THE MICROBIOME SUMMIT : The Paradigm Shift

The Microbiome and Brain Health

Dr. John Cryan, PhD

dr-john-cryan-phd-2

Dr. John Cryan, PhD

University College Cork

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Overview

Gut microbes play a huge factor in our thoughts, our cognition and our social behaviour, so we need to know how to take care of our microbiome to better support our brain and mental health. Dr. John Cryan leads us through some of the ways we may be hurting our microbiome, and how to fix it. In this interview, you will learn about “psychobiotics” – a live organism that confers a mental health benefit. In other words, it’s a probiotic for your brain. But Dr. Cryan argues that prebiotics should also be considered psychobiotic, as they can target the brain via the microbiome as well. We can all live a psychobiotic life.

Transcript

  • Tracey:
  • We’re here with Dr. John Cryan, a neuroscientist, professor at the University College Cork, Ireland and principal investigator of the APC Microbiome Ireland. Thank you for joining me here today, John.
  • John:
  • My pleasure Tracey.
  • Tracey:
  • You and your colleagues — are championing the term psychobiotics. Would
    you mind explaining to us what psychobiotics are?
  • John:
  • Sure, indeed psychobiotic is a term that my colleague Ted Dinan came up with a number of years ago. And, we feel it’s an important term because it encapsulates a lot of where we’re going at the interface between microbiome science and psychological medicine. So, that’s really what we’re trying to do. But, its initial definition that we put forward was that a psychobiotic was a live organism which when taken in adequate amounts conferred a mental health benefit. Kind of like a probiotic for your brain. But, more recently, together with Phil Burnet’s group at Oxford, we’ve decided to kind of expand the meaning because there are other ways to get at your microbiome than just through bacteria intake, and so, we’ve expanded to include prebiotics which are basically foods on which beneficial bacteria love to use and thrive on. Also, it includes — in very specific cases, even antibiotics or fecal transplants. So, really any targeted intervention for the microbiome that is going to support brain health, we feel is a psychobiotic.
  • Tracey:
  • Yeah, so interesting. At the microbiome level, what are the microbes doing?
  • John:
  • Some of the things we do know, and some of the things that are important just to point out for your listeners, one is that we do know is microbes are little factories. They produce all kinds of you know, weird and wonderful chemicals that our bodies wouldn’t have without them. And so, that’s why it’s so important that you know, they have the right substrates to work on. Let me give you an example.
  • Tracey:
  • Okay.
  • John:
  • Breast milk is known to be better for the infant in terms of a lot of different outcomes. But, one of them is in relation to IQ and cognitive behaviour, it’s been shown. Well, the intriguing thing about breast milk is that the complexity of the sugars in human breast milk is so much more than that of other animals. So much more than bovine milk which would be in formula. And so, it’s an evolution we drive towards having this complexity of sugars. Now, these sugars cannot be broken down by the human body.
  • Tracey:
  • Right.
  • John:
  • So, why does breast milk have them? And, the reason is it’s because of the microbes. The microbes act on these really diverse milk oligosaccharides to produce very important chemicals that our body wouldn’t be able to have, that are critical for things like neurodevelopment and leading to some of these things. And, among them is a chemical called sciatic acid which is really important for neurodevelopment and may — some of the reasons of the beneficial effects of breast feeding on cognition, etcetera. But, that’s just an example of how powerful microbes are because without these microbes, we couldn’t have these chemicals. And, that’s the case with a lot of chemicals. And, we’re only beginning to understand what these chemicals are doing where they’re formed and then the question is, where are they acting?
  • Tracey:
  • Right, in your book, you have a really clever example that perhaps maybe we have bacteria that craves donuts.
  • John:
  • The donuts, yes. Well, perhaps. Again, there is a nice study that just came out in the last few months that we didn’t have time to talk about in our book but it’s really cool study from Carlos Ribeiro’s group in Lisbon. And you know, you might think well, what can the fruit fly tell me about any of this? Well, Carlos’ lab works on the fruit fly and he’s interested in food and the drives that underpin food choice behaviour. And so, flies in the lab are more or less germ-free. They have no bacteria in them. And, if you deprive them of protein, they start to crave protein. And for a fly, yeast is their steak so they really want get the yeast. If you give them an opportunity to really go towards the yeast if they’re protein deprived. Now, if you put bacteria back into these flies. He’s put five strains. It completely changes their choice. They no longer choose the protein. They’ll go now towards sugar. And so, this is telling us, using a very simple model that we can affect food choice behaviour by tinkering with what’s going on in the microbiome. So, maybe that donut is being driven by what’s going on there. And again, this is a really interesting, relatively new study but it allows us to really parse some of the fundamental mechanisms that are at play. And, the question now of course is translating that up into humans and then, does it play a role in disorders where things like food choice have gone awry? Whether it’s obesity or anorexia or other aspects of behaviour.
