouldn't have otherwise. And some of these chemicals can get into the circulation, get across the blood brain barrier, and enter the hippocampus. So so that was, that was quite intriguing. We also looked at microglia microglia, or the brain's immune cells. And we found, again, that there there as the brain ages, the content, increased activation of microglia. And this there was a diminution of this, when we get the transplant, we did look at other things that didn't change. So not everything changed. So we were really interested in a process in the in the hippocampus called Adult hippocampal neurogenesis, which is the birth of new neurons that occurs throughout the lifespan. And you know, it starts to get less and less as we age. And so we found the age effect, but it was still there, that the transplant wasn't able to recover these new neurons to be more. So not everything changed, but quite a lot of things did. And then on behavior, we found that they, they, when we put the mouse in a maze, in particular Morris water maze, so it's basically a spatial learning task. They were able to find the hidden platform and develop a strategy, again, similar to younger animals when they had been given the transplant.

Nick Jikomes 29:27

And I suppose one of the things that's interesting here is the fact that you see this effect means at least for some of these things, the because you're able to reverse some of these inflammatory markers and even behavior and things like that. It's not like the aging process has just sort of accumulated over time that some of the stuff actually is acutely reversible. That was, that seems surprising,

John Cryan 29:48

ya know, and for me, too, it you know, it reminds us that the brain is so plastic that reminds us that there is so much potential for this and it reminds us that it's never too late to focus On, on on doing these things.

Nick Jikomes 30:02

And when you do these microbiome transplants, so in this case you're going, putting the young microbiome, or the microbiome from the young mouse into the old mouse, you see these remarkable effects? Does that new microbiome? Is it stable? Or does it revert passively back? Yeah,

John Cryan 30:18

no, great question. And we don't know, we didn't do them experiment. Yes. Get again, getting age might cost us a fortune, because we don't have a National Institute of Aging here. And that can deliver these to us. And so So, you know, we were we it is an important aspect to know, you know, in terms of Do you have to keep doing, we did give them boosters twice a week, during all of the testing that was going on. So just to ensure that we got some engraftment continuing?

Nick Jikomes 30:52

And, I mean, just, I mean, when you look at the when you look at the mice, do they? Do they look healthier? Just visibly?

John Cryan 31:00

No, not really. I mean, when we, you know, not really, we didn't see a huge, they are quite healthy, and it's one of the functions of working with age animals is that you work with healthy aging animals anyway. Because if the animal starts to deteriorate, you have to for human reasons, you have to decide, you know, to sacrifice air, you know, when you start seeing anything going wrong, so so they weren't that visibly aged, you know, there weren't, unfortunately, no walking sticks or glasses, or anything that we could look at, that would be able to tell them, or they were going for Early Bird menus or anything, you know?

Nick Jikomes 31:42

And so what about what about effects in the periphery in the entire system, or inflammation markers there.

John Cryan 31:49

So again, peripheral immune immune markers, we did a whole panel of different peripheral immune markers. And it was somewhat selective. But it was, it was really there, that a lot of the aging or induced effects were sensitive to it. And, and that makes sense. And, you know, we have this process that's been coined, inflammed aging. And basically, as we age, you know, our immune systems, and that's why, you know, during the pandemic, we were so focused on keeping our vulnerable people over, you know, 80, initially, and then down to over 65, because their immune systems are just not able to tolerate things. And so we were able to push back some of the signs of aging in the peripheral and locally in the gut immune system as well. So that was kind of cool. You know, again, we don't know what's driving walk first, we don't know, is it immune? You know, if you reverse the immune, it does that have is that what's causing the knock on effect. And we'd like to dig into the pathways that might be at play here. And we really need to invest in more effort in that.

Nick Jikomes 32:59

One of the, you know, one of the things here, that's, that's obviously interesting is, you're seeing these effects at all, and it goes all the way into the brain stuff is getting all the way into the brain and having behavioral effects. I know that there's also been some work linking the microbiome to social behavior and animals. So starting wherever you think is most appropriate, what of what has the link been so far between the microbiome is ability to modulate social behavior? Okay,

John Cryan 33:25

so yeah, this is a really intriguing topic. And when I, I, I'm quite excited about in terms of where we could go with this. In 2013, almost Yeah, we showed in mice that lack microbes. So So, so So let me rewind. So I've been talking about the microbiome gut bracket for quite some time. And my neuroscience colleagues are a good skeptical bunch of people, you know. And so I can talk about correlations. And I can talk about gut feelings, and I can talk about things, but they really like, you know, they want mechanisms, and they want more evidence that something is, you know, that the microbiome, so a decade ago, you know, we first published in 2011, showing a specific strain of bacteria could have effects on brain and behavior through the vagus nerve. And that got a lot of attention. And it was kind of one of the breakthrough moments for me in terms of really getting good evidence that this was, this was relevant, but I wouldn't, you know, we need more data. And so how do you get more data that something is important to a process? Well, you take it out and see what happens. And so that's why I always say to my, to my neuroscience colleagues is that, you know, here's here's some really hard data. If we take microbes out of mice, and we have a germ free facility here in court, and we look at the brain and behavior of these animals, then we start to get an idea of is the microbiome involved? Yes or no? Early work out of Japan showed that the microbiome it was involved in, in in stress response work from Karolinska from Russia. steatite, and from Jane Foster in McMaster. And our own group showed that brain development and Riley brain processes were gone awry in these germ free mice, especially in the context of anxiety behavior. And then in 2013, we looked at social behavior. And we found that mice have that are growing up without microbes have clear deficits in both social sociability and, and social cognition. So, sociability is basically when we give the mouse the opportunity to spend time with a, another mouse or an object, it will gravitate, a normal mouse will gravitate towards a mouse, their social, they want to spend time, but not a germ free mouse. Also, then, for social cognition, we want the animal to be able to distinguish between its everyday playmate and a new playmate. And mice will gravitate towards the new playmates. So they're, you know, pickled, like maybe some humans, but they're, they're quite fickle in that regard, but not if they're germ free. And so this was really important data for us to show at the time, that if you're lacking microbes in your gut, and you're a mouse, that you're having different social experiences overall. So that really got me excited. And we did a lot more digging into the mechanism that this, we showed that in these germ free animals that they have deficits in their amygdala in terms of the arborization of the amygdala, which is a key brain area involved in in, in social behavior. In the prefrontal cortex, which is also very much part of the social circuit, we show that there is increased myelination, and people think about myelination in the context of multiple sclerosis where it's a demyelinating disorder. Well, here we are, increase myelination, we also get changes in the hippocampus and in arborization, and in neurogenesis. So we're beginning to build a circuit based approach to understand that the brains of these animals are pretty messed up. But they have the social deficits. And then when we put the animals in social contact, we also looked at using onbuy, RNA seek approaches, we looked at the transcriptome, and were able to show how different activation of a variety of key molecular pathways were underpinning social behavior were also gone awry in these animals. So around the same time, a link alien child group, then a Caltech now UCLA showed, again, social deficits in animals that have been given early life infection with maternal immune activation protocol, and this correlated with the

