Updated 17th November 2022

How your gut can change your mind

In a lab in Ireland, a group of scientists stand around a stainless steel table. One is holding a device not unlike a small turkey baster.

His free hand plunges into a box on the table and pulls out a mouse. Using his device, he administers a brown solution rectally. 

This mouse has just received a fecal microbiota transplant. The donor was not another mouse, but a human being. And the person in question had symptoms of severe depression. 

In today's episode, Jonathan speaks with Prof. John Cryan, an author of the study, which showed a relationship between the gut and the brain.

Listen in to learn more about his fascinating research, how microbes may affect our brains, and how to eat to appease your gut bugs.

John Cryan is a professor at University College Cork and a world-leading researcher who looks into the relationship between the brain and the gut microbiome.

If you want to uncover the right foods for your body, head to joinZOE.com/podcast and get 10% off your personalized nutrition program.

Other episode transcripts are available here.

You can follow John on Twitter.

And you can follow ZOE on Instagram.

This podcast was produced by Fascinate Productions.

Transcript

[00:00:00] Jonathan Wolf: Welcome to ZOE Science & Nutrition, where world-leading scientists explain how their research can improve your health.

If you're listening to this, you probably know there's a community of bacteria living in your gut, and you already know how they impact your health, right? You may be less aware that right now these microbes might be affecting your mood, your brain speed, and even how your brain ages.

In a lab in Ireland, a group of scientists stands around a stainless steel table. One of them is holding a device, not unlike a small turkey baster. He inserts the tip into a vial of brown solution and sucks up a tiny sample. His free hand plunges into a box on the table and retrieves a mouse to whom he administers a solution... Rectally. 

This unfortunate soul has just received a fecal microbiota transplant. The donor was not another mouse, but a human being, and the person in question had symptoms of severe depression. In the days and months after this procedure, the scientists kept a close eye on our rodent friend and countless others who'd undergone the same procedure. As it transpires the microbes have had an effect. These mice can no longer derive joy from food.

By demonstrating behavior change through microbial transfer, this study proved a relationship between the gut and the brain. Although using mice, this is evidence that the same could be true for humans. Today's guest, Professor John Cryan, is the author of that study. He's a professor at University College Cork and a world-leading researcher into the relationship between the brain and our gut microbiome.

Professor John Cryan, thank you for joining me today. And why don't we start, as always, with a quick-fire round of questions from our listeners? Let's start at the beginning. Do you believe our gut bacteria affect our brains? 

[00:02:18] John Cryan: Yes. 

[00:02:19] Jonathan Wolf: Could the microbes in my gut influence my behavior? 

[00:02:23] John Cryan: Yes. 

[00:02:24] Jonathan Wolf: If I'm stressed a lot right now, does this mean I have a bad gut microbiome?

[00:02:29] John Cryan: Potentially.

[00:02:30] Jonathan Wolf: Should I give my children probiotics to reduce their risk of mental health conditions? 

[00:02:36] John Cryan: Unlikely. 

[00:02:37] Jonathan Wolf: Could poo transplants be a medical prescription in the future? 

[00:02:41] John Cryan: Yes. 

[00:02:42] Jonathan Wolf: What are three things that anyone can start doing today to improve their microbiome and their mental health? 

[00:02:49] John Cryan: So, it's diversity like in all aspects of life is key. Increasing the levels of fiber, and fermented foods in their diet, and then reducing things like processed foods and things that we know negatively affect their microbiome. 

[00:03:03] Jonathan Wolf: All right. Well, I think we're gonna dig into all of those over the rest of the podcast. And I have to say, for some of our listeners who joined us on a previous podcast, we had this fascinating discussion with Felice Jacka on food and mood.

I'm really excited to sort of dig deeper and understand the role of our gut bacteria, this gut microbiome, not just in mental health, but sort of the brain overall. And I think we've got the best person on the planet to help us with that. So maybe we could just start at the beginning. You know, are there links between the gut and the brain?

[00:03:33] John Cryan: Yeah. I mean, it's not that new, although people in my field of neuroscience think it's quite new. I mean, it goes back to Hippocrates who thought that all diseases began in the gut, but what we know now, and there's been an evolution over the last two decades, I would say, is that there is now concrete evidence that the composition of the microbes in your gut influences brain development, influences brain function, and can help steer the brain in specific ways. 

The evidence is coming, largely from studies in animal models. 