  • Tracey:
  • Yeah, so many interesting questions to be answered. So John, what are the main communication channels that are being used between your gut and your brain?
  • John:
  • Yeah, and we’re just beginning to work this out and still a long way to go but I’d say it’s early days, but we have some really strong hints. As you can see in this picture that’s from our book, we simplify it very much but it charts some of the main ones that you need to really understand. And, of course you know, a brain is central to it and communication is not just one-way but it’s two-way. So, it’s not just from microbes to gut but it’s also — or to brain, but it’s also the other way as well. So, if we think about substrates from our diet coming in like fibre and how that is acted or like these milk oligosaccharides I talked about in relation to breast milk. They’re acted on by the bacteria and they can produce all sorts of these chemicals that our body can’t produce without them. And, these chemicals can perhaps get through the gut lining and be able to activate specific cells that are there. Among these are the enteroendocrine cells, hormone cells. Also, you can see on diagram, we nicely laid out the immune cells because immune cells are able to you know, detect what’s going on in the environment and be able to produce some key chemicals that are going to affect the immune system and drive a pro-inflammatory phenotype. We can’t neglect the enteric nervous system. Now, the enteric nervous system is also referred to as our second brain. And indeed, there are more nerves in that enteric nervous system than there is in our entire spinal cords. And, the enteric nervous system allows communication, this is essential for motility and how the gut works and keeping it in terms of proper peristaltic mode, but what we’re learning more and more is that it’s also able to sense what is going on in the environment and be able to talk to other systems like the vagus nerve.
  • Tracey:
  • Right.
  • John:
  • And so, the vagus nerve is this long wandering nerve that is so important for communication between what’s going on in the periphery to the brain. And so, this is kind of a neuro highway that signals from the enteric nervous system or elsewhere through these chemicals and are able to basically highjack and get all the way into the base of the brain, into the brain stem area of the brain and from
    there, they travel then to the centers of the brain that are involved in emotion. And, that’s very important. Our immune system is really tightly connected with our hypothalamic- pituitary- adrenal axis. The HPA axis than is our central stress response, it allows us to respond to threats in the environment and you know, it allows us to acutely be able to survive really. And, in stressful situations, this axis goes awry and we also know from the work of Sudo originally and then into our own work that is also regulated by the presence of microbes in the gut. And so, how that’s happening we’re still not clear but what’s also important and we just use generic word metabolites but it is the microbes are producing these chemicals that can interfere with all of these systems. Some of these chemicals could be known as neurochemicals because they’re neuroactive and then, neurotransmitters in their own right because
    they’re interfering with how cells communicate. And, we’re beginning to slowly understand the wealth of different bacterial-derived neuroactive compounds and trying to parse out how can they affect what’s going on in the body.
  • Tracey:
  • Right, yeah. It’s all so fascinating. Now, you have learned all of this information from animal studies. And now, you’re sort of trying to figure out how this applies to humans?
  • John:
  • Exactly. You know, we use animals as model systems but they’re very good for helping us, getting us in a certain direction, but, they have their limitations. And, we know that a human is not just a big mouse. Some humans are but as a whole, they’re not. And, so we’re trying to now go from some of these studies we have in animals and see can we have similar effects in humans. An example we would have is a study where in animals, we’ve screened now quite a number of bacterial strains, largely from the bifidobacterium or lactobacillus family but there’s huge differences between these strains. And, we found a strain of Bifidobacterium longum and we published on this, that has very nice ways of dampening down the stress response in a normal mouse. And then, it also improved cognitive performance. And so, that was kind of straightforward and we were like, “Wow I wonder, could this happen in humans?” So, we took a cohort of healthy volunteers and we subjected them to a stressful situation and that was basically a public speaking interview called The Trigger Social Stress Test. And, we also subjected them to what’s called Cold Compressor Test where it’s like the ice bucket challenge for your hands and you basically put your hands into an ice bucket of water and you feel the stress. So, it’s a socially evaluated compressor test. And, we were able to show that people who had taken this bifidobacterium, they didn’t have the same stress response. They were much more chilled out, just like our animals. We also were able to show when we looked at EEG which is — people what EKG is, it’s for their hearts. Well, EEG is for what’s going on in their brain electroencephalography. And, you can look at what’s going on in terms of brain activity and we found that there was signature in the people that had taken the potential psychobiotic, for