How The Microbiome Affects Stress, Pain And Mood with Dr. John Cryan, PhD

Welcome back to the Healing Pain Podcast with Dr. John Cryan, PhD

The microbiome is an interesting and rapidly growing area of research. There are trillions of microbes inhabiting our bodies, and we have more microbial cells than we do human cells. Dr. John Cryan, PhD, professor and Chair of the Department of Anatomy and Neuroscience at the University of Cork, Ireland, talks about everything involved with the microbiome, from mood to pain to neurotransmitters through our nutrition. His current research includes the neurobiological basis of stress-related disorders including depression, anxiety, pain, and drug dependence. His research group is also focused on understanding the interaction between brain, gut, and microbiome and how it applies to stress and immune-related disorders, including irritable bowel syndrome, obesity, and other disorders such as autism. His research into the microbiome has far-reaching public health implications – from how he views his area and sections to how the microbiome influences brain development, chronic pain development, and of course the impact of probiotics on mood. Dr. John Cryan, PhD discusses the influence of the microbiome on pain, mood and stress.


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How The Microbiome Affects Stress, Pain And Mood with Dr. John Cryan, PhD

On this episode, we’re discussing the influence of the microbiome on pain, mood and stress. Joining me as our expert guest is neuroscientist John Cryan. Professor Cryan is Chair of the Department of Anatomy and Neuroscience and Principal Investigator in the Alimentary Pharmabiotic Center at the University of Cork in Ireland. His current research includes the neurobiological basis of stress-related disorders including depression, anxiety, pain and drug dependence. His research group is also focused on understanding the interaction between brain, gut and microbiome. How it applies to stress and immune-related disorders, including irritable bowel syndrome, obesity and other disorders such as autism. His research into the microbiome has far-reaching public health implications from how he views Caesarean section to how the microbiome influences brain development, chronic pain development and the impact of probiotics on mood.

He has published over 440 peer-reviewed articles. He is a senior editor of Neuropharmacology and of Nutritional Neuroscience. He’s also the co-author of the bestselling book called The Psychobiotic Revolution. The microbiome is an interesting and rapidly growing area of research. We cover a lot of ground on this interview in a short period of time. John’s a wealth of information and I know this is one that you’ll enjoy.

John, welcome to the podcast. It’s great to have you on.

Thanks, Joe. It’s great to be here.

I’m excited to talk to you about everything involved with the microbiome, everything from mood to pain to neurotransmitters, to our nutrition. I’m curious and I’ve watched your TED Talk. Your TED Talk was interesting. How did you get interested in studying the microbiome? Is that what you started out studying?

It’s not what I’ve started out studying at all. Originally, I’m trained as a pharmacologist, neuropharmacologist and neuroscientist. I got dragged into the microbiome world by following the data and basically over a decade ago, we were working on stress. That’s the one team that has permeated my career for the last two decades, but we were interested in the impact of stress is having on our entire body. We were working on a model of early life stress and we were able to show that this created a whole-body syndrome. Changes in behavior and the immune system and in pain responses, in particular, specifically a visceral pain response in a variety of neurochemicals in the brain, in what was going on even locally in the gut.

One of the things we found back then, we noticed that the diversity of the microbiome was greatly reduced in these animals that had been stressed in early life. That there was a signature in their microbiome of this early life trauma. This could have been epiphenomenological. It could be due to many other things that could be impacting it. It got us on this journey and it got us thinking, “What if it is the fact that stress is affecting what’s going on in the microbiome?” Then we started noticing in the literature some random papers that have been out there for a number of years showing that if you take the microbiome out in animals, you alter the stress response. These germ-free animals that grow up without ever having microbes in their gut, they have an exaggerated hormonal response to stress. That was the second part of it.

We have more microbial cells than we do human cells. In terms of genes, we are more than 99% microbial.

Then we started working on these germ-free animals to see what was going on with them in their brains and how the brain was dealing with stress. We showed, along with groups in Canada and in Sweden, that there were very marked neurodevelopmental alterations in these animals. We’ve more recently shown that they have exaggerated visceral pain responses, for example. We’ve looked at myelination in the brain and found that there’s hypermyelination of the prefrontal cortex. A very much important area for higher cognitive function. We use these animals then to validate our stress studies. We’re showing that stress is affecting the microbiome. The microbiome, if you don’t have them is affecting how we deal with stress. That leads us to the concept of could we modify the reaction to stress by targeting the microbiome. That brings us to the area of psychobiotics.