[00:04:08] Jonathan Wolf: And John, just to make sure everyone understands, an animal model, what does that mean? 

[00:04:11] John Cryan: Usually a mouse or a rat. So because we can get mice that can grow up without microbes ever having a microbe, you know, if you want to find out if something is important in a process we know from engineering or other areas of biology that if you take it out and see what happens, it's probably one of the best ways to see if it's important.

So mice that have grown up without bacteria, allow us to answer the question is the microbiome relevant, yes or no. And studies from our lab and other labs over the past decade or more have shown that in these mice that grow up without any bacteria in their gut, their brains don't develop normally.

[00:04:48] Jonathan Wolf: That's amazing. And do you find special mice that you found somewhere in the world that grew up without any gut microbiome? Is that how you compare this? 

[00:04:56] John Cryan: No, this is an unusual lab-based situation. So these animals are kept in this ultra-sterile condition where they've never been exposed to microbes.

And this concept goes back to Louis Pasteur. He's first tried to do these, work with these types of mice and they are not really translatable to anything human. Maybe the exception is the boy in the bubble that Paul sang about in the 1980s. These mice in the bubble, allow us to have this specific question, is the microbiome involved? Yes or no? 

[00:05:27] Jonathan Wolf: Got it. So it's quite unnatural is what you're saying. You have to create this incredibly sterile.

[00:05:30] John Cryan: Yeah. 

[00:05:31] Jonathan Wolf: Situation because we're constantly surrounded by these bacteria who want to get into us and presumably these mice. So, you create this incredibly sterile situation to discover what happens if a mammal grows up without any bacteria?

And that's what you're comparing then with a normal situation for mice and, and I guess for us, right? Which is, we're stuff full of trillions of them. 

[00:05:52] John Cryan: Absolutely. And our group and the group of Rush Heights in Karolinska and Jane Foster in McMaster, well over a decade ago, all showed roughly around the same time that these mice have messed up brains in different ways in terms of their behavior, they respond differently to stress. We show that they don't have proper social behavior, that they don't have proper fear learning, and that their pain processing is different. So they've given us a real entry point into convincing us that there's something about microbes and brain function that we need to pay more attention to.

And that's taken us on this journey that my lab has been on for well over a decade. 

[00:06:31] Jonathan Wolf: And John, one of the words that I think we often hear is like gut-brain axis, which is a great sort of phrase, which I don't really understand what it is, but I'm hoping you're about to explain. Is that this or is that something different?

[00:06:45] John Cryan: Well, yeah, so the gut-brain axis has been long, long known. It's basically how signals from your gut go to your brain to change your behavior. Now, that's been very well studied in the context of food intake. Because we take food into our bodies. But the reason we do that is in response to hunger signals that come from our brain and then we take it in and then we stop eating based on signals that are telling us we're full and they're also brain-derived.

And so the gut-brain axis has been around for a long time, mainly in that context. Then people started being more understanding of disorders like irritable bowel syndrome, which is a very common, unloved disorder associated with abdominal pain and bloating and various other functional side effects, that this is really a disorder of how our gut and our brains talk to each other. What we now think of is a microbiome-gut-brain axis. So the microbes are the new players. So it makes things even more complex and what we're trying to figure out is how the microbes in the gut talk to the aspects of gut-brain signaling to change brain and behavior. So it's a new dimension, a new player if you will.

We have to think that the microbes were there first, and so that's an important aspect of all of this in our learning. From an evolutionary perspective, microbes were there and so there's never been a time when our brain or our gut existed without microbial signals. So we kind of have to contextualize that.

And we're very human-focused in our primacy of what's the most important. But, you know, we have to remember also that the mitochondria, the powerhouses of cells, you know, are actually microbes that got lost into the cells. And so there's such a close relationship between our microbes and everything through evolution.

And so once you start contextualizing, in that way, it's probably not surprising that the microbiome could play such a key role in so many aspects of our physiology and our behavior. 

[00:08:47] Jonathan Wolf: So, just to make sure I got that, what you're saying is, hey, the microbes were there before there were any human beings. In fact, before there were any mammals.

And so, you know, even from the very beginning of building this gut, there would've been microbes there. So it's hardly surprising that they are a sort of built-in feature if you like, of our body rather than how, you know, I think, we obviously all thought about them until a few years ago as a sort of irrelevance.

[00:09:13] John Cryan: Yeah. Absolutely. 