microbiome changes, and she could reverse this specific probiotic. So again, the social interaction, and, you know, she was able to cite our paper in that, and that was really cool. And then since then, I'm just really, I want to know more about why just the social brain so sensitive. So two things that I learned on this journey, one is that you can't do everything yourself, and you need to collaborate with experts, and experts get a bad name, but it's good to have experts. And so I had a very great postdoc in the lab, Roman stealing. And when we got this data on the social brain, then then we started reflecting from an evolutionary perspective about why would you need microbes in the lumen of your golf, if, you know for normal social interactions, and so we started building a kind of a framework based around the the the the cortical development theories of Robin Dunbar where he shows that social elaboration of the cortex is greater and social animals may be driving social behaviors. So we know that so social behavior is driving brain development. We know the microbiome is driving brain development, we know the microbiome is changing social behavior. So is all of this just all linked up in some way? Overall, and, and then we start thinking about, okay, and this is before pandemic, before people were, we were much more attuned to this, but, you know, if you're in a social environment, your microbes are getting passed on much quicker to other people, you know, and so I started thinking about what's in it for the microbes. And Rob and I were gonna write we're writing something on this and then I go collaborated with a guy in Vanderbilt Seth Borenstein, and said, This is Howard Hughes, there is an evolutionary microbiologist and I put some of these ideas to him. And he basically told me that I was completely wrong to even be thinking like this. And every now and then, as a pie, it's really good to be told you're wrong. And why was I wrong? Well, I'm wrong, because I forgotten, you know, something that's very fundamental to this whole story, which is that the microbes were there. First, our brains have never existed without microbial signals, our mitochondria in our cells are just microbes that got lost. So we need to really reframe how we think about the gut and the brain as if they're two separate things completely. And this is the problem with modern medicine, we love to compartmentalize the body. And and, and, but there has never been a time where, where brain development haven't had the signals coming from it. And they've evolved into allowing for appropriate social behavior. And they're our friends with benefits and our friends with social benefits. And so in, we wrote an article, and it was kind of a kind of cool idea. And it led to a lot of other thinking, then you start to look across the animal kingdom. And then I collaborated with a geologist, John Quinn here, as well as we'd set. And we started looking well, if you start interfering with social dynamics, or hierarchies across the animal kingdom, one of the things that keeps coming up is that you've changed the microbiome. So whether it's in a bumblebee in a hive, or a baboon in the wild, these data exists. And and vice versa. If you start to change the microbiome, by either diet or other approaches, from insects, all the way to non human primates, we begin to see that the social behavior is the one thing that seems to be quite sensitive to this. So there's something about the social brain, and that makes it sensitive to such signals. And yeah, I kind of I haven't talked about disease on purpose yet. But but but but that's where goes a little bit. But I want to before I go into talk about disease, I want to talk about normal social behavior, how much of our decision making how much of our social decision, how much about how we eat, and how much of our teamwork, our altruistic behavior or cooperative behavior, our empathy, our competitiveness, is all driven by what's going on in our gut and how it's speaking to the brain in terms of normal behavior, then, when it goes wrong, what happens?

Nick Jikomes 42:47

So how do you start thinking about that normal behavior stuff, you know, one of the places where my mind goes naturally, having a background in evolution and behavior is, you know, if the microbiome is inherently tied up with things like the state of not only your metabolism, but your immune system, then you know, the the compounds and the markers that a consequence of it can perceive which are connected to those microbes is going to contain information about the general physiological state and health of the other individuals. So that might be used in, you know, in terms of mating behavior that might be used in terms of avoidance behavior, if you want to avoid someone who's potentially contagious or something like that.

John Cryan 43:34

Absolutely. I mean, social immunity is really important in this and so. So we put all this together. And if your listeners are interested in a review article, we wrote in science probably two years ago now, because we wanted to capture these exact same things. And of course, insects and, and mammals in the wild will have a different need for sensory. And so there's a sensory components of social, and some of these chemicals that are coming from bacteria can have really olfactory or various other cues to Elijah. But I guess the main thing, Nick, that I'm trying to get across is it's all connected. It's all connected. And the microbes were there first. And that's really, you know, my mantra, some of this when I tried to explain to people like, you know, people always think it's something completely different. And, and what we don't know Yes, and this is some of the studies I want to do is really like if we took 1000 people and stratify them based on their social decision making within a normal range, could could we look at what's going on their microbiomes in terms of driving that? And then could we change that through diets?