Stress is so important for anyone, whether it’s someone with chronic pain or pretty much everyday life stress. If someone were to open PubMed and read about the microbiome, there are different types of terms and terminology that come up. It’s important before we go on if we clarify some of those. Can you describe the difference between the microbiome versus the microbiota for people?

These are words that are often used interchangeably. The way I see it is that your microbiome is a collection of genes that make up your microbiota. Your microbiome is like your genome and your microbiota are the cells themselves. What we measure at the genetic level, we’re often measuring the microbiome but we’re trying to infer function on the microbiota.

The microbiota, you can see with the naked eye but we’ve heard numbers about how many there are. Give us an idea of what that’s like.

There are trillions of microbes inhabiting our bodies. In terms of genes, we are more than 99% microbial. We have more microbial cells than we do human cells. It’s quite humbling when you think about it. You think of all the amount of money we spend on genetic research and it’s less than 1% of our actual genes. A lot of focus has been on what’s there and trying to delineate what the composition of the microbiome is. It’s also getting important now and put a lot of emphasis on what they’re doing because you can have different populations doing different things. That’s where the metabolome comes in and how these metabolites are important as well.

I want to talk about some of those metabolites. First, I want to talk about the microbiome over the course of someone’s life. How does that develop and potentially changes and what affects it?

For the most part, we’re told to be sterile in utero, although our placental microbiome has been discovered. We get our early frontier microbes as we come through the birth canal from our mothers. These bacteria in particular, and that’s something I should point out, is when we say microbiome, we normally are only referring to the bacterium. Our microbes make up the viruses and the fungi. There is much broader repertoire of organisms than just bacteria. For the most part, largely for technological reasons, what people are studying are bacteria. In areas like these, bacteria are critical. They informed the developing immune system. They lay down how that interacts with the developing gut. What we’ve shown then, it can also influence the developing brain and spinal cord.

We’re beginning to slowly see that how perturbation in this early life period of this microbiome could have long-term enduring effects. Perturbations can be quite ranging from serious things like prematurity and to a mode of delivery at birth. If you’re born by C-Section, you have a different microbiome, to the widespread use of antibiotics, to not being breastfed, to the cleanliness of the environment. Where we’re beginning to see in a variety of different studies that there are long-term effects potentially of this perturbation on the programming of the immune system, on the developing guts and potentially on the brain, although we still have a long way to go to drive a causal link there.

In the average adults, let’s say in their 30s, 40s, 50s, is the microbiome stable or is it changing on a day-by-day, week-by-week, month-by-month basis?

It’s a great question and it’s one that we’re still grappling with. For the most part, once we become an adult, our microbiomes remained relatively stable as long as the environment we live in and the diet we take remained stable. Once you modify them considerably, you can alter the microbiome. Then as we age, it starts to decline. There are studies, including studies from here in Cork in Ireland, where people have begun to look at the relationship between the stability of the microbiome and aging and the health outcomes. Specifically in relation to frailty and sarcopenia and showing that the more diverse the microbiome has maintained the better the health outcome. That’s a good lesson for all of our lives. We want to keep a diverse microbiome for a better health outcome and we need to look at ways to do that. Perhaps one of the best ways, at least with the most evidence is through nutritional sources and through the diet.

HPP 109 | Microbiome
The microbiome is fighting what’s going on locally in the gut, but we’re also seeing this more and more with many inflammatory disease.

The topic of frailty is so important especially as we have a population in the United States and probably around the world that’s aging. It’s the largest population that we have. The topic of frailty is important. Let’s go back to the function of the microbiome and what it affects. When we think of the gut, we first think of food. How does the microbiome affect the food we take in? How does it interact with our food?

It depends where you are in the gut. A lot of the research is focusing on the microbiome in the lower gut. It’s almost in a post-absorptive phase of digestion. In a way, it’s like a big sensor for many of the metabolites that are coming from our food. If you think about that the microbes can basically use nutritional substrates to create a lot of chemicals that our bodies would not have otherwise. Among the best studies that are there are what we called short chain fatty acids. These include butyrate and acetate. These chemicals are important for priming our immune system and developing gastrointestinal tract and are seen as very positive molecules. We would not have them in our bodies without microbes. Microbes basically attack fibers in the diet to create these molecules. That’s just one example, but there are thousands of examples of how nutrition interacts with the microbiome to give chemicals that our body wouldn’t have. Not all of these chemicals are good.