[00:09:15] Jonathan Wolf: So I think lots of listeners have asked this question about, well, how does that work? Because I think they can understand that your microbes affect the way you digest your food. They're in the same place. That makes sense. But you know, my gut and my brain are in two different places. Bacteria are really small.

How do these bacteria affect what's going on in my brain? And I know this is something that you study. 

[00:09:37] John Cryan: Yeah, and it's a large part of what our lab is focused on, is really trying to delineate the mechanisms and pathways for its communication. And there are a number of ways. First of all, it's worth noting that within our gut we have a second brain.

This is called the enteric nervous system, and this second brain has more nerve cells than our spinal cord. The enteric nervous system is very important for digestion, motility, and various aspects of gut function, but it's also a really good conduit for signaling directly to the brain. So that's an important first path on it.

The second thing is we have a nerve. It's one of the major cranial nerves, which then signals from the brain to all the organs and from organs back up to the brain. It's called the vagus nerve. Now vagus comes from the Latin for wandering. It's the same derivation as vagabond or vagrant. And this nerve is really well poised to be an important highway of communication between the gut and the brain and between the microbes and the brain.

And so over a decade ago, we showed together with the late John Binstock's lab, that when you cut the vagus nerve in a mouse model, we sever all of the effects of a specific lactobacillus bacteria on brain and behavior were gone. So as I like to remind people, this tells us that what happens in the vagus doesn't just stay in the vagus, but will actually affect our emotions in certain ways.

[00:11:01] Jonathan Wolf: Okay. I love that. So I've got a vagus nerve inside me, which, a bit like Vegas, all sorts of bad things can happen and come back to haunt me afterward. Related to this, you recently published a paper where you described the microbiome as the chamber of secrets, which I absolutely loved and I think sort of fits in with this story.

Can you explain what you meant by that before we move off and start to talk about how this then links obviously to mental health conditions and things like that?

[00:11:28] John Cryan: Yeah, that was driven by a student in my lab, Sofia Cussotto, who was a real Harry Potter fan and really wanted to relate some of the mysteries of what's going on within the microbiome to the basilisk in the Chamber of Secrets.

But secrets are things that we just don't know enough about right now, but that is hidden within. But they have the potential to unleash a lot of both positive but also potentially negative aspects. And we were very interested in that paper really in understanding the relationship between medications that we take and the microbiome.

We talk a lot about harnessing the microbiome for positive aspects of brain health, but also could there be a relationship with some of the side effects of certain medications, and could this be kind of one of the secrets there that could be looked at? And indeed, about 25% of all drugs in pharmacies today have some effect on the microbiome.

[00:12:22] Jonathan Wolf: 25%. That's amazing. 

[00:12:24] John Cryan: Yeah. And so when we work in mental health where there are chronic treatments, we want to know, well, what are they doing to your microbiome? And could this be, you know, part of what's going on in the context of some of the side effects? And that's something that we're very interested in looking at, particularly in the context of some of the obesity-related metabolic changes that occur with antipsychotic medications.

And, we've just got funding now from the health research board here in Ireland to do a study to see if could we attenuate some of the effects of antipsychotic medication by targeting the microbiome. So it may sound a bit out there, but the best example of this is actually in oncology in cancer treatment where some of the newer immunotherapies for cancer, the effectiveness of some of these has been shown to be dependent on the composition of the microbiome.

So we're now beginning to see that there's a whole area, what we call pharmacomicrobiomics, that's unlocking some of these secrets that have been able to tell us that maybe we may need to, in addition to the efficacy and safety of drugs, we may need to also understand how they can have collateral effects on the microbiome.

[00:13:32] Jonathan Wolf: So it's amazing. I think we talk quite often on this show with many different scientists about this idea of the microbiome as this whole new organ that basically no one really knew mattered 20 years ago, and talking today about the brain, which is very different from many of the topics we talk about.

What's interesting, therefore, is you're now starting to focus on, well, hang on a minute, we're giving all these drugs to improve our health, but actually, maybe they're having this side effect on this organ. 

[00:13:56] John Cryan: Yeah. 

[00:13:57] Jonathan Wolf: That we didn't really even know existed 20 years ago. So it's hardly surprising that we never thought about the impact of some drug that I might have taken for a particular disease.

And I think you're painting this picture, if I understand rightly, John, of the microbiome is so central in how it creates these chemicals. So if you're starting to reshape it, if I understand right, you're saying that might be part of the reason you're getting these side effects. 