Nick Jikomes 44:42

Yeah, I mean, it strikes me too, that animals are effectively sampling each other microbiomes are at least portions of it in terms of the behaviors they display. Like, for example, if you just think about like, affectionate behaviors that humans have, I mean, like, why do we kiss each other? I don't know that The answer to that or how it evolved, but you are going to be sampling a portion of someone's microbiome and it probably contains real information about their, what you might just think of as their physiological compatibility with you.

John Cryan 45:12

Well, people are looking at that. And indeed, one of my colleagues in Germany, that's one of her, you know, areas is looking at how couples interact. There's been studies on houses, when people move houses, and how their microbiome change and how I want people start going into relationships among people. All of this is becoming becoming, we're getting more data. And it's got to be more complicated than we think. And it may not be as you know, I guess the relative contribution of it to the specific behaviors, versus other environmental factors or lifestyle factors that could be overriding some of this under normal basis, it needs need some form of investigation. But I do think, you know, when we talk about the social brain and microbiome, we do need to look a little bit more at normal aspects of social life. And I think some of the work in the honeybees is just phenomenal. Because, you know, they're such a social insect. And, you know, if you, you know, some of the problems we're seeing in the world with, with pesticides, and various other things are impacting the microbiomes, and the social behavior and various things.

Nick Jikomes 46:26

What is, what are some of the salient results from the honeybee work? Um, I'm not familiar with it. Yeah, no, it

John Cryan 46:33

does. It does this accumulating data now showing that if you mess up with the microbiome, in honeybees, you mess up social behavior. And if you mess up honey, bee social behavior, it has a lot of knock on effect on biodiversity because of what they're doing. etc. So it's, it's building it into a planetary health framework that you wouldn't even interpret beforehand. And what what's disturbing the microbiome? Well, you know, a lot of the work is experimental right now, but we do know that certain pesticides and various other things can do that. And there's a whole environmental aspect to that.

Nick Jikomes 47:09

I mean, you know, based on that, and based on, you know, the experiments you described, using antibiotics in mice, you know, one naturally wonders what the effects of things like antibiotics and the food supply chain are having on humans.

John Cryan 47:23

Yeah, and this is really, especially in the US, because, you know, there's a higher tolerability for antibiotics within the food chain in the US than there is in in Europe, for example, but Marty Blaser, who's now at Rutgers has written extensively about this in the context and metabolic health. And, you know, he's he's data and animals, and then he's human data. And he basically thinks that the obesity epidemic is driven by early life exposure to sub clinical levels of antibiotics overall, and there were missing microbes. Overall, that was the title of his book about this. But he, you know, he also shows, you know, the correlations, but correlations of antibiotic prescription rates in the US on a county by county level, and then maps over the obesity levels, like almost, you know, and so there's become a bigger appreciation of the importance of the microbiome in all aspects of health, particularly metabolic and cardio metabolic health, the other things that's informing the studies where people are going out and looking at the microbes of ancestral tribes. So going to Tanzania, and there you can see the microbiome is very diverse, largely driven by the hunter gatherer lifestyle that they have, the gathering part is often neglected. And this is eat a lot of fiber and a lot of grains and a lot of things. And so so that's, and then if you go to more agrarian communities, like in Malawi or Venezuela, you see what the what was farming, introduction of farming has done to the microbiome, you start seeing a devaluation, and then our western world, whether it's in the US or here in Europe, with the introduction of processed food, the increased stressful lifestyle, the antibiotic exposure, the environmental pollution that around us, you we have an extinction of these microbes that our ancestors have and work from the Sonnenberg Justin in our Erica Sonnenberg. At Stanford for for some years. Now, I've been really highlighting how this could have long term consequences because we don't know if we can get them back, you know, is what's gone gone. And you know, you can eat as much fiber or whatever good food you want. If you don't have the microbes there to actually get the you know, good stuff from it. Then it becomes a problem and, but that enables us to start Looking at the John studies on these microbes and being able to link it to overall health,

Nick Jikomes 50:07

I think, you know, a skeptic might say, well, of course, a hunter gatherers microbiome is different, every, you know, virtually every aspect of their physiology is probably different because their entire lifestyle from diet activity level is different. But to connect it with some of the experimental work, you talked about the beginning, we at least have wrote evidence that transplantation of microbiomes can be causally related to at least some some changes, and presumably,

John Cryan 50:32

and that's and that's where we want to go. And, and what our lab is doing is like a lot of the work is being done in metabolic health or immune health, and gut health, we want to bring it to brain house. And that's really our like, you know, the different perspective that we have on this overall.

Nick Jikomes 50:49

Now, I think if the if there's more to talk about normal animal behavior and its relationship to the microbiome, we should definitely do that. But some of the results that you're describing with respect to social deficits, naturally make one think about things like autism.