One of the other well-studied examples is from a chemical called TMAO, which is made by specific microbes from carnitine and red meat. This TMAO is what forms the basis of some atherosclerotic plaques. Without certain bacteria, you won’t form this TMAO and therefore you’ll be immune from some of the effects of red meat on cardiovascular function. You can either stop eating red meat or modify your microbiome or both. That principle applies to many other areas. What we’re interested in is can we do this in relation to brain health or in relation to pain or other processes? Can we modify or understand the extent to which the diet is being transformed by the microbes into chemicals that are both useful and those that might have a more pernicious outcome?

The point on red meat is interesting because there’s a lot of controversy over how much red meat to have or should you have red meat at all? What you’re saying is make sure you have the right microbes there that will help digest it. As most things in diet, don’t eat too much of any one thing. When we start to look at the function of the microbiome as far as creating neurotransmitters, which are important when it comes to things like anxiety or depression or cognitive function or chronic pain. Can you talk about the role of the microbiome as far as neurotransmitters go? We often think that neurotransmitters are made in our brain.

Neurotransmitters are made in our gut. 90% of the body’s serotonin, for example, is made in the gut. Serotonin is very important neurotransmitter for our pain process. What’s not clear, and this can get often overstated, is what is the relationship between luminol, which is in the gut levels of these neurotransmitters and complex processes related to the emotional aspects of pain or other disorders? That we don’t know enough about right now. What we do know is microbes are modulating at the levels of specific neurotransmitters. We’ve worked on GABA producing ones for example. We’ve also shown that certain microbes can affect GABA in the brain, but these may be completely dissociated. I have to bring a level of caution that we don’t know what’s going on. Just because neurotransmitters are in the gut, it doesn’t mean they can’t have effects on neurons in the gut.

We have the enteric nervous system, the body’s second brain, which is a very important conduit for signaling the gut-brain axis. If we can get neurotransmitters modulating the ENS function, it could play a role in in visceral pain and how it sends overall. A lot of work is trying to understand the relationship between the microbiome and certain neurotransmitters as well as other neural hormones. Also, the microbes can stimulate the release of hormones from what we call enteroendocrine cells in the gut. These hormones, which also includes serotonin, but other peptides can also interact with the local nervous system within the gut as well as the immune system in the gut and drive aspects of inflammation that would be having negative effects, especially in relation to pain responses.

When you say inflammation in relation to pain responses, do you mean inflammation and pain responses locally in the gut or they have more of a systemic effect?

It’s actually both. We know that the microbiome is affecting what’s going on locally in the gut. We’re seeing this more and more with many inflammatory diseases as been shown to be regulated by the composition of the microbiome. It can be a much more widespread effect. That’s why there are great efforts now to try and find interventions that are targeting the microbiome that will have a systemic anti-inflammatory-like effect.

You mentioned serotonin and you mentioned 90% of it is produced in the gut. It can act locally in the gut on different cells or the nervous system in the gut. I guess the question is the neurotransmitters that are produced in the gut, do they circulate to the brain or do they stay local? Do we have enough information on that?

It’s unlikely that many of them will get into the brain. We know some of the precursors. For example, serotonin is made from the precursor tryptophan, and tryptophan comes from the diet, and we know that tryptophan metabolism is regulated by the microbes. That would be an indirect way of getting to the brain and influencing what’s going on in the brain. It would be premature to think that the levels of neurotransmitters, even if they get to the systemic circulation, that that would be enough to get it through the brain. The brain is very well-protected in terms of allowing different molecules in and out.

HPP 109 | Microbiome
We have ongoing studies testing whether specific strains of bacteria are direct ways of boosting the microbiome and could actually dampen down the stress response.

It might not cross the blood-brain barrier at least in that form. As we talk about the gut-brain connection, which is where we’re heading, the role of the vagus nerve and the gut-brain connection, how does that interact with the microbiome?