[00:14:20] John Cryan: Yeah.

[00:14:20] Jonathan Wolf: Does that explain why so many drugs - the side effects are very personalized, we're obviously very interested in personalized responses, but one of the interesting things, you know, I think whenever you open up a drug, right? It says, you know, one in five people get this side effect. One in 20, get this one in a hundred. Is that related to the microbiome or is that something else completely? 

[00:14:39] John Cryan: No, no. Potentially. Like anywhere we see individual responses. I think we have to look at the microbiome as being a potential driver of that. Genetics is another part, you know, and certain epigenetic factors and environmental factors. So, but it's kind of like that trifecta that we need to really understand the microbiome is a part of that individual response.

And so we need to do them studies to be able to really understand that and that's what's happening now in cancer. 

[00:15:04] Jonathan Wolf: And this is still very early, right? We should say to our listeners, I've had a few discussions with some other scientists, and cancer, I think, is one of the areas where people are obviously very focused on it.

I've seen a lot of excitement. This is not yet figured out. You're not going to be able to go and talk to your physician to discover the impact of a particular drug on your microbiome today. 

[00:15:23] John Cryan: No, no, no. But there may be practical things that people who are on medications who have, let's say, side effects such as weight gain, may be able to look at in terms of looking at the microbiome as a way of resolving some of the other side effects. And we need a lot more data. 

[00:15:37] Jonathan Wolf: Fantastic. And we were definitely gonna come to actionable advice a little bit later in the podcast. Before I do that though, I'd love to talk a bit about sort of mental health issues. You've just talked about how it supports a sort of healthy brain function. Are there links between our gut microbiomes and then, you know, mental health conditions like depression and anxiety?

[00:15:57] John Cryan: Yeah, I mean, again, the field is emerging overall, but we're beginning to see a certain level of consensus coming through. I guess the early studies were quite small, but now we're, we're seeing larger-scale studies and we need a lot more large-scale longitudinal studies. In some of the larger cross-sectional studies, people have identified clear microbial signatures, and so when some recent meta-analyses have been put together, for example, in depression, but even across multiple diagnoses, there seems to be for where there's negative mental health occurring, that there seems to be a lack of diversity in certain bacteria and in particular, there seems to be a lack of bacteria that produce short chain fatty acids.

These are the types of chemicals that our body can't make, and we have outsourced this to bacteria. They provide essential energy for the cells in our gut and some of our immune cells, but they may also be very relevant for blood-brain barrier function and maybe direct effects on the brain.

And so if we lack the bacteria that are producing these, there are maybe issues in terms of predisposing to mental health disorders. Now it's early days, but slowly we're beginning to see consensus there. Other evidence for a role in depression and anxiety comes from work that we did and work from Channel Burik Group in Canada where we've taken people's microbes, who are suffering from different mental health disorders and transplanted them again into mice or rats and these animals start to display symptoms of depression or anxiety. And so that was really remarkable. 

[00:17:39] Jonathan Wolf: Just to make sure that I guess we all follow that, that's not just because suddenly you went and put like the bacteria that are inside humans into a mouse. Explain a little bit because I think people will be fascinated.

[00:17:51] John Cryan: This is an older study we did where we took the microbes from people who had depression and we transferred them to, in this case, it was rats, and we took the microbes from people who were not suffering from depression, who were healthy controls and rats that received the microbes from the depressed individuals changed their behavior in ways that we were really surprised.

So rats and mice like sugary solutions and they'll be able to distinguish a sugary solution from a non-sugary solution. And when they got these microbes they no longer found any pleasure in the sugar and weren't able to go there. Most also notably we associate depression with an increase in inflammation.

Depression could be seen as a chronic inflammatory disorder. And so when we transplanted into the animals, the animals also developed an increase in inflammation. And that was quite remarkable. And then they also, we looked at their brains and saw changes in their brains as well, So, It becomes quite a fascinating area that we're able to transfer the blues through the microbes.

[00:18:49] Jonathan Wolf: Which is amazing, right? Because you know, I grew up like, I think a lot of people with, you know, my parents and my grandparents, basically not really believing in mental health, right? This is just sort of stiff up a lip, get on with it, keep going, and you can take these bacteria, you can implant them into somebody else, like just as if you'd taken a virus or something and you've given it to somebody else.

So I just wanna stop there for a second, because that is really remarkable and does really force you to think about this in a different way I think than people did in the past. 