John Cryan 51:03

Yeah, so but we also now come on to autism, I have no, but but but we also should remember that there are other disorders of sociability besides autism. Social anxiety disorder, is something that we're studying right now a lot and quite intrigued on and it's a fascinating disorder. And it is really a, you know, more common than people think it is. And we have new data to show that the microbiome is different than people with social anxiety disorder, social deficits are a core symptom of schizophrenia, and really are quite hard to treat with anti psychotic medication overall. So, and social disorder, social anxiety, anxiety aspects can can be a subclinical level, with general shyness or general social awkwardness overall, but let's go to autism. Because, you know, it is probably one of the most studied areas in relation to the microbiome. It also is one of the most emotive and one of the most, that can be the most challenging to to discuss and manage expectations of individuals overall, on it. My take on it so far on the data, where we are, is that there seems to be some very clear relationship between the microbiome and early life, and the natural history of certain aspects symptoms of autism. Now, the early experiments in this field were coming from, for example, a Sydney finals lab in UCLA, where they showed that vancomycin as an antibiotic might have some beneficial effects in an autism. They did some very small scale human studies, promising there's been lots of anecdotal data. Some are promising. And then in the when people started measuring the microbiome and a compendium like way, just what microbes are different in autism versus not. The early studies were largely small, androgynous, didn't really take into account Dyess, were a bit of a mess, to be honest, he couldn't really interpret anything. Yeah, just changes. But what do they mean? And Are they consistent, and I recall, has probably almost a decade ago or good number of years ago, looking at one of these better papers in the autism field that was emerging to show that there were links between microbial changes and a subset of, of individuals in this larger study with autism. And particular thing in the study was they had very good dietary data. And what the dietary data showed was that it wasn't that there was a link between autism and the microbiome, but it was a link between what these kids ate and they ate a lot of chia seeds. Now, I didn't even know what a chia seed was, but chia seeds, but are like a superfood that are often in smoothies, and used a lot by autistic kids and their families. So so that was just a clear example of we need to be very careful with this field about where where it's going, where things have got exciting is where coming from Arizona, where they've they've shown using a kind of a fecal transplant approach that I alluded to, but but it did developed a consortium of bacteria. And they showed in a again, a small enough study some years ago, this is Rosa chromic Browns work, where she's really along with Jim Adams day showed that when they gave a fecal transplant to a group of kids with autism that their guts and their social problems resolved somewhat, and that this persisted up to four years. So that was kind of a it's a small study, it's not placebo controlled. It has, you know, it has issues, but it is exciting. And then the animals from that Sarkis Mazmanian group at Caltech took the microbes from these infants or other now children. And then she

showed that they could induce autistic like behaviors, when they transplanted them into mice, germ free mice, and allow them to breed for one generation. Now, these studies got some kickback because people felt that they were over interpreting some of the statistics and over interpreting some of the things. But, you know, there was lots of really intriguing data in this paper overall, it did show that the microbes from kids with autism induce different effects on brain on behavior on the metabolome, on immunity in these compared to those from normal neurotypical kids. So for me, it was quite a, you know, it was kind of exciting overall. And then, just two weeks ago, Sarkis, his lab, showed, again, based on our work on myelination, and others that show that the data metabolize from that that was identified in these kids could could also induce autistic like symptoms in in mouse behavior. And the question is, you know, how, how real is social behavior in a mouse for humans, and then they had a paper a proof of concept paper in Nature Medicine, showing that a new compound that it basically kit marks up these metabolites are basically quenches them in the gas was having beneficial effects. So the story is really there. Oh, yeah. And then I will do my one minor pivot just because in the interest of, of clarity, is a large study from Australia that came out about three months ago, where they looked at it from a genetics group there, which looked at the microbiome and really good detail, to really good characterization study. And they looked at food intake, and they looked at Food behavior, and they looked at different aspects of eating. And what they showed that the microbiome changes in these kids was driven by picky eating in these kids, and wasn't specific to the actual behavioral changes, per se, but we're, you know, so So the press interpreted this, and the press releases, allow them to interpret this, that there's no relationship between the microbiome and an autism, but it's actually more more nuanced, because we don't know what what led these kids to be picky eaters, and what led their neuro developmental trajectories. And so it is complex, and it is Gene environments, microbiome and Gene interactions that are going to be at play. But you know, we need to kind of understand this in a different way. So our research is very much looking at aerial life microbiome changes. And we've shown this now germ free in animals born by cesarean section, because C section changes the microbiome, and by giving antibiotics, maternal antibiotics, two minds, all three of them, the one behavior, we see that that comes out of time and time, again, is social deficits. So there's something about the social brain. So why wouldn't a disorder like autism, which is war? Very spectral, very distinct? The Why wouldn't it be also involving how to the microbiome or share big talking to the brain? A key Windows key critical windows? Interesting. I hope you didn't want a short answer.

Nick Jikomes 58:52

No, no, no, it's fascinating. So you know, so you mentioned, you know, autism is just one form of social disorder. And there's many other afflictions that people have that might be related to the microbiome, I suspect. So when we think about things like social anxiety and depression, what are we starting to learn there?