Once we started finding that certain strains of bacteria could modulate behavior and dampen down the stress response in animals, we started looking at how can bacteria in lumen in the gut signals to the brain? The vagus nerve comes up quite quickly as a potential conduit for such signals. This is a long wandering nerve that basically senses how various organs are operating and sends the signals to the brain continuously. Also from the brain, it tells from the brain back down to these organs. It plays a crucial role. We know that people have been tapping into the power of the vagus for many years now in a variety of different syndromes, including chronic pain syndromes where people are using vagus nerve stimulation. Also in resistant depression as well as in some aspects of epilepsy.

We wanted to see what would happen if we cut off this highway of communication? Would they affect some of those specific bacteria, in this case, with the Lactobacillus rhamnosus? Would it have any effect? We collaborated with John Bienenstock’s group in McMaster in Canada. We did these experiments where basically the animals were vagotomized. The signals were no longer able to get from the gut to the brain and all of the effects of this lactobacillus were gone. I thought I’d like to say, this tells us that what happens in vagus doesn’t stay in vagus, but it will affect our emotions at least for these bacteria and at least in these animals. It is an intriguing part of the story. It’s probably not the whole story but it’s part of it for sure.

It is super interesting how many connections there are and how many connections there can be. You mentioned stress and the connection between the brain and the gut. I’m assuming when you talk about stress, you’re referring to HPA axis function or dysfunction, is that correct?

In that context, mainly yes.

Does our gut affect HPA axis function because HPA axis dysfunction is seen quite frequently in those who have chronic pain?

Indeed we know, for example, not only the gut but the gut microbiome is regulating the levels of the equivalent of cortisol in animals. That’s been well-worked out overall. We know that again locally in the gut, many of the hormones that are like corticotropin-releasing factor, which is very important in the HPA axis, is also playing a role locally in the gut. We now see from a neuroendocrinological point of view that the microbiome is a new part of this puzzle as a key regulator of how our HPA axis is actually working. It will potentially gaze the drive for a susceptibility to acute stressors on this axis. That’s something we’re studying a lot right now in our lab. We’re trying to understand why if two individuals are subjected to the same stress that they might respond differently. How they might respond differently in terms of the HPA axis, but also in terms of the microbiome and is there a link between the two?

These are ongoing studies that we have. They’re also looking at ways in humans to translate some of these animal studies into the human situation. We have very nice ethical ways of stressing people in the lab. We look at HPA axis function as one of the key readouts. For example, we showed in a publication that a specific bacterial strain, a bifidobacteria that had come through our animal studies that have shown quite a lot of potential in dampening down the stress response and reducing anxiety in animals. We’re going then into healthy volunteer and we stress them in the lab. One of the ways we do that is get them to put their hand into an ice bucket of water and have someone observe them that they don’t know. It amounts to a very nice stress response. Those that have taken this specific strain of bacteria, they had a much reduce stress in their HPA axis and in the psychological responses.

That’s helping us to validate that targeting the microbiome will be useful for having effects on the stress response. We have ongoing studies now where we’re looking at chronic stress and we can ethically chronically stress people because we are educators and we make them be subjected to examination periods. We can look at how chronic stress is affecting the microbiome. We have ongoing studies testing whether specific strains of bacteria or prebiotics, which are direct ways of boosting the microbiome could actually dampen down the stress response. This will have, potentially down the road, a lot of implications for pain research because of the comorbidities and because of the risk of flare up and because of their relationship with the immune system.

It’s super exciting that they studied the HPA axis when it comes to stress and pain. Just from what I’ve seen in clinical practice, I noticed that when people stay on mostly plant-based Mediterranean style diet that they have less of a flare-up. That’s anecdotal and I’m sure that needs to be studied in the research. Your research is starting to support what so many of us see in practice or patients have discovered on their own by changing their diet. Most practitioners, when they think about the HPA axis, they think about that classic motto where it’s a hypothalamic, pituitary, adrenal. You’re inserting this whole other, in many ways an organ in our body that helps us buffer a potential stress response. You’re known for starting what’s called the psychobiotic revolution. You have a book on it called The Psychobiotic Revolution. Can you tell us a little bit about what that means and what it entails?

HPP 109 | Microbiome
We have no idea what the normal microbiome is. All we know is what an individual’s microbiome is when they’re healthy.