instance vs. controls. We looked at cognitive performance and they seemed to be a little bit better. So, that was really exciting and we were really buoyed by this. Now, our animal studies are really telling us what is going on in humans. Great, however, there’s always a but. We then took the strain of bacteria that probably has the most robust effects in animals. This was a Lactobacillus rhamnosus from John Bienenstock’s group in Hamilton. And, that you know had so many robust effects and we had worked on the mechanisms from the vagus nerve so we were sure now we were going to get the same robust effects in our healthy volunteers. And, we used the same paradigm as I just described for the Bifidobacterium and I can tell you, you cannot get more negative data in to the publication that we have on that. It did absolutely nothing. So, we called the paper, Lost in Translation? because all of these differences. But, this highlights some of the challenges that we have going from animal studies, animals kept in a very controlled environment with the same diets, they are normal animals versus going out into the human population where everyone has a different microbiome to start with and we’re trying to go with it. So, there’s caution in understanding this but it’s very important movement forward. That said there’s a neat study from New Zealand that just came out a few months ago on a similar Lactobacillus Rhamnosus, a different strain but it was L. Rhamnosus where pregnant women had taken a drink in the last trimester and through lactation. If I recall correctly, the really robust attenuation of the incidents of post-partum depression and anxiety in the people who had taken the Lactobacillus vs. controls. I mean, that’s really an important public health result because post-partum depression is huge and you know, pregnancy is one of the key things we know that can in women, stimulate a depressive episode so — in a controlled fashion. This was a placebo-controlled trial, it was a secondary outcome though but it was really intriguing. So, it may not work in healthy volunteers, it may help prevent people who are going to go through other types of stresses or other types of challenges. And so, I guess the big question is: where are we now? Where are we in this — and that you know, our book has this big bold statement that says, “Psychobiotic Revolution.” I think it’s kind of the beginning of a revolution. It’s a beginning of also a change in people’s perspective and their mind. And, we have to — with a lot of caution needed as we navigate that, but you know people want to know, well where will we be in five years? And, where is this field going? I think where it’s really going is where we’re beginning to get evidence-based approaches where we have real robust, human trials supporting the beneficial effects of psychobiotics, by whatever means. I think that we should have in the next five years, a whole slew of a variety of different strains of bacteria where different prebiotic approaches or even symbiotic approaches that we know do something in certain populations under certain conditions.
  • Tracey:
  • In your book, The Psychobiotic Revolution, you mention that there are things that can cause dysbiosis or a need for psychobiotics in the gut. Would you mind going through some of those things that can cause distress in the gut?
  • John:
  • Yeah, it’s really important question to try and understand you know, what are the factors in certain individuals because it’s not that everyone who is subjected to some of these will go through changes — functional changes in their gut microbiome. I guess you know, infections and inflammation are very key because a lot of them target our immune system, and our immune system is prime of what’s going on in our gut. But, what I would say is almost every chronic disease has now been shown to have you know, changes in gut microbiome. And, that’s you know an important aspect. Some of them are better studied than others but like inflammatory bowel diseases, but there are very few diseases now where the gut microbiome is left intact. And, that tells us two things. One is that the importance that we need to look across multiple syndromes or partly that you know, if the microbiome changes in all of these, could it be an underpinning factor that could be tapped into to try and mend what is going on and treat. So, in addition, we did a lot of work on stress and we know that across multiple species, the chronic stress is going to affect the microbiome. But then, what about medications? Like you know, the variety of medications that people take every day and a lot of things are also interfering with the microbiome, ranging from pain killers which will affect gut function and cause constipation to chemotherapeutic agents, whose side effects, many of them are driven by what’s going on in the microbiome. But there’s another side because even some of the — efficacy of some of these drugs, like new studies from cancer checkpoint inhibitors as well as even drugs for diabetes, like Metformin, are shown to have their efficacy is driven by composition of your microbiome. So, you may need to switch your microbiome to make it more responsive to a specific drug. It’s a whole new area that we haven’t really thought of, talked of before. We’ve done studies in animals with antipsychotic medications which you know, one percent of the population are on an antipsychotic medication and they have really bad side effects in relation to weight gain and we’ve shown that this weight gain is due to changes in the microbiome. So, could we target the microbiome through — to reverse this? Indeed, a very recent study from Phil Burnet’s group in Oxford, an animal study but it has shown that by giving a prebiotic, they could restore some of the altered microbial composition that’s driven by antipsychotics. And, this change in the gut microbiome is also seen in a different human population as well. Alcohol, well excessive alcohol is not good for anyone and it’s also been shown to change the microbiome. We’ve done some work in again in animals to be able to look at mechanisms underpinning that, that’s showing again that there is an effect that is very pro-inflammatory. This is what’s also showing in the human study from Leclercq and colleagues in Belgium so that’s quite important.