John Cryan 59:10

Yeah. So in social anxiety, we are finding that there are distinct changes in certain microbes. And we're getting this ready for publication now. And we're doing the the the experiments in animals to look at the mechanisms underlying that. And depression. It's a little bit complicated, again, because a lot of the early studies are heterogeneous, using not the best tools. But when we were we're really interested in this some years ago, where we wanted to see what if you took a bunch of people with clinical depression. And this was in collaboration with my colleague, Ted Diane, who was the chair of psychiatry, clinically depressed individuals versus healthy individuals took their microbiome. What we found was that were the like, changes between them wasn't a big number. So you know, we all caveats with that. And then there was a lack of diversity or reduction in diversity. In the depressed individuals, so kind of like almost accelerated aging and their microbiome if you want. And what we did is we took their microbes, and we transplanted them as we're prone to do, in this case to rats. And too much to our surprise, the rats develop depression like symptoms. So this was kind of really cool, because it helps us with causality, it helps us really answer you know, now, how do you know rats depressed? Well, you know, that's a really hard question. But we look at key into phenotypes of depression. So anhedonia, the abilities to experience pleasure, microbes, when they're actually taken microbes from depressed people, they had less interest in Sweden, sugar, compared to normal animals, they were more anxious when you put them on a maze that where they can go and explore open arms or stay close, they stayed in the closed arms, we looked at their immune inflammatory profile. And we know inflammation is also present in depression, and we able to change completely their inflammatory profile. So it's remarkable. And this has been reproduced by a group in China, it's been reproduced by a group in Canada, the Czech purchase group is working on this in the context of anxiety. And so, you know, it really helps us develop kind of a causal relationship. So that's one of the things the other thing, and that's happened in the Depression field is work from Belgium, where they looked at 1000 people. So that's good, good size to start with. So because one of the big problems here is all about sample size, and they looked at those that were depressed, and they found that they had a specific changes in their microbiome, they talked about inteiro types, which is kind of just subtyping them their microbiome in different ways. And, and they went one step further to show that they potential of that microbes to make certain neuro active chemicals that could potentially get to the brain. So they were able to identify which bacteria make which chemicals. And they were showing depression, that there was a reduction in certain bacteria and an enrichment in others, they will verify these data in another 1000 People in Netherlands, and then in a very small sample of really depressed people in a hospital in Belgium. So that's kind of neat, and we're collaborating with them to do more, to do more mechanistic work on where this is going. And I think what we're beginning to see really, is that the microbiome could be targeted for mental health benefits. And, and then that's why we coined the term here in Cork, we coined the term psycho biotic, which is basically a way to target the microbiome for mental health benefits. Not to be confused with your psychedelic, but psycho biotic is something that were were very interested in.

Nick Jikomes 1:03:06

Well, so there's something really interesting I'm thinking about here, which is, you know, you've mentioned, I mean, everything that when I think about everything that you've mentioned, you know, the microbiome can have, it seems, effects on the brain through through a variety of different pathways. You know, we've been talking about things like depression, anxiety, and and these things that involve psychoactive effects. There are, as people may know, there's a lot of serotonin used in the gut and the enteric nervous system. And I wonder if you know, we've got anything from selective serotonin reuptake inhibitors to search Sara nergic psychedelics often have in people got gut related side effects. And I'm wondering if the microbiome itself can be affected by some of the psychoactive drugs that people are consuming by the millions?

John Cryan 1:03:56

Absolutely. We've done these studies and animals and and characterize it, well, we initially would. We were interested in antipsychotics. So atypical antipsychotics are widely used 1% of the population in the western world are on them, which is quite a loss. And it's not they're not just used to treat schizophrenia, but they're used to treat many aspects of depression and bipolar depression, as well. So but one of their side effects is metabolic dysregulation, and obesity, and people just just blew. And so we were interested in looking at could this be driven by the microbiome, or the microbiome gut brain axis? And so we showed in 2013 that olanzapine was mediating effects through Well, that was affecting the microbiome. We follow that up with a paper where we in antibiotic target target animals that this didn't happen as much. So you know, we're really getting to that, to that to that level. And then Sophia Kasota, when she was a PhD, she in the lab looked at Haven't read other seven or eight other psychotropic drugs, so including mood stabilizers and SSRIs. And show that had quite a profound effect on the microbiome. And just as we were getting that ready for publication, paper from Germany came out in nature, which over, you know, 1000 drugs in it. So, but it showed very clearly that a quarter of all drugs in pharmacies today are having deleterious effects on your microbiome. And in the drug class they highlighted was anti psychotic, so it was really cool. In relation to psychedelics are that, I don't know, is there that much data, but I know people put forward this idea game called Risk lab as talked about this in some of her reviews.

Nick Jikomes 1:05:45

So um, so it's super interesting, a lot of the pharmaceuticals that we're using are affecting the microbiome. It's not so surprising that that's happening to some extent, but it's maybe surprising that it's happening so widely. So just to give people more concrete sense of this, you're saying you've done experiments where you give rodents an anti psychotic, there is some sort of downstream metabolic effect. And the size of that effect is diminished if the animal is taking antibiotics? Yeah. And what are those effects typically for like an anti psychotic,

John Cryan 1:06:17

so this weight gain, it's accumulation of, of, of factor pose, it can lead to diabetes and a really high level, but we in our animals, we don't get that far. It you know, it was really it really surprising data, and it's really a clinical problem. But But now, there's a whole area of research called pharmaco. microbiome, and so looking at, so you know, I tried this in your pharmacologist, so so. So I'm interested when I when I, when I, when I would teach, I would tell students that you need to think about pharmacodynamics and pharmacokinetics. Now, if I'm teaching, I say you need to probably dynamic family, and pharma got microbiome, because that that's really important to how drugs are impacting the microbiome, and how the microbiome is impacting drugs, because we just also published a paper showing that the bioavailability of this antipsychotic olanzapine was also affected if we wiped out the microbiome, or we gave a probiotic. So there was differential effects there. And it's really exciting, again, not so much yet in neuroscience or in Psychiatry and Neurology field. Yes. Both in oncology. Right, today, people are starting a trial, people are starting a treatment for melanoma will take checkpoint inhibitors, the efficacy of them, checkpoint inhibitors will be dependent on their microbiome composition. And that is really, really dramatic. And so that the the question we're also interested in, this is work my colleague, Dr. Clark and I are doing right now into the future, we're looking at the side effects of some of these chemotherapeutic agents, brain fog, cognitive changes, social effects, you know, could these be driven by the data about what these drugs are doing on on the microbiome? And, you know, it's opening up a whole new potential in that regard?