Based on this research together with my colleague, Ted Dinan, we came up with this concept of if stress is affecting the microbiome, the microbiome is affecting stress, so therefore we should target the microbiome to affect a stress response. That’s where Ted actually came up with the term psychobiotic. We felt it was a good way of capturing the potential impact of the microbiome on our mental health. We’ve expanded the definition. We collaborated with colleagues in Oxford who were very interested in prebiotic approaches. We see psychobiotic as any targeted intervention of the microbiome that will support brain health. We feel that diet is perhaps one of the best ways of doing that. In the book, we wrote the book with Scott Anderson, a journalist in the US and it has a very strong US flavor to it. Scott played a big role in making sure it got done and in writing it and to try and make sure that in it, we can communicate to the everyday layperson about where this research is going. That we are at the beginning of a revolution in terms of turning medical concepts upside down. Also it’s important to say that it’s just the beginning and every revolution began somewhere. We’re at very early days and we need a lot more evidence-based to actually support a lot of what we’re trying to do. It’s exciting and fun.

It’s super exciting research, especially for those who are interested in diet and nutrition as far as helping people with chronic disease and chronic health problems, which is most of what we have in our medical systems. Talk to us a little bit about diet. Diet influences the microbiome. What types of things should people be aware that could adversely affect their microbiome?

The interesting thing about diet in this regard is that there are things we know that you can do to benefit your microbiome and things that you don’t. You asked about what we shouldn’t do, perhaps the best evidence is in terms of having repetitive diets. Typically, white diets that are full of processed food. We live in a world where we can’t ignore processed food, it’s what we do but it is part of the evidence to show that this has the most negative effect on the microbiome. We know that emulsifiers that are often present in a variety of foods and also artificial sweeteners are quite bad to the microbiome. There are things we know we can say no to. What we can do and the great thing about the microbiome, unlike your genome, your genome you can’t do much about it except blame your grandparents and your parents.

Your microbiome, you can have some agency over. You can have a potential to actually shift it. We know that diets that are rich in green vegetables and high in fiber, that have lots of Omega-3 fatty acids and polyphenols. These are all the magical components that we know right now are very good on the microbiome and that they support rich diverse dieters and that’s good. The other aspect of all of this, which is starting to brew up on purpose is the whole area of fermented foods. Things like the three Ks: Kefir, Kombucha and Kimchi, but also sauerkraut and yogurt. There are also more and more studies and that’s why we have ongoing work as well. Trying to look at the relationship between fermented foods, the microbiome and the psychological well-being.

That starts to bring us to the next question, which is probiotics. Let’s talk about the consumer first. You walk into a store and there are probiotics on the shelves. Should someone add a probiotic supplement to their diet? Do we have information on that yet?

It’s still very early days. In the book, we try to take people on that journey in terms of trying to read the label because it’s a minefield. What I would say to any consumer, anything in the microbiome field, they should ask the question, “Where’s the evidence? Is there evidence?” They’ll find that for the most part, the evidence isn’t there yet. That’s my buyer beware scenario with probiotics. A probiotic by definition is a bacteria taking an adequate amount that confers a health benefit. To prove that you have a probiotic, you should have proven health benefits. The vast majority of what’s in health food stores have never been tested and never proven. It’s not clear what they actually even are what they say on the TED. My advice to anyone is to only look at things that have health pamphlets. You wouldn’t go into a pharmacy and pick random drugs and say that might affect my chronic pain because it says the word drug on it. That’s what we’re doing. We’re going in and we’re picking random strains of bacteria that have no evidence that they’ll do anything and expecting them to do things and they don’t. I’m a little bit cautious. That’s why in Europe the word probiotic is banned in many countries.

It’s protected in a way so to speak.

The European Food and Safety Authority have but in the US, still it’s a little bit Wild West.

In the US what I’m starting to see, not everywhere but I’m starting to see slowly here and there certain practitioners using single strands to try to target things or treat things or modify the microbiome. If you go to the health food store, you might find 50 different strains in the probiotic. Some clinicians, mostly physicians with licenses are starting to say, “Let’s try this one single strand.” What’s your thought in the single strand approach?