[00:19:23] John Cryan: Absolutely. Absolutely. And, it helps to prove causality because one of the issues we have in the field is like, well, what's causal and what's not?

And like we were really surprised by this and more and more studies are emerging across a variety of mental health disorders showing that you can, there's something in the microbes that are affecting physiology in a way and it helps prove it, overall. And so it is quite remarkable. 

[00:19:47] Jonathan Wolf: And are you saying that the microbiome is the complete cause of mental health issues?

[00:19:54] John Cryan: No. No, No. And we don't know, is it the cause or is it driving the consequences either? You know, this helps to add to causality mechanisms, but we know the microbes change, but we don't know what's driving the change. So like for example, depression can be associated with early life trauma. But the question is what are the long-term effects of that stress on physiology and could the microbiome changes be part of what's driving it?

[00:20:21] Jonathan Wolf: So you could sort of create a vicious circle where something else starts with the depression. 

[00:20:26] John Cryan: Yeah.

[00:20:26] Jonathan Wolf: It leads you to this microbiome, which is no longer healthy, which then, reinforces it, which is why you can implant it into mice. But it still might have started somewhere else. 

[00:20:37] John Cryan: Exactly, exactly.

[00:20:38] Jonathan Wolf: Got it. And so if that's the case, does that mean that if you just improve the microbiome, you can't improve the mental health symptoms? Or actually, can you improve the mental health symptoms by directly trying to improve these chemicals that are being created by these microbes? 

[00:20:56] John Cryan: So that's the key question, Jonathan.

[00:20:59] Jonathan Wolf: And our listeners want to know the answer, so. 

[00:21:03] John Cryan: So it brings us to the whole area of what we call psychobiotics. Psychobiotics is a term we coined here in Cork. My colleague Ted Diamond and myself and psychobiotics are targeting the microbiome for mental health benefits.

We initially focused on bacteria strains as being the way, but we now know there's an increased repertoire of strategies that we can use to use microbial interventions for our mental health. The simple answer is potentially, and hopefully, and we're very optimistic, but we need a lot more data. Some of the early signs are really good there are studies you can find and lots of studies showing that certain strains of bacteria will have positive effects on mental health and increase in humans.

So that's good. But the big issue here is why you select one strain of bacteria over another, and how you get into that, basically precision aspects of it overall, and I think the field has been neglectful of trying to understand why you would choose a certain intervention for a certain trial.

However, when people do lump everything together, now, I hate lumping, but you know, so far when they do meta-analysis and look at all the studies that have been published, there seems to be a signal of a positive effect about probiotics. So, these are live bacterial strains or prebiotics, which are basically the dietary substances that support beneficial bacteria from blooming that have positive effects on anxiety and depression overall. 

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I think we're not there yet. I think we have a lot of ways to try with some more precision, select the right strains of bacteria and test them more longitudinally in larger-scale studies and understand why certain people may respond to a certain bacteria and other people not in this way.

So that's kind of a lot of activity in this field right now. But for the consumer, it's challenging because all of these bacteria sound the same. And so when you go to a health food store and you see all these drains, it becomes quite tricky to understand because the science hasn't been there for all of them.

And so what I tell people is ask the question, has there been a human study done with this strain of bacteria or combination to support what you're taking it for? And if it hasn't, then it won't do you any harm probably. But it's probably no evidence that it's going to do you any good. 

[00:23:28] Jonathan Wolf: So I think the same picture that we see in general, which is the current generation of probiotics is not showing a really big impact in most areas and is that fair to say?

[00:23:41] John Cryan: Well, I would challenge that. I would just say they haven't been tested. They haven't been tested. So people haven't done the studies. So, you know, for me the word probiotic is a bit like the word drug. And so you wouldn't go into a pharmacy and just pick random things that sound the same and say, that might be good for my depression.

And that's what people are doing. They're picking things that are quite randomly sounding the same. The bifidobacteria must be the same. But what we know is these strains of bacteria in the lab behave very differently and the chemicals they produce are very different. And they can sound very similar, but they can a very different abilities to make different chemicals that can interfere and they can have different proteins on their cells to decorate their cells to interact with the immune system in different ways. So it's very easy to be dismissive of what we have currently. And to say it's not good, it's just that I would say a lot of it just hasn't been tested.