Nick Jikomes 1:08:17

And what was the number that you cited for the percentage of drugs in a typical pharmacy 20,

John Cryan 1:08:22

approximately 25% of a quarter of all drugs and pharmacies in this paper where they looked at 1000 drugs. Now, this was all in vitro. So it wasn't, you know, we were doing our stuff in animals. They just didn't I mean, you know, but but they went for the, you know, we had nine drugs that 1000, you know, so they went on breath over. And it's really exciting to think that, but it's also worrying so. So the question is for any drug now, is it side effects could be due to collateral effects on the microbiome? Or could its efficacy be enhanced by you know, and so understanding and, and this is also relevant to foodstuffs, because foods, most of them are chemicals, not a million miles, you know, so if you take polyphenols in your, which are all the color in your vegetables, if you take them into your diet, they get broken down into flavonoids and then into other and they get broken down by the microbiome into other chemicals that can have other effects. And so So, you know, it is something that that that's receiving a lot more attention. Now. We're also interested in environmental chemicals like pesticides and what they're doing and how they're being taken in and how they're been acting on the microbiome and could have a long term effect overall. Yeah, it's, as I like to remind people everything is connected, I guess.

Nick Jikomes 1:09:46

It would be so it'll take me a second to build this up. But it would be shocking to me if there weren't some drugs that weren't directly metabolized by some some of my that can be in the microbiome. And I wonder, you know, if there are any clear examples where say, you give drugs to, to a group of people, or you give drugs to a group of animals? And if there are multiple cohorts of animals in terms of microbiome composition, are some of those drugs being made active by some of those core cohorts?

John Cryan 1:10:23

That Oh, yeah, no, but but people have been using Pro drugs for years. So that can be broken down in the treatment of IBD. And varices. The variety of drugs that are that are they use microbial metabolism as part of their delivery device, because you wait till they get to the to the small intestine or whatever else. And so that is already happening in pharmaceutical sciences.

Nick Jikomes 1:10:46

Interesting. So So, I mean, that would imply that sometimes when a drug does or does not work, it may or may not be because of the drug, per se, but because, you know, maybe the active ingredient wasn't there, and some people because they didn't have the microbes for it.

John Cryan 1:11:00

Yeah, I you know, it? Well, it could be it could be, and that's definitely what's happening in some of these cancer treatments now.

Nick Jikomes 1:11:09

So what does that so

John Cryan 1:11:11

like in with these newer checkpoint inhibitor treatments? In cancer, if you don't have the certain microbes, these drugs are not working? Hmm, interesting. And that's probably more to do with the immune system, though, that's probably more to do with, with immune tolerance and various other things. And so what they're doing, there's a study on last year where they took a fecal transplant, and were able to change the microbiome and then be able to, to get the drug to be working.

Nick Jikomes 1:11:38

Interesting. One of the things, you know, one of the common denominators based on all the things that we've touched on so far seems to be the diversity of microbiomes. So within an individual so you know, you talked about the differences between people like us and hunter gatherers, you talked about old versus young. And it seems in almost every case, like a more diverse microbiome is better and more homogenous one is going to have that with

John Cryan 1:12:02

one exception. Hmm, one big exception in early life. So in early life, they ideal microbiome is the least diverse. Because so we know this from studies where we compare vaginally born breastfed infants, compared to C section born Bockingford. Infants, for example, at two extremes there, you know, and what we want in early life is we want a lot of the bacteria, the good bacteria that are just there, we don't want diversity, we just want things that are just going to be doing the good stuff. So we have these back Bifido genic bacteria that are there to harvest the goodness out of breast milk, for example. And so that's an example where less diversity can be, but you're right, on the whole as we age, then you want like in all aspects of life, diversity is really important. But that's just an interesting exception in their lives.

Nick Jikomes 1:13:07

So you know, on the subject that you just alluded to, when you think about an infant child, and their ability to metabolize the natural food that they're going to consume, which is breast milk. How much of that is it sounds like a lot of that is microbiome connected? And how much of the infant's microbiome is being inherited through the birth process itself?

John Cryan 1:13:27

Oh, these great question. Um, so two parts there, let me deal with the breast milk first, because it was really surprising to me many years ago, when I learned that human breast milk is among the most complex of all types of milk milk that can be in the mammalian world, but 20 times more complex than than that of bovine milk, which we use in formulas. And so evolution doesn't give us complexity without some reasons. Usually, what was really surprising was that these sugars that these complex sugars is human milk oligosaccharides that, that I'm really alluding to, when I talk about complexity, that these sugars cannot be broken down by, we have no capacity to break them down in the body. Hmm. So why would evolution do that? And the reason it evolution is doing that is because the microbes were there first, and the microbes are there are doing that job. And so microbes take these human milk oligosaccharides and break them down into key chemicals like cyanuric acid. So like acid is a really important part of brain development. So there that is really intriguing data, and it may and I put all caveats out there, but it may reflect why breastfed infants in large scale population studies show a little higher IQ than bottle fed. infant's overall population wide. It also is in line with work that Jeff Gordon's group have been doing in Sub Saharan Africa, where they've been looking as in moms that are not able to produce this milk, that there is a less of the sciatic acid being formed in the infants. And then there's stunted growth and cognitive decline, and all of that being driven through this lack of a prebiotic, which is essentially what these human milk oligosaccharides are. And they've done elegant work over the years, both in the human population but also in mouse models and pig models to really show this injury, let interrelationship between the microbiome, and the diet in driving brain developmental change. And it offers, you know, huge ramifications for our public global public health policies, in terms of how we manage that. So it is quite, you know, it's, you know, we work a lot with industry in Ireland is our funding model in for researchers is very much an applied aspects, we often work with industry, and often these industry are trying to make, you know, recapitulate human breast milk in some way. And it's just such a hard job, you know, because nature has done it so well, for it for what it's doing. And we have relatively little breastfeeding rates in Ireland. So it's one of these things we really need to get across. Regarding the other part of your question, which was about vertical transmission, or? Yeah, I think I think this is a really important question. And we we we now, you know, we know a lot more about this, I like to refer to some baby during pregnancy, the moms microbiome changes, it adopts to the needs of the mom metabolically in every other way. But it's really getting ready to be handed over at birth, as a kind of a birthday present to the infant to basically start programming the infant's immune system. For the most part, the infant is taught to be sterile and neutral, and gets the microbes as it emerges through the birth canal. And when in that, then this is kind of a really good example of potential epigenetic modifications that are going to guard because we get vertical transmission from from one generation to the next, the activation of the immune system starts pretty rapidly. And therefore, anything that upsets this switch has been born by C section, which you basically have a when you kind of drop the baton, in evolutionary relay race, and are antibiotics. Not breastfeeding, all of these things will factor in relatively to change these early life microbes that will program the developing immune system and body overall. So we are, you know, one of the that's one of the the other things, and from a public health perspective, there are certain countries where C section rates have just gone skyrocketing. Brazil is, you know, parts of Brazil, 70%, China, but even in Ireland, it's doubled in 30 years, parts of the US it's gone really, really high. And so the question is,