We’ve worked a lot on specific single strains of bacteria and they never stopped surprising me what they can do. Intuitively you think one strain atop of a trillion, it shouldn’t do much but it does. If you look at where the evidence is in certain disorders, say for example irritable bowel syndrome, which is one of the more widely talked about areas. There is evidence that single-strains will have benefits. That’s important. I can counter the argument in the opposite way that all it takes is one strain of bacteria to make us feel lousy in terms of getting an infection or food poisoning. What we’re seeing is almost the opposite. That one strain, in adequate amounts taken confer a health benefit. It’s getting the right strain for the right patient at the right time. That’s the level of precision where we’re not there yet. That’s where we need to go in all fields. Particularly in fields like pain disorders where there’s been very little research.

Then slowly starting to pop out are these home kits that someone can send away so they can test on their own microbiome. Do you have any thoughts about those? Have you tried those?

The thing with microbiome is that unlike your blood pressure or your cholesterol, people can come to you and say, “Am I in the normal range?” You’ll be able to tell them exactly, “This is what the normal range and this is where you are.” With the microbiome, we don’t know. We have no idea what the normal microbiome is. All we know is that what an individual’s microbiome is when they’re healthy. Therefore, longitudinal measures are going to be important in the future. You’ll know where you are when you’re healthy. Then you start to see how that waxes and wanes as you age or as you go in and out of the disease. What people are starting to look at, although we haven’t got enough evidence yet, but like how does flare-up for a variety of conditions and it’s most studied in Crohn’s disease. Can what’s going on in the microbiome predicts a flare-up? Can you adjust your microbiome back to what it was through your diet or your lifestyle or other ways? That’s the future precision medicine. It will fit in there. We’re not there yet but we’re on that road and it’s very exciting.

What’s interesting is that when you think of the gut and the microbiome, diet is a huge component of it. You also realize that stress affects it and exercise affects it and sleep affects it. You do start to see how lifestyle, precision medicine, all come together and influence it. Tell us what’s next for you? You have quite a big research team over there.

We have a very exciting team in the whole translational space. The two big things that we need to the last decade and we focused on proving and finding out that the microbiome is involved in brain function and in pain responses, in stress responses and in cognitive and neuro-developmental processes. We’ve shown that. We need now to translate that to the human situation. That’s one of our big things for the next number of years. We need to get at the mechanisms because we talked about some of these already, vagus, short-chain fatty acids and the neurotransmitters. We still don’t know where we are. That’s what we have a lot of focus right now. It’s an exciting time and we think that moving forward, we can develop a level of precision into this. Many of the things that animals may never translate to humans. In our animal studies, they have the same diet or kept the same sleep-wake cycle. It’s not so stressful for them overall, whereas human beings are so heterogeneous and to see where this is going to go to impact clinical practice is going to be important as well.

It’s fascinating the work you’re doing. It’s definitely a work I’ll be following either on your research or on PubMed. People can watch your TED Talk. People will enjoy that. Can you tell people how they can find more information about you at the university level?

I’m at the University College of Cork. I can be very easily found in my department. I’m Chair of the Department of Anatomy and Neuroscience there and PI in the APC Microbiome Ireland Center. The book is The Psychobiotic Revolution, so it’s You can follow me on Twitter, @JFCryan and you can see it all there and the links to both my TEDx Talk and my TEDMED.

The book is great for practitioners as well as the layperson who wants to learn more about the probiotic revolution, the microbiome and health. I want to thank John for joining us and giving us this time and learning all about the microbiome. Make sure to share this information out with your friends and family on Facebook, Twitter and LinkedIn, anywhere that you’re social. Sign up for the podcast at I’ll send you the latest podcast to your inbox each week. Thanks for being here and we’ll see you next week on the podcast.

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About Dr. John Cryan, PhD

HPP 109 | Microbiome

John F. Cryan is Professor & Chair, Dept. of Anatomy & Neuroscience, University College Cork. He received a B.Sc. (Hons) and PhD from the National University of Ireland, Galway, Ireland. He was a visiting fellow at the Dept Psychiatry, University of Melbourne, Australia (1997-1998), which was followed by postdoctoral fellowships at the University of Pennsylvania, Philadelphia, USA and The Scripps Research Institute, La Jolla, California. He spent four years at the Novartis Institutes for BioMedical Research in Basel Switzerland, as a LabHead, Behavioural Pharmacology prior to joining UCC in 2005 where he was a Senior Lecturer in Pharmacology in the School of Pharmacy and in the Dept. Pharmacology & Therapeutics UCC. He is a Principal Investigator in the APC Microbiome Institute.

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