Dr. Victoria Maizes: Okay. Hi, Andy

Dr. Andrew Weil: Hi Victoria.

Dr. Victoria Maizes: Today, we are going, going to be speaking with an Irish researcher, Dr. John Cryan about the microbiome, and this is really a fascinating new field of medicine so for listeners who are new it's about the bacteria, viruses, and fungi that live in and on our bodies with whom we have co-evolved for millions of years…

Dr. Andrew Weil: And particularly about how they influence brain function, and mental and emotional wellness and how the brain influences that.

Dr. Victoria Maizes: Andy, you have talked about the mind body connection for so many years. How'd you get it before the microbiome research?

Dr. Andrew Weil: You know one of the observations that I made was I often tell people about, and this is from my college days it very interesting to go into a student health services. Couple of days before exams and see the numbers of people that come in with gut disturbances, with diarrhea, with nausea, with, stomach pain, obvious, you know, it just hits you in the face.

So that kind of thing alerted in the early on to the, you know, to that connection.

Dr. Victoria Maizes: Well, let's welcome, John.

Dr. John Cryan: Okay.

Dr. Victoria Maizes: Dr. John Cryan is a neuroscientist who investigates how the gut microbiome affects the mammalian brain. He is the chair of the department of anatomy and neuroscience at the University College of Cork in Ireland. His research has far reaching public health implications ranging from how we view cesarean sections to how the microbiome influences brain development to the impact of probiotics on mood. John's work shows that the term gut-feeling might actually make neuro-biological sense.

Welcome John.

Dr. John Cryan: Hi, Victoria.

Dr. Victoria Maizes: Hi, we're so glad to have you on the show. So I want to jump right in and say that the ability of the gut microbiome to communicate with the brain and maybe modulate our behavior is an emerging and exciting concept in medicine. Can you start by just defining what is meant by the gut-brain-axis?

Dr. John Cryan: That's a great question. The concept of the gut-brain axis is something that has fascinated physiologists for hundreds years, it's really an important aspect of homeostasis in the body, teaching us to feel how we feel. It's a very fundamental part of a process what we call “interoception”. Well, that might sound like something, you know, from sort of a sci-fi movie, but it's actually really important way that the brain is able to, know how the body is feeling. And it's regulated by key circuits in the brain. And also with the gut-brain axis, we have a second brain enteric nervous system, which is an important driver and it's been understudied and it's worth pointing out we have more nerve cells in the second brain, then we actually do in the first and than in the spinal cord. And so, you know, this is really important part, but then for me, the most exciting thing is over the last, decades we've got a new player. We've got the microbiome. These trillions of bacteria and other microorganisms that inhabit the gut. And this microbiome is seen as a key regulator of what's going on in the gut-brain axis.

And so not only do we have a gut-brain axis, we really have a microbiome-gut-brain axis.

Dr. Victoria Maizes: So that's really helpful. I know, more than 20 years ago, there was a book that came out that I think stirred a lot of interest in people who were interested in this topic called the Second Brain. It was written by Dr. Michael Gershon. And he said that the nerve cells in the gut could act as a brain, but you are now talking about a whole new evolution of research that really looks at bi-directional signaling from the GI tract to the brain and back that helps us with homeostasis and, and can be messed with. So that's, I think the focus of your research, can you give us a broad overview of, of what your research is telling us?

Dr. John Cryan: Sure, sure. I mean, you know the gut-brain has been best studied in the area of food intake, you know, hunger is coming from your gut and how you feel. And therefore your behavior is changed by these signals driven often by specific hormones in the gut. But, and so it's not, so it shouldn't be that weird to the community, that, that we have this other system.

And really, what we're interested in doing is understanding how could microbes and be important in this. So why did we get into this? I guess it's part of it and why do we think it is so important? Well, you know, it's one of the things you start to realize, and this is very fundamental in medicine is that we like to compartmentalize things.