Because no one wants to pay to do these studies. To be honest, you can do a lot of this by marketing. And so if you can market things without expensive human clinical trials and then that's been the way a lot of the companies have gone. So I would be advocating, we need a lot more studies and the power of a single strain, we see it time and time again.

So we just have to make sure our selection of the right strain is there. 

[00:24:58] Jonathan Wolf: What about the role of food? Because one thing is to try and get a probiotic, but another one would be to say, could you feed the bacteria you have, different sorts of food to create more of the chemicals? Does that have any effect here? Or do we really need to be in these situations trying to get new bacteria into individuals? 

[00:25:19] John Cryan: It's a great question and it's one that we're very excited to be working on right now as well. I mentioned prebiotics because prebiotics is from your diet and so if you can create a prebiotic or what we've called a psychobiotic diet, so basically a diet that's really ramping up in fiber and fermented foods.

That's something that we were like, Well, if our hypothesis is that the microbes could be affecting stress and mental health and various aspects there, then we should be able, through a whole diet approach, be able to create something that would work. And so Kirsten Berding Harold was a fantastic dietician in my team and we created this diet and we took people that had bad diets and are, were stress sensitive in particular, so our student population, A lot of them fit into that. 

[00:26:02] Jonathan Wolf: You mean they're not eating really healthy foods? Your students? I'm shocked to hear that. 

[00:26:08] John Cryan: So we took them and we changed their diets for one month. Just one month. So it was a short-term intervention, but we thought we wanted something that we could actually test and we looked at really ramping up their fiber, dramatically. Fermented foods, educated them about that.

We also took another group we just gave them some basic nutrition advice, but didn't change their diet. And it was remarkable. After one month on this diet, those that had switched to increasing their fiber, fermented foods had a much better response to stress in the laboratory setting. Their feelings of depression, weren't depressed and none of them had a clinical disorder, but just their feelings on the depression scales that we looked at were much better and their overall sleep quality improved.

And so, what this tells us is that by feeding the microbes, we could actually switch people into being much more resilient to a stressful situation. And that's one month. That's one month. 

[00:27:08] Jonathan Wolf: That's amazing. That's a really brilliant study. 

[00:27:11] John Cryan: So for me, this offers a lot of opportunity and we're getting this ready for publication now and it should be out soon, but it's something that we feel really can help democratize some of the solutions that we're talking about for mental health, because what we don't want to do is just come up with solutions that will be useful for a certain socioeconomic class that can afford supplements and various other things.

We wanna come up with solutions that will help people who are more prone to mental health problems from other backgrounds and really increase that.

And so the great thing about fiber and fermented foods is that they shouldn't be expensive. Kefir, you can grow at home yourself. It doesn't cost anything except the milk or water you use in it. Fiber is present in a lot of vegetables and grains. So we can really do this without going extravagant.

And I think for your listeners, I think it's also important to understand that the big problem always is compliance. So how do you keep people on a diet and keep them motivated for a long period of time? 

[00:28:13] Jonathan Wolf: Totally agree with that. And I think it's an important message that I think, can't be repeated enough, right?

That this is not just about eating food that's super expensive. We've had a number of people talk on the call about like how many tin foods there are that are really high in fiber and very healthy and that we see most people following ZOE's recommendations also receive that. Can I pick up just for a minute on this sort of behavior side that you've touched on here?

Because I think we've talked quite a bit about mental health and depression, but you touched a little bit earlier on some of these studies that you had on, mice and about how the absence of this microbiome was affecting other aspects of behavior, and I just think that was too fascinating not to talk a bit more, and I think lots of people would be listening who were saying, Well, look, I don't have depression or anxiety, so is this relevant to me?

Could you talk a bit more about what aspects of how the microbiome might be affecting my behavior now? Because I'd really love to understand. 

[00:29:10] John Cryan: So one of the things we found, we made this really important discovery in 2014 was that mice, like humans, are quite social. So if you give a mouse an opportunity to spend time with another mouse, they'll interact and they'll have a chat and they'll sniff each other out and whatever else, but not if they're lacking microbes.

They just don't care. Mice like, well, maybe some humans are a bit fickle, so if you give them the chance to spend time with a new playmate versus their everyday playmate, they'll gravitate towards the new playmate.

But again, not if they're germs pre. So that was a remarkable finding for us was that if you want to have normal social behavior, you need to have appropriate microbes in your guts, at least if you're a mouse.