    The other factor that influences the gut microbiome is the timing on which we eat and the timing on which — things like jet lag and circadian dysfunction and shift-work, all affect the microbiome. And living a sedentary lifestyle has negative effects but then also, exercising. People are looking at the microbiome of elite athletes that’s what my colleagues here in Cork are doing such studies overall. And then, unfortunately, as we age, our microbiomes starts to lose its diversity and that’s really an important aspect. And then, I should mention also because we’re quite interested in for our own research is that early in life, we know for the most part we get our microbes from our mom as we are emerged through the birth canal. And, that’s kind of evolution’s way of passing this really good baton of microbial health onto the infant, and that colonizes the infants gut and then supports what’s is going on. However, if the
    infant is born by C-section, then things are different because you missed this — what’s going on. And then, this is important to know because we know in C- section, there is increased relative risk of asthma, allergy, type I diabetes. We have yet to explore brain health outcomes in epidemiological studies in C-
    section and we find subtle and we thought we found more robust changes but there is definitely something there. C-section rates are basically spiralling out of control in the developed world. They are really, really high in the developing world. If you look at parts of China and Brazil, their C-sections can be as much as 70 percent. So, you know we need to take that as a public health concern. However, C-section is a medically indicated, life-saving intervention that will have to happen in modern obstetric practice for about 15 percent of the population by WHO Guidelines. So, what do you do? Can we do anything with infants that are born by C-section? And, a lot better than the – you know, than what is going on. So, that’s another thing we’re quite interested in developing these kind of new psychobiotic approaches early in life that are going to be able to you know, take on board and replace some of the missing microbes that the C-section is causing.
  • Tracey:
  • SO, John you have led us through some of the things that could be causing distress to the microbiome and the need for a psychobiotic. Can you lead us through the action plan for utilizing psychobiotics?
  • John:
  • Right, so basically towards having a better, what we would call a psychobiotic life?
  • Tracey:
  • Yeah.
  • John:
  • Okay, so it’s almost the opposite of what I said in some ways. So, things that cause/avoid and things that you know — but you know, I’ll go through it because I think it’s important and worth reinforcing. Okay, one is diet?
  • Tracey:
  • Right.
  • John:
  • You know, can you increase your prebiotic intake? And, you know that comes down to fibres and vegetables in general. Can you increase your Omega-3 fatty acid concentrations? So Omega-3’s we hear a lot about Omega-3’s, their beneficial effects overall. Recent data emerge that Omega-3 fatty acids actually affect the microbiome. Both from animal studies and also from human studies. Where people are seeing specific, subtle, but significant changes in the composition of beneficial bacteria following taking either capsules of Omega-3 or through Omega-3 rich — enriched diet. I think that’s really exciting because we know Omega-3’s support brain health in different time windows. For example, they — have been shown by Felice Jacka and others to be part of the Mediterranean diet and dampen down depressive scores so I think that’s quite [something] and, we have to understand Omega-3’s have multitude effects, it’s not just affecting the microbiome. But, it is an important new way of thinking that maybe Omega-3’s are indirectly being prebiotics.
  • Tracey:
  • That’s interesting, okay. Can you elaborate more on the polyphenols?
  • John:
  • Yeah, polyphenols. I mean, it sounds like a 1970’s disco queen but polyphenol is a — these are really important aspects of diet from nuts and seeds, from coffee, dark chocolate and red wine. How could you complain? But also, olive oil and different berries. Well, polyphenols have been shown also to have beneficial effects in health largely thought to be because of their antioxidant potential. However, a vast amount of polyphenols don’t actually get broken down in the upper gut and actually get all the way to the colon where they are acted upon by the microbes to produce novel flavonoid based chemicals. They also, intriguingly can affect the microbial composition in a positive way. So, again where we begin to see that you know — and these are also part of the Mediterranean diet. You know, so basically a Mediterranean diet is really good. So, another aspect of your diet that you can actually take control of to have a psychobiotic life is to increase the intake of fermented foods. Those that we see from yogurts and fermented milk, like kefir and a lot of people are focusing on kefir and its benefits. We still need studies to validate this on brain health but it is — one thing we’re working one now, I’m looking at can we optimize a fermented milk drink that might benefit what’s going on. Also, other fermented foods ranging from sauerkraut to miso to kombucha are also important in this regard. So, that’s what you can increase. So, like everything in life, optimal diet is all about you know balance so if you’re increasing something, perhaps you should decrease something else. And, what would be decreasing levels of processed foods for sure, and emulsifiers and sweeteners have been shown to be particularly perniciously damaging for the microbiome.