And so the body we compartmentalize. And so if you're interested in brain and behavior like me, then you should just focus really on the neck upwards. And that's how we train our medical students, but really once you start thinking in a more holistic way and you start looking at things in a more integrated fashion, you start to see that that they're all parts of the puzzle together. The first thing I want to remind people is that microbes were here first. There never has been a time where the brain has existed without microbial signals. We are living in a microbial world, you know, and so people, you know, mitochondria, which we study in cells are just microbes that got lost and they provide the engines of how cells work in the body.

So, you know, these are important things for people that they may, might not realize. If you look at the genes we have, we are more than 99% microbiome, all of that money on the human genome projects and less than 1% of our genes. So that's quite startling. You know, the weight of our gut microbes is about the same as our brain.

So as a neuroscientist and as a professor of anatomy, this is really humbling to think about, you know, overall. and so, you know these are some of the things that amazed me about this, but we chose, quite a number of years ago, using initially in animal models, we showed that stress in early life and we're quite interested in early life trauma and the long-term consequences that that has on later susceptibility to psychopathology. And so we develop animal models of this, and we showed in an animal model that when, they grew up, they had a whole body syndrome, which is really what we predict from our stress research.

We're very interested in, in trying to understand the impact that stress has on the immune system on local even in the cost in terms of gut barrier function and, and then variety of biomarkers. But one of the things we found back then, and it's went over a decade ago now with, we showed that these animals had a change in the diversity of microbes in their gut, that there was a signature of this early life trauma, that persisted, we followed this up with studies and prenatal stress models.

And this has been now shown in human, small cohorts of individuals, like a study from the Netherlands, which showed that moms that have high stress during pregnancy for first-time moms pregnancy can be quite stressful, that there was a signature of this stress in the microbiome, in the infants. And so that, that was our, one of our first really interesting points that the microbiome might be regular might be important for stress, but it could also be epi-phenomenological. It could be due to anything else. So we wanted to really dig into this. And, then we're very fortunate here to have a facility, which basically allows us to ask the question are microbes important in us.

It's basically a facility that allows mice to grow up without any microbes at all, and, you know, only look into engineering and other aspects of biology, the best way to get evidence that something is important just to take it out and see what happens and how the system works.

And so that's something that we've worked on and we showed in the early days that the brains of these animals do not develop appropriately. And this is at the very same time we work from Canada, from Jane Foster's group and from the Karlinsky Institute, but Russia, Lefties Heights also had the same data.

And so, you know, things started to come together and this is a great thing in science When you start seeing, you know, we see it now with, with, with vaccines and [00:12:00] various things, things start to come together and that was really remarkable. So, and then we noticed there was a paper from Japan that had been published that was ignored. It was published in a non-glamour journal. It was published in the society journal, Journal of Physiology. Some years earlier would show that these germ-free mice also have exaggerated stress responses. So not only does stress affect the microbiome, but the microbiome is affecting stress.

Dr. Andrew Weil: I'm very impressed when I just scan the news headlines these days. It seems every day, there is a report on new correlations between the gut microbiome and general health and mental health. So my impression is that research in this field has just exploded. And it's such a contrast to when I was in medical school, when there was no attention paid to the gut microbiome and to see all these correlations now being uncovered is just fascinating.

Dr. John Cryan: It really is. It really is the puzzle for us is to move from correlation to understanding the causal relevance and the relative contribution that they have. But you're so right. In Cork here, we're very lucky cause we have a microbiome center. That's now 18 years old. It's one of the oldest in the world, you know, in terms of really appreciating the impact the microbiome has on health, but you know, it's not new at all.

So, you know, Eli Metchnikoff. So he's one of the heroes in this story, fought one of the fathers of modern immunology discovered the process of phagocytosis. So later on in his career, he started coming up with some were seen as crazy ideas. And one of these ideas was why did people in parts of rural Bulgaria?

And this was, you know, the turn of the 20th century why do they seem to live longer and healthier? And he Rose about this in a very famous book and he put it down to what they ate [00:14:00] and what the ate was a lot of fermented foods containing lactic acid bacteria. So, you know, you can find out, I have this wonderful paper from 1904 in the British Journal of Psychiatry, about treating melancholia with lactobacillus know and, and, you know, there's all of this rich literature and it's an important part of folk medicine and various other parts of traditional medicines but it really reinforces, certain things that we forget about. We forget about, because we don't want to think because we compartmentalize things.