you know, what are the consequences of that. And so we, as I mentioned earlier, we worked on our animal model of this and show that there are enduring effects. But we just published the paper, which is another one of these papers that, you know, take it with all of the health warnings, it's a small study, but it shouldn't have worked, but it did. And we got funding for it. Where we took 40 I was gonna say normal, but Irish medical students and stratify them based on their motor delivery. So we put 40 C section 40 of Johnny born, and we bring them into the lab, and we have really good ethical ways of stressing people. And so we found that those born by C section respond to acute stress from an immunological and behavioral point of view much greater. We also then wanted to look at chronic stress. And this is before the pandemic. So we wanted to see, you know, how can we, if how could we, if people were born by C section, would they have a different response to chronic stress. And but we have to do this in an ethical way. And the best way we had as educators is submit our students to exams. And so we can chart a variety of biomarkers over the examination period. And we found for example, like the Colin's perceived stress scale, which is a very well invalidated. marker of stress was really higher over the exam period, and those worn by C section versus not. Now, again, this is many other things could be a play here. We don't know why they had to have C section. This was you know, some time ago, but our animal data backs it up very nicely and shows that the microbiome is what's playing because in the animal studies, we could reverse these changes the social deficits by fecal transplants and by feeding With bifidobacteria. So these two questions you ask are really relevant to this perinatal critical Windows idea. Because we in neuroscience, we talk about critical windows a lot, from visual development, to sensory, and cotton and cognitive development. But there's probably also a critical window in our microbiome that we really need to watch, and how these two talk to each other is going to be really important.

Nick Jikomes 1:20:25

So I mean, based on everything you've said, and just all of the interconnectedness here, you know, have we just have you ever thought about just how much, you know, in modernity, we've essentially just completely removed ourselves from the ecological context that our species evolved in for so long? You know, how does that make you feel in terms of your optimism or pessimism for our species? Because when you look at all of the chronic conditions, whether metabolic or psychiatric, and how much of this is just due to us, you know, basically inventing our way out of the ecological context that all of this stuff was was formed? It

John Cryan 1:21:02

is a great question. And I do think about it in in different ways. One is in the last few years, what we've just done, you know, we're just look at what we've done, at least here. We we've had multiple lockdowns, social isolation, you know, changed our whole social behavior, and then cleanliness, and all of the effects we're having on our microbiome, even when we do so we're affecting our microbiome, and we're affecting our social behavior. There will be many PhD thesis in the future on this from from a sociological and other ways. So I do reflect on it. In that regard, am I optimistic about us as a society? I am? Because I think, you know, we are still a social species, and we want to talk and people are want to listen to to you, Nick. And so I think, you know, yes, we're doing things to damage our world, but we've been doing it, you know, for centuries, and will continue to, and we will continue to have wars and will continue to have pandemics and various things. And we will prevail. We are living longer. We are living probably healthier. We're just understanding this more. But as long as we remember, the microbes were there first, and we need to look after them.

Nick Jikomes 1:22:27

So one of the last things I want to ask you about is given all of your experience and everything that you've learned, how has that affected how you look after your own microbiome?

John Cryan 1:22:39

Yeah, everyone asked me that. Yeah, no, it does make me more aware of what I'm doing. I'm also, you know, do I take probiotics? No, do I? You know, I, you know, my lifestyle was also changed a lot over the pandemic, but I used to be on a plane like three times a week, and you know, you're running around, it's very hard to be looking after your gut. If you're in an airport all the time, I can tell you that. So so with the pandemic, it got me to reflect a lot more on my own health as well and understanding what I need to do to appreciate with it. And with my kids, as my kids get older, I'm trying to foster in them. The one thing I do the people always want to know what what does he do like, like I could say, you know, the, you know, there are things that I can tell you are good for your microbes, but I don't necessarily do them. But the thing I do is I take fermented foods, which we have no culture of in this country in Holland at all, but I take milk kefir, and try and have it every day and the days I you know, the days I haven't had the last few days because i i bought milk kefir, kefir keys. What is that? Ke Fitr. So this is a fermented grains that you have, it's a ball of bacteria and yeast. And it's one of the three Ks i the kombucha kimchi and kefir, or like the three fermented foods that people talk about, overall, why I why I mentioned fermented foods is they don't cost anything except the what you put them in. So you have kind of Water Kefir or milk kefir. So if you buy milk, that that's the only thing of the day, and you ferment it overnight. And you take it every day. And it's really, it's really good for your microbes. And we've done studies in animals where we've given kefir to some mice with autism, and they have better social behavior, mice with autistic related symptoms after and, and we've shown that if they have positive effects on stress, we've done a study in students where we've really ramped up their levels of caffeine and fermented foods and also the levels of fiber and we've shown that their stress levels and their sleep quality gets much better. So but the good thing about it is that it's a solution that you when you know we can offer to people that might benefit from it most, you know, not everyone wants to solutions that are going to be in Whole Foods. So you need to come up with, you know, for certain populations, you need to democratize, we need to democratize gut brain Access Health. And so that's why I also like to tell people about

