ZOE Science & Nutrition - How your gut affects your mental health

Episode Date: November 10, 2022

In a lab in Ireland, a group of scientists stand around a stainless steel table. One of them is holding a device, not unlike a small turkey baster. His free hand plunges into a box on the table and retrieves a mouse.   Using his device, he administers the brown solution within…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.  Jonathan speaks to John Cryan, author of the study that showed a relationship between gut and brain. In this episode, we learn more about his fascinating research, how microbes may affect our brain, and to eat to appease your gut bugs.  John Cryan is a professor at University College Cork and a world-leading researcher into the relationship between our brain and our gut microbiome. Download our FREE guide — Top 10 Tips to Live Healthier: https://zoe.com/freeguide Timecodes: 00:00 - Introduction 02:05 - Quickfire questions 03:26 - Are there links between the gut and the brain? 06:31 - The gut-brain axis 09:17 - How do gut bacteria affect our brains? 11:12 - Why does John call the microbiome “the chamber of secrets”? 14:20 - Does the microbiome explain drug side effects? 15:51 - Are there links between our microbiomes and mental health? 20:40 - If we improve our microbiome health can we improve our mental health? 24:58 - Can food help improve the microbiome and thus improve mental health? 28:33 - Microbiome’s effect on behavior 29:54 - Actionable advice 34:43 - Microbiome in adolescence 37:18 - Summary 38:26 - Goodbyes 38:48 - Outro Episode transcripts are available here. Follow John: https://twitter.com/jfcryan Follow ZOE on Instagram: https://www.instagram.com/zoe/ This podcast was produced by Fascinate Productions.

Welcome to ZOE Science and 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 stand 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 the 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 gut and brain. Although using mice,

this is evidence that the same could be true for humans. Today's guest, Professor John Kryan, 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 Kryan, 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 brain? Yes.

Could the microbes in my gut influence my behavior? Yes. If I'm stressed a lot right now, does this mean I have a bad gut microbiome? Potentially. Should I give my children probiotics to reduce their risk of mental health conditions? Unlikely. Could poo transplants be a medical prescription in the future? Yes. What are three things that anyone can start doing today to improve their microbiome and their mental health? 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 that negatively affect their microbiome. All right. Well, I think we're going to 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 Phyllis Jacker 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. Are there links between the gut and the brain? 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 taught 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. And John, just to make sure everyone has an animal model, what does that mean? 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, they allow us to answer the question, is the microbiome relevant, yes or no? And studies from our lab and from other labs over the past decade or more have shown that in these mice that grow up without any bacteria in their gut that their brains don't develop normally. 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? 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 first tried to do this, work with these types of mice, and they are not really translatable to anything human. With maybe the exception being the boy in the bubble that Paul

sang about in the 1980s. These mice in the bubble, they allow us to have this specific question, is the microbiome involved? Yes or no? Got it. So it's quite unnatural is what you're saying. You have to create this incredibly sterile 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 the normal situation for mice. And I guess for us, right,

which is where we're stuffed full of trillions of them. Absolutely. And our group and the group of Rushdolls 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 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. 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? Well, yeah. So the gut-brain axis has been 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 are 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 that 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 do the microbes in the gut talk to the aspects of gut-brain signaling to change brain 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 learnings.

From an evolutionary perspective, microbes were there. And so there's never been a time where 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 we have to remember also that the mitochondria, the powerhouses of cells, 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 it in that way, it's probably not surprising that the microbiome can play such a key role in so many aspects of our physiology and our behavior.

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 have 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 an irrelevance. Yeah, absolutely. 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. They're in the same place. That makes sense. But 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. Yeah. And it's a large part of what our lab is focused on is really trying to delineate the mechanisms and pathways for this 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. Enteric nervous system is very important for digestion, motility, 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 pass on it. The second thing is we have a nerve. It's one of the major cranial nerves, which sends 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 Bienenstock's lab that when you cut the vagus nerve in a mouse model, we severed 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 vagus doesn't just stay in vagus, but will actually affect our emotions in certain ways. Okay, I love that. So I've got a Vegas nerve inside me, which a bit like Vegas, all sorts of bad things can happen and come back to haunt me afterwards. 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? Yeah, that was driven by a student in my lab, Sophia Cusotto, who is a real Harry Potter fan and really wanted to relase 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 are hidden within, but that 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 for 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 has some effect on the microbiome. 25%. That's amazing. Yeah. And so when we work in mental health, we're just 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 could we attenuate

some of the effects of antipsychotic medication by targeting the microbiome. So it may sound a bit out there, but 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's been able to tell us that maybe we may need to, in addition to the efficacy and safety of drugs, 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. So it's amazing. I think we talk quite often on the 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 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 being 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.

Yeah. Does that explain why so many drugs, the side effects are very personalized? I think one of the, 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? 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 are 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 as 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. And this is still very early, right? We should say to our listeners, I know 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 see 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. No, no, no. But there may be practical things that people who

are on medications who have, let's say, side, 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.