Dr. Andrew Weil: So, well, let me ask you a practical question that always comes up.

When we talk about this research. Is, can you change your gut microbiomes or you saddled with this certain population from birth what do you think?

Dr. John Cryan: So, so it is, it is a really brilliant question this is what I like to tell people especially when I give patient talks, we've come through a genetic revolution in medicine, you know, and the great, the, you know, it's proved quiet a lot but you know, from the human genome project upwards, what, you know, there isn't an awful lot we can do except blame our parents and our grandparents about our genes. But with your microbiome, with your microbiome you have a real opportunity to actually take agency over your own health. And modify it.

And we're only understanding what are the constraints on that. And so some of the best studies are people who are, who move from certain cultures to others or people who go from extreme, meat-based diet to plant-based diets or whatever else. And you can see these changes in the microbiome, but you are right in terms of that at the beginning, you know, there is a kind of a priming and a setting up, and there is some genetic influence on what gives you your microbiome as well.

But I think there is huge opportunities here but we need a lot more data. We need a lot more evidence, to, to really get at why does my diet, does my microbiome respond to this diet? And yours might not. And it does epitome, really a personalized medicine it's really is. It really is. So how do you, you know, commercial here then make it into other things? Is it harder for the people but for people interested in, you know in integrative approaches it really is, is part of the us. We're not there yet. You know, we're not, you can get your blood pressure, measured and you know exactly whether you're where you are, you can get your cholesterol measured and you know where you are, you can get your glucose, you can go get your microbiome measured and it doesn't tell you, you know, it will just.

The look of despair on the traditional physicians would be, if you go in with your microbiome, you know, we don't know what to do fully with the information.

Dr. Victoria Maizes: Okay. But we don't know fully, and we may not know exactly what is normal, that's exactly what our patients ask us all the time. So, Andy, I'm wondering if you would be willing, like you often are to step out into, what's not fully known and give recommendations that people ask, what can we do?

What do we know at this moment in time that a person could do to have a really healthy gut.

Dr. Andrew Weil: What I tell people is first of all, be very cautious about using antibiotics unless they're absolutely necessary, second I think a plant-based diet is, favors the diversity and, microbial populations that you want. I think it is useful to eat fermented foods. probably more important than taking probiotic supplements and it's so easy to make fermented foods at home. I do that and I tell other people to do that and there's a whole variety of them. So it's not just a, you know, it's not just pickles and sauerkraut, but it's fermented dairy products, fermented soy foods [00:18:00] and so forth.

I think it is useful to eat, a variety of prebiotic foods, foods that nourish the healthy organisms in the microbiome. I mean, I would say those are the, and, and to really reduce consumption of refined, processed, and manufactured food.

Dr. Andrew Weil: So that's the basic advice that I would give.

Dr. Victoria Maizes: So I want to just add to that amazing lists that get your mother to have you by vaginal delivery instead of C-section. this is advice we should give to all our patients in an era where some C-sections are elective and where some might be avoided with different planning and different conversations a C-section can be life-saving. So of course, we don't want to eliminate all C-section, but sometimes it can be avoided, have your mother breastfeed you because that's going to nourish the developing microbiome and then, avoid artificial sweeteners, avoid diet sodas and other things that are sweetened with artificial sweeteners, because there are human studies to show that that can alter the microbiome in some dangerous ways.

John, what would you add?

Dr. John Cryan: Yeah, so, so there, there exactly, you know, we coined this phrase psychobiotic in Cork carrier as a way of, and to have a psychobiotic lifestyle. That's exactly what we feel is really relevant. Sleep. Sleep and the microbiome are very closely intertwined. We're very, we're very excited about circadian rhythms and, and the microbiome, and we have ongoing projects there.

And, and so once you get your sleep disturbed, it will affect. So, so, you know, when I was traveling all the time, my jet lag, wasn't good for my microbiome and it was obvious. The other thing is it's known also having a pet. Especially a dog. Having a dog is really good for your microbiome. And there's really great studies now on pet ownership and early life and allergy and asthma

Dr. Andrew Weil: John, help out the kissing your dog, or I can avoid that sometimes they have one dog that really likes to kiss me.