Nick Jikomes 1:25:16

it. Tastes like is like so

John Cryan 1:25:20

the here's, I got a trick on this. So, so my wife used to like it a lot night and I was like, Oh, God, you know, but so it tastes a bit like buttermilk or sour, you know, it's a tangy flavor. But what what I do is I ferment it overnight, and then I leave it in the fridge for so you drink it cold and and then I put in some other yogurt flavored yogurt and within other people, but honey are some you know, and then it tastes like the yogurt just went to Tang. It's a tangy, you know, thing flavor on it. It's really good. It's really good.

Nick Jikomes 1:25:54

I see. And when you say you fermented overnight, like what exactly does that involve?

John Cryan 1:25:59

It means you take milk and you put it into the milk. And it's really, it ferments the milk?

Nick Jikomes 1:26:06

I see. Okay, so you're adding something, you're buying something that you add to milk and basically just let it sit for a while?

John Cryan 1:26:11

Yeah, yeah. And then you keep it again, like so. So it becomes your own people have these these like to do with kombucha, they have their own mothers that they they see you keep the these key programs, and you put them into the next one milk, and they grow, and they grow and then you give it to your friends. And then and then it becomes you know, it travels with you like that, you know, copy of Ulysses you'll never read, you know?

Nick Jikomes 1:26:35

I see. And does this only work with like animal milk? Is there a particular like a works

John Cryan 1:26:43

best with with it does work best with with with animal milk, I don't think it works so much with plant based milks to the same level. But there are other there are other Fermented Plant drinks and other fermented I just think fermented foods, you know, people think of them as sauerkraut and, and things that are not that flavor, some and pickles and stuff, but they're a really good way of really giving bacteria back to your Gosh, interesting. I have data now and animals and humans, I'm really, and we're, you know, I we have a really nice team now working on this to do more comprehensive studies, and we've just got some funding from the US to look at this. And it's really exciting to in humans to see, you know, the temporal effects of what's changing, and how is it changing in individuals versus otherwise, the other thing that in relation to practical aspects is in circadian rhythms and understanding the relationship between sleep and the microbes, and, and so see my microbes. So it may not just be watching, these are what your microbes eat, but when your microbes ease, so my microbes are just so you know, they love carbs, they just do. And then you know, but you know, so the but it's one of these things, personally, that I think some of the beneficial effects of intermittent fasting, time restricted eating, etc, is now being seen to be driven by the microbiome. And we're really investigating the brain level, at the level of super cosmic nucleus in terms of clock, signaling and trying to understand this, because I think, again, everything being connected, but sleep, and the microbiome is really relevant. And that's why I don't miss my jetlag days at all.

Nick Jikomes 1:28:30

Interesting. Is there any I mean, I'm sure you've got a bunch, but what's what's like one area right now that you guys are actively pursuing, that you think is going to be really exciting, just in terms of giving us some interesting results in the near future?

John Cryan 1:28:43

Okay, so we didn't talk. So we, I pretended to talk to you about the microbiome for this last hour and a half. But I actually only talked about the bacteria. So, so one of the things I'm really excited about right now is an area of the microbiome called driven by bacteria, phages. Bacteria phages are viruses that target bacteria. So what if you have bacteria you don't want and, you know, one of the best ways is to get viruses to selectively kill them. And we, you know, we bought viruses, we've got a bad rap. Now with COVID. But like, not all viruses are bad. And so this is a really exciting way. And that's something that we're working on right now, in our animal models to show that maybe some of the effects of stress, you know, could be alleviated through this type of mechanism. Really precision, interesting, going to change a little bit how we think about these things. So I'm excited about it.

Nick Jikomes 1:29:45

Interesting, but the basic idea is, if you've got certain bacteria phages that are adapted to infecting and killing specific species of bacteria, you could you could leverage that to alter an animal's microbiome in a beneficial way.

John Cryan 1:29:59

Yeah, Yep, are you take them like one of the experiments we're doing is we've taken the microbes before you get stressed, or before you go to a negative, and you take the bacteria phages from there, and then you put them back in at the end and make sure that they're able to, to work again and be able to counteract some of the effects.

Nick Jikomes 1:30:21

Interesting. Well, we covered a lot of ground. John, thank you for your time. And if you have any, any parting thoughts you want to leave people with? Go for it?

John Cryan 1:30:31

I'm not really I mean, I mean, it's been a real pleasure, Nick, and thanks for chatting with me. Overall, I guess you know, the things I like to remind people is that, unlike your genome was you not allowed you can do about except blame your parents and your grandparents. your microbiome is potentially modifiable, and that gives you great potential agency, but we have a long way to go. There's a lot of snake oil out there. Watch out first, look for evidence based look for where this data to support claims and data to support things. And if someone is telling you something, be careful. That's kind of where I'm leaving.

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