Fantastic. And we were definitely going to 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 the mental health issues. You've just talked about how it supports sort of healthy brain function. Are there links between our gut

microbiomes and then, you know, mental health conditions like depression and anxiety? 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 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 these types of chemicals that our body can't make. We have outsourced this to the bacteria. They provide essential energy for the cells in our gut and some of our immune cells, but we 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 may be 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 a Czernik-Berczyk group in Canada

where we've taken people's microbes who are suffering from different mental health disorders and transplanted them into, again, into mice or rats. And these animals start to display symptoms of depression or anxiety. And so that was really remarkable. And just to make sure that, I guess we'll 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 that's, people will be fascinated. 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, with 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 is we associate in 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 its blues through the microbes. Which is amazing, right? Because, you know, I grew up, like I think a lot of people with, you know, my parents or my grandparents, basically not really believing in mental health, right? This is just sort of stiff upper 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're giving it to somebody else. So I just want to 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. 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 with 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 is affecting physiology in a way, and it helps prove it overall. And so it is quite remarkable. And are you saying that the microbiome is the complete cause of mental health issues? 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 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. And so that's what's... 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? So you could sort of create a vicious circle where something else starts with the depression, it leads you to this microbiome, which is no longer healthy, which is then reinforces it, which is why you can implant it into mice, but it still might have started somewhere else. Exactly. Exactly. Exactly. 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? So that's the key question, Jonathan. I think... And our listeners want to know the answer. 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 Dinan and myself, and psychobiotics are basically 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 mental health. So 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. Like there are studies, you can find

lots of studies showing that certain strains of bacteria will have positive effects on mental health and increasingly in humans. So that's good. But the big issue here is why do you select one strain of bacteria or another? And how do 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 this is live bacterial strains or prebiotics which are basically the dietary substances which support beneficial bacteria from blooming that they have positive effects in anxiety and depression overall i think we're not there yet i think we have a lot of way to

actually try and 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 strains, 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. So I think the same picture that we see in general, which is the current generation of probiotics are not showing really big impact in most areas. And is that fair to say? 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, that bifidobacteria, that 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 have very different abilities to make different chemicals that can interfere. And they can have different proteins on their cells to decorating 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. 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?

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 are 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 to a whole diet approach, be able to create something that would work. And so Kirsten Birding-Harald was a fantastic dietitian in my team. And we created this diet and we took people that had bad diets and were stress sensitive in particular. So our student population, a lot of them fit into that. You mean they're not eating really healthy food, your students? I'm shocked to hear that. 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, educating them about that. We also took another group that 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 and fermented foods had a much better response to stress in the laboratory setting. Their feelings of depression, they weren't depressed. None of them had a clinical disorder, but just their feelings on 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 stressful situation. And that's one month. That's one month. It's amazing. That's a really brilliant study.

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 for mental health you know 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 want to 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 can use in it. Fiber is present in a lot of vegetables and lots of 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? 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 tinned 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 will be listening and 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. 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 germ-free.

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 gut, at least if you're a mouse. 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 it might be fascinating 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?

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 maximise what it can get from milk overall. And then into adolescence there's less 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 a deleterious effect of ageing on the microbiome which 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 has some evidence although we could do it more so there are certain things to enrich in 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 k's of kimchi kefir and kombucha but there's loads of other fermented foods and 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 from

Justin Sonnenberg's group and now more recently from our own has shown that there's a science of 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 they can be broken down to chemicals that are really important. 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 as much as we can. And that's the processed food, artificial sweeteners in particular have been shown to have consistently negative effects on the microbiome overall. We know that certain lifestyle other factors can influence the microbiome. So our sleep and our circadian rhythms and jet lag all has effects. So we need to be careful on that exercise in particular aerobic exercise has been shown to have really good effects on the microbiome and potentially then onto brain function overall mode of delivery at birth 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's 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 a really intriguing area overall. I just want to 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 has 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? 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, your microbiome starts to shift and change. The best study on old age then have shown that things like the diversity in the diet is 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 the studies like the New Age Study and the Eldermatt 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. That makes sense. And what about adolescence? I think you talked about like a big shift going on in the brain at this point. 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 cells are saying, okay, keep or not keep what's going to be essential for what you need to keep you going. So this is where my son decides 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.

Let's ignore that. And if we disturb these pruning processes, then you can increase the susceptibility to a variety of mental health problems which start to emerge in adolescence. And there's quite a number that that's quite a vulnerable period. In tandem, there's an increased stress of all this change. There's increased exposure to alcohol, drugs, abuse, 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 diet and nutrition during adolescence is going to be really important. And we need to feed these microbes really well. We need more studies. We need more people working on the microbiome gut-brain axis in adolescence, 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. Did you mention something specifically about alcohol in adolescence? 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, cognitive tasks, shifts. So that's another area we feel that, you know, diet could be, you know, could be a way. We're not going to, 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 nutrition, counter some of the deleterious effects of binge drinking

also. 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 covered to the best of my ability. And please correct me if I got it wrong. So we started off 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 that, 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 the brain, 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, that you've seen that in these studies. So, and then I think 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. Absolutely. That's great.

Great summary. John, that was a lot of stuff. I think it's 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. No problem. I'd be happy to. It was such a pleasure. Thank you so much, John. Thank you, John. Thank you to Professor John Kryan for joining me on

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