Dr. John Cryan: But everything else is what you captured there. and the, the early life priming is really important, but, but as an adult we can still do a lot. We've just completed a short study, here in, in Cork, where we give people a chance to change their diet for one month. the, and these were stress sensitive.

People were relatively bad diets. And, we up the fiber doubled their fiber intake and, really up to fermented foods and give a Mediterranean style based diet too. And you know, their stress levels, these were students coming through exams, you know, their stress levels were much great, greatly reduced.

They had left signs of, of depression. And so we think, you know, tired getting the microbiome is going to be a really important way of wellbeing. But what we don't know is what works for you may not for the next person. So you'll, you're gonna need to try it.

I would encourage people also to be, somewhat skeptical of anything you see out there that's, that's being sold, from a commercial point of view, without evidence, because there's a lot of, there's a lot of snake oil out there and regulation isn't very good. So I would be, you know, exactly what I need talked about there in terms of that low cost. Fermented foods are really good but there are lots of other products that are, may not be as well studied.

Dr. Andrew Weil: John, one other, possibility is I I'm, I'm sure you are, a friend of the hygiene hypothesis and I, you know, I think, avoiding germicidal products in the home and not being too concerned about, you know, ingesting some dirt here and there.

Dr. John Cryan: Harder in the COVID world.

Dr. Andrew Weil: Of course.

Dr. John Cryan: it's really harder.

Dr. Andrew Weil: I'm an avid gardener. I think having your hands in soil and getting little bits of that stuff in your mouth and you know, not being so fastidious about [00:22:00] washing vegetables that you pull from your own garden, that probably also contributes to a healthy microbiome.

Dr. John Cryan: Absolutely. Absolutely.

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Dr. Victoria Maizes: John, where is the science on fecal transplant for mental health? I have heard so many people intrigued with, could their depression go away. If only they could get a transplant that's not legal in the US where, where is it in the UK and when, when might it show up?

Dr. John Cryan: Yeah. So in here in Ireland, it's not either we're very cautious, as well.

it's an intriguing, it's an intriguing possibility because, you know, it's basically, I like to give the analogy, you know, if your microbiome is like a lawn, sometimes you're alone, it just needs extra, fertilizer. So that's like giving, prebiotics and stimulating. Sometimes you have to plant new seeds. So that's giving probiotics, but sometimes, sometimes you just have to take up the lawn and extreme situations and plant a new lawn. And that's what a fecal transplant is about. So the data is, is really good and infections, but outside of that, it's, it's more equivocal in areas like inflammatory bowel disease.

There was an interesting small study out of, St. Louis where they were looking at people with severe alcoholics and showing that FMTs were beneficial. There has been one small study in autism on compassionate grounds, which would show us potential it's small it's only got 20 patients or less and has no real control groups. So we caution, but it's very promising. there are studies and I'm involved in collaborating on studies in Australia where we're trying to set up the protocols for doing this in depression and then Valerie Taylor's group now in Calgary in Canada has an ongoing study

So, We'll see how, how it becomes mainstream there's safety concerns. There's regulatory concerns, you know, how do you call this a medicine or how do you, what do you do with it? So I, my advice to people who are suffering with depression would be to try radical changing their diet towards this kind of psychobiotic diets at first, the other factor we didn't mention in the previous, this conversation was about exercise and the role is now becoming quite clear that an exercise, especially aerobic exercise has real beneficial effects on the, on the microbiome. And we have ongoing studies they’re early, but we're trying to see is the beneficial effects of exercise and depression clearly be due to shifts in the microbiome.

And that's something, as well. So I think caution in the fecal transplant world, and we'll, we'll see whether the data, you know, comes together, but there was a nice study just published in we talked about C-sections where they did a fecal transplant in, in C-section.

So it was small, it was an obsession, but it was in the biggest journal Cell. So, you know, People are doing more and more. You were going to see this more and more and anything that disrupts medicine is good in terms of, you know, it takes us out of our comfort zone and challenges, our whole idea, of how we can target specific areas.