  • Tracey:
  • Is it all emulsifiers and sweeteners or can you clarify?
  • John:
  • Yeah, there are differences between them and certain ones — but a lot of them are having pretty bad effects on what is going on. So, I think we do need to get into more granularity in terms of teasing that question apart but a lot of the studies — I mean, a lot of these studies happen to come from animal studies and then, the findings in humans are maybe not as robust. But we need to do more
    on that and it’s quite clear that these are having direct negative effects. And, that’s probably linking into the processed foods aspects. The next thing: stress. Try to avoid it but it’s part of our everyday life so it’s in dealing with it and looking at alternative approaches that might help you deal with stress. Because I cannot mention this top-down regulation that where microbiomes as well as the microbiome up. So, you know things like mindfulness and yoga and meditation, people are exploring. The impact that they have on the microbiome right now, just like exercise would have. Sleep. The sleep field is beginning to
    wake up to the microbiome and we know from studies — in human studies in jet lag how really disturbing that jet lag will have on microbiome composition. And, our microbes are driven by synchronicity and our food intake is driven by this because we eat in a very patterned fashion, in a specific — I know microbes have evolved to respond to foods in the morning, in the afternoon and in the
    evening but then, as you go in a different time zone, then you’re eating at a time when you might go thought like well, what is happening here? I’m getting — you know, so that’s important. Or if your sleep is disturbed, then that’s very important. Okay, easy to say but you know, avoiding C-section or minimizing C-section, you can’t affect how you are born now but moving forward, we should try as a society to try and make people aware about the potential issues around C-section and just, you know, to try and minimize that. And then, on supporting breast-feeding in society. So, that would be very important because we know that the human breast milk, as I mentioned has been so evolutionary
    driven to support the microbiome and the psychobiotic way of life. Minimizing antibiotic use, that goes without saying. Antibiotic resistance is our modern plague but on top of that, we know that the impact in the long-term enduring effects of antibiotics both given in early life and throughout life are having on our microbiomes causing distress so we should try and minimize this. And then, there’s growing field of research about the built environment and the environment we live in and the microbiome. So, things like — it’s been shown that having a pet increases your diversity. Or, the type of building you live in
    or whether you live in the countryside or live in a rural urbanised setting. That’s quite different and people are looking now at population-based studies where for example, if we look at the microbiome of people who grow up in a modern hunter/gatherer situation in Tanzania, which is very rural and they eat a lot of fibre, that they have a much more robust and diverse microbiome than a westernised culture. We also know from studies also, to see the impact that agriculture has had on the microbiome by examining modern life in Malawi and Venezuela, parts of Venezuela, rural Venezuela, you can see that
    agriculture is — has led to a loss of some of these microbes. But, in these populations, whether it’s in Malawian population or in the African populations, like Tanzania, what we know is that there’s no — very little autoimmune disease or inflammatory disease. That these diseases are modern responses to perhaps an extinction of key bacteria that our ancestors had. And, we know also that multiple sclerosis as a brain disorder isn’t present in these populations as well. We know very little about psychiatric illness or whatever because of transcultural differences in trying to tease them apart but to me, it’s quite clear that what we had done in making our diet our lifestyle so different than what our ancestors had is basically entrenching us with the susceptibility factors that come with some of these chronic diseases.
  • Tracey:
  • Right, so in essence, I think what you’re studying and what your lab is you know sort of saying is that the microbes are really playing a huge factor in our thoughts, our cognition and our social behaviour.
  • John:
  • Absolutely, absolutely and I didn’t go into great detail on all of the evidence on that, but that’s exactly where we are. All aspects of our behaviour and our brain are being in some way regulated by what is going on in our microbiome. So, while in the 20 th century microbial medicine was all about killing germs and getting rid of bacteria, well we now need to appreciate the importance that the
    microbiome has in maintaining our health and especially our brain health.
  • Tracey:
  • Right, absolutely. Thank you so much, John.
  • John:
  • My pleasure.