[00:29:52] Jonathan Wolf: That's amazing. And one of the things we talked about before we started recording is sort of this lifespan approach. So actually I think might be fascinated to talk a little bit about like early life nutrition and adolescence. So maybe sort of old age. How would you think about what people should be doing either for themselves or as they're thinking about their children or relatives?

[00:30:11] John Cryan: The important thing is to realize that your microbiome changes as you navigate life naturally. There's a natural change overall in early life. It takes about two years for stability to start to come in and it's really primed to maximize what it can get from milk overall. And then into adolescents. There are fewer studies, but we're beginning to see more and more relationships between the microbiome.

And then we get a stable microbiome unless we shift our environment. And then as we age, then we see deleterious effective aging on the microbiome. We've been showing, for example, that that affects brain health.

So we've been able to take the microbes from young animals and reverse the effects of aging on brain health, and that's been quite remarkable. So we know that we need to mind our microbes for optimal brain health. And so some of the practical things that I would tell people to do that, have some evidence, although we could do it more.

So there are certain things to enrich your diet, and we've talked about them already, which is increasing the levels of prebiotics. Fibers in particular would be really, really important. Fermented foods, the three Ks of kimchi, kefir, and kombucha, but there are loads of other fermented foods and throughout the world, we have a rich cultural history of fermented foods.

And not so much in Ireland, I would say, but in other places. But studies like, Justin Sonnenburg's group and now more recently from our own, have shown that this a science, biology, how these fermented foods are interacting with the host to have positive effects. So really, really doing that.

We know color is great. Polyphenols give lots of foods color and polyphenols are broken down by microbes, but they also act on microbes and can be broken down into really important chemicals. So heavily present in things like onions and grapes and nuts, and also in green tea. And people often talk about it in the context of red wine, of course, but it's also in grape juice.

But polyphenols are really good. There's been an increasing interest in polyunsaturated fatty acids. So these are the PUFAs that are very good for how membranes and cells work, but they also can have effects directly on the microbiome. And so maybe some of the positive effects of these polyunsaturated fatty acids may be really good.

And then there are things we should avoid in our diet or as much as we can, and that's processed food, artificial sweeteners in particular had been shown to have consistently negative effects on the microbiome overall. We know that certain lifestyles and other factors can influence the microbiome. So our sleep and our circadian rhythms and jet lag all have effects. So we need to be careful, about that.

Exercise and particularly aerobic exercise has been shown to have really good effects on the microbiome and potentially then on brain function, overall. Modal delivery at births. So we should, as a public health, should be really encouraging more people to, if they can give birth naturally as opposed to by C-section because there are enduring effects of C-section on the microbiome that can potentially translate to behavior in later life.

And then finally, there's great data now, accumulating from population-wide studies that having a pet and particularly a dog is good for your microbiome, and probably maybe some of the beneficial effects of companion dogs on behavior may be related to their effects on the microbiome and gut-brain signaling that needs to be figured out.

But I think it's really intriguing area, overall. 

[00:33:35] Jonathan Wolf: I just wanna pick up on this sort of older age thing. So if you're listening to this and you want to maintain your brain health, which I think is become an increasing focus for many people, right? As we age and we see all of these problems, is there anything specifically within that or on top of that that you need to do?

Should they all be immediately going out and getting a pet? Is that the key additional activity? 

[00:33:56] John Cryan: Well, it's interesting, a lot of the pet work is coming from early life studies, so there hasn't been much data that I'm aware of in older people right now, and we know the social interactions themselves by living with someone else through microbiome starts to shift and change.

The best study on old age then has shown that things like the diversity in the diet are what gives the best health outcomes in the context of frailty and other medical outcomes. There's been no reasonably good data yet on brain function as we age in humans, but studies like the new age study and the Elma studies, which would really support this increase in diversity of foods and Mediterranean-style diets are really good for your microbes.

So, therefore, they should be also good for your brain.

[00:34:42] Jonathan Wolf: That makes sense. And what about adolescence? I think you talked about like a big shift going on in the brain at this point.

[00:34:48] John Cryan: So the adolescent brain is really a brain that's still under construction. We often forget that our brain goes through quite remarkable changes during this period.

And basically, it's a period where the brain has to decide what to keep for the rest of life. So there's a lot of what we call pruning, so synaptic pruning, where basically our immune cell is saying, ok, keep or not keep, what's going to be essential for what you need to keep you going.