Dr. Victoria Maizes: John, you've used the term psychobiotic a couple of times now, can you define it for our listeners and explain what a psychobiotic diet is?

Dr. John Cryan: Yeah, so, so we originally my colleague, Ted Dinen who's the head of psychiatry. He just retired. And I, you know, we call him this a few years ago and we originally were, had a very narrow definition, which was just about bacteria, that when taken an adequate amounts could confer a health benefits, but more recently we've actually expanded it to being any way of targeting the microbiome. That will be good for preventing mental illness and supporting people who have mental health issues. So anything that affects the brain. and so we really wanted to put this. In the context of nutrition, because nutrition is really one of the best ways that we can get at the microbiome.

And we know from studies that, you know, the best way to try and recover some of the lack of diversity. This is studies for example, here in Cork have been done in elderly individuals. And it show that those that had a, a Mediterranean style diet, that they had a much increased diversity in their microbiome and better health outcomes.

We were quite passionate about it because also we realized we both worked in the medical school and the curriculum is so full. They got so little nutritional, you know, study our dentists get more than our physicians and so, so we really wanted to push this concept that by targeting the microbiome gut brain axis, we could actually you know, have beneficial effects. We need to create more and more evidence, but, but we're excited about it. And we have some really strong, hence that it's working as an approach.

And what we're trying to do then is triangulate. the relation, we know diets, certain diets are good for the brain, but we think that uncertain diets are good for the microbiome. So the question is, is the healthy effects of diet on the brain mediated by what they're doing on the microbiome. And we're trying to deconvolute this and trying to understand this.

and it's understanding that the microbiome. It's really a factory. It's really like, you know, one of these rust belt factories that is taking in raw material from the diet and acting on that raw material and producing chemicals that our body wouldn't have without it. And, and, and that's really, once you start thinking of that, that you have this factory within you, that, and you can tailor what's coming in by tailoring your diets, then, you know, and so in a psychobiotic diet, what we're trying to do is increase the amount of fermented foods increase the amounts of fibers.

Fiber is king in this regard, if you get to a tolerability level, like a lot of fibers can not be broken down by the body, but they're broken down by the microbes. So we have co-evolved with these microbes to allow them, we've kind of, you know, privatized some of the work to the microbes, take it from the diet.

And, and, and this is really, really interesting. And, you know, one of the most interesting examples of this, and you mentioned breastfeeding earlier, is that, and this was really surprising to me when I when I was told this is that if you look at the sugars, In breast milk and human breast milk, these human milk oligosaccharides, they were about 20 times more complex than that hat's you guess in cow's milk now, nature doesn't make things complex for no reasons just to be difficult. And it's, these sugars cannot be broken down by the infant but they're broken down by the microbes. And what are they broken down into broken down with chemicals like sialic acid, which is really important for brain development.

And so we're beginning to see. That you know, these sugars have involved this complexity to be able to support the evolution of the brain and the development of the brain to be optimal. And so some of the beneficial effects that are in well reported in breastfeeding, in terms of cognitive development, maybe due to some of the effects of the microbiome.

And the opposite is also work from Jeff Gordon's group in St. Louis and others is showing that in severe malnutrition, especially in parts of Sub-Saharan Africa, where you have stunted growth and brain development issues, that this is due to a lack of these microbes that can actually work and of the sugars.

And so you kind of need to have a two-pronged approach, replaced the microbes and replaced the raw materials

Dr. Victoria Maizes: You have also been researching the Vegas nerve. The vagus nerve is super interesting in that. It is the most [00:30:00] important nerve, I believe in calming the nervous system. And in integrative medicine, we teach people a lot of different strategies ranging from breathing exercises to yoga practice, to meditation, to tone the nervous system, specifically the quieting side that is, led by the vagus nerve. So how are you thinking about the vagus nerve? Does the vagus nerve change the microbiome? Does the microbiome change the vagus nerve signals? What has your research shown you?

Dr. John Cryan: So our research showed, and this goes back to a paper we published in 2011, where we showed again, it was an animal study initially, where we still showed that a specific strain of lactobacillus when we, when we give it to, into a mouse model, it had effects on the neurotransmitters, in the brain effective stress-related behaviors, fear learning a variety of different things. And all of these effects were gone when we cut the vagus nerve. So, this is a, as I like to remind people

Dr. Victoria Maizes: What happened instead,

Dr. John Cryan: They behaved, it behaves just like as if they were given a placebo.

So there was no negative effects, no negative effects, really but they didn't respond to this lactobacillus. So this tells us that what happens in vagus doesn't just stay in vagus, but will actually affect our mind. And that's something that, you know, I finally published that in the title of a, an article last year, what happens in vagus because I think it's really important.

What we're doing now is, a number of the postdocs in my lab. We're trying to. Figure this out. How do you get to vagus from the microbes? Because there's still a fair bit of room to go. And then when you get from the vagus into their brainstem, where does it go, which circuits in the brain become activated and how do you basically hijack them?

And it's such an exciting area right now and, and it's really important. And, and vagus is definitely one of the main communication pathways and, and of course this is [00:32:00] the one that is being, used, during meditation and mindfulness and various other things as well. And it's bi-directional I think that's the other important part of it.

Bus, but as I, you know, I neglect to mention a lot, a lot of times the vagus doesn't innovate the lower coli. so it's not the whole story. So a lot of the fermentation goes on in the lower colon. So, so, so there are other, there are other pathways I play and we are very interested in these metabolites right now.

And these what these microbes make, because I think there's going to be a lot of interesting things emerging from that.

Dr. Victoria Maizes: Have you studied the effects of these mindfulness practices, meditation, yoga, breathing, other things.

Dr. John Cryan: Point study that it's completed. Now we're analyzing the microbiome in it, in where we looked at mindfulness training. There is the one thing that gels all our studies together. And so, this was, in caregivers of people who have Alzheimer's disease. We put them through a mindfulness intervention and we're now looking at their microbiome.

And so we'll be interested to see, you know, I mean, these, these are tough studies to do because these people have a lot going on anyway. And so adding to their burden by getting them to, you know, take biological samples and things can be tricky. So, so, but we have the, we will, we have the data now and we're beginning, we're mining it now to see what exactly is going on. I'd love to see a lot more. Work in this field. I guess that's one of my take home messages is that we need to, I'm always encouraged when, when more and more people, you know, get interested in this field, overall, because the more data we have, the more evidence we can say about, you know, what will work for what person in what situation.

Dr. Victoria Maizes: So Andy, when you look into the future of medical practice, where do you see the individualized care of the gut going?

Dr. Andrew Weil: I think it's going to be huge, especially really knowing what practical advice we can give people for, how to get and maintain a healthy gut microbiome. how do you use interventions directed at the gut to modify brain function and emotional and, and mental wellness, how to use your mind and ways to harmonize gut function and, and treat many of the common, functional elements of the gut.

I just think we're at the beginning of this. you know, new, new kind of medicine. That's very exciting.

Dr. Victoria Maizes: Thanks Andy. John, do you want to add to that?

Dr. John Cryan: I, I agree I think, you know, it is opening the door and, you know, there was a paper just published, but all the confines and microbiome science, and some people see this as a negative, but it's actually a really positive because we're really being able to see how do we design these studies better, what type of sample size we need and really to build up evidence. And I'm always about the evidence. So where is, where is the evidence. But it is a paradigm shift in thinking about the brain and the mind and, how we behave in a different way. One of the areas where I'm really wondering about it in this COVID world, you know, with lockdowns and increased hygiene, how much we're interfering with our everyday microbiomes and what are the long-term consequences of that? We've been very interested in social. One does something about the social brain and the microbiome and how they interact with each other. And that's something that we've been very, interested in as well.

Dr. Victoria Maizes: Thank you, John. So very much for taking this time to speak with us, on our body of wonder podcast. We really appreciate it.

Dr. John Cryan: Really my pleasure, Andy. Great to meet you.

Dr. Andrew Weil: Nice to meet you

Dr. John Cryan: And thank you Victoria, for being such a great host.

Dr. Victoria Maizes: Well, we appreciate having you on the show. Thank you so much.