[00:35:13] Jonathan Wolf: So this is where my son decides, or you know, to discard almost all the advice I've been giving him up to this point is it? It's pruning.

It's like, Oh, my dad is so boring. I just, let's ignore that.

[00:35:23] John Cryan: And if we disturbed these pruning processes, then you can increase susceptibility to a variety of mental health problems, which start to emerge in adolescents. And there's quite a number that that's quite a vulnerable period. In tandem, there's increased stress of all this change, there's increased exposure to alcohol, drugs, or abuse, and eating disorders can start to arise and so it's a critical period where we need to really look after the microbiome. And that's why diets and nutrition during adolescents are gonna be really important. And we need to feed these microbes really well. We need more studies. We need more people working on the microbiome, and gut-brain axis in adolescents, especially in humans.

But it is an interesting area. And as you know, Jonathan, the cool thing about the microbiome, compared to our genome, with our genome, all we can do is blame our parents and our grandparents, which you know, our adolescents love to do. But with your microbiome, there's potential to modify it, and that gives individuals potential agency over their own health and hopefully their own brain health. 

[00:36:25] Jonathan Wolf: Did you mention something specific about alcohol and adolescents? 

[00:36:28] John Cryan: Yeah. We've been doing studies looking at the impact of human binge drinking in a student-type population and showing that it has quite negative inflammatory effects on the microbiome.

Basically, the microbiome shifts and we get this kind of inflammation going on. And that shifts brain function as well because with binge drinking, then the decision-making changes, and their ability to inhibit responses in different tasks that we use, psychological, and cognitive tasks shifts.

So that's another area we feel that you know, diet could be, if, you know, could be a way. You know, of course, we tell young people not to binge drink, but you know, we also have to be realistic about what is going on. But perhaps we can also, through the nutrition counter some of the deleterious effects of binge drinking also.

[00:37:13] Jonathan Wolf: Brilliant. John, I have so many more questions, but I think we'll have to pull a pause there. And I'm going to try to summarize what we cover to the best of my ability, and please correct me if I got it wrong. So we sort of start by just saying that there's a lot of evidence now that microbes really do affect our brains and that indeed, it might also be true and I think you think it is true that the microbes inside us can really influence what we want to eat. Out of this, you're now developing this whole new idea of psychobiotics, so how can we target the microbiome for mental health benefits? And then I think you talked a bit about some really interesting things at particular points in our lives.

So in terms of adolescence, there's all of this development going on in in the brain, this, this mental pruning, and we want to look after this. So this is probably a critical period to look after the microbiome. On old age, what you said is like the microbiome really seems to influence brain function. Again, you see that in these studies.

So, then I think of two other fun things. Have a pet, which is good for your microbiome. So, you know, go out and get yourself a dog and more social interaction. You said that just in the same way that the microbiome might be shaping the social interaction, the social interaction might also be supporting the microbiome.

[00:38:24] John Cryan: Absolutely. That's great. Great summary. 

[00:38:26] Jonathan Wolf: John, that was a lot of stuff I think is incredibly exciting and I know that this is really moving fast. So we hope that you can have you back again in the future to talk about some of these ongoing, studies and as we understand more and more about how the microbiome is really shaping our brain and our mental health.

[00:38:42] John Cryan: No problem. I'd be happy to. 

[00:38:44] Jonathan Wolf: It was such a pleasure. Thank you so much, John. 

[00:38:46] John Cryan: Thank you, Jonathan. 

[00:38:48] Jonathan Wolf: Thank you to Professor John Cryan for joining me on ZOE's Science and Nutrition today. I hope you found today's episode as fascinating as I did. If you did, please be sure to subscribe and leave us a review. We do read all of them.

If this episode left you with any questions, please send them in on Instagram or Facebook and we will try to answer them in a future episode. At ZOE, we want to improve your health with personalized nutrition. By understanding how your body responds to food, we can build a personalized program to improve your health and manage your weight.

Every ZOE membership starts with an at-home test, and that test includes a gut microbiome test to understand those bacteria we've been talking about today, and then we compare you with participants in the world's largest nutrition science study, and deliver this program, personalize your unique biology.

If you're interested in learning more about ZOE, you can head to joinZOE.com/podcast and get 10% off your personalized nutrition program. As always, I'm your host, Jonathan Wolf. ZOE Science and Nutrition are produced by Fascinate Productions with support from Sharon Fedder, Dr. Yella Hewings-Martin, and Alex Jones here at ZOE.

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