THE MICROBIOME SUMMIT : The Paradigm Shift
The Brain-Gut-Microbiome Connection
Dr. Emeran Mayer, MD, PhD
Dr. Emeran Mayer is a neuroscientist and a gastroenterologist so well known, he is often quoted by other researchers. He is also one of the pioneers of the gut-brain axis. He has published more than 300 scientific papers, and is the author of The Mind Gut Connection, published by Harper&Collins. In this interview, Dr. Mayer will make the “invisible” concept of the gut-brain axis visible, by painting a clear picture of this complex relationship. You will learn all about the relationship between our gut microbiome and brain – and its huge impact on our health.
- TRACEY:
- Thank you for joining me here this morning Emeran. I really appreciate you coming to speak with us. I really enjoyed your book the Mind Gut Connection. I learned so much from you and was really excited to speak with you and get you to elaborate more on what is the – the Gut Brain microbiome axis?
- EMERAN:
- Thanks for having me on this show. So the gut brain microbiome axis something that most people probably have not thought about in these terms. So, as the word says, it’s the connection between integrated and bio-directional connection between the brain, the gut various cells within the gut and systems within the gut. The internal nervous system. The immune system and the endocrine system. And then the latest player in this is where they become the gut microbes. It’s just by the sheer numbers is a very impressive system. So, we have 100 trillion microorganisms in the gut, and they make up microbiome. We have 50 million nerve cells that make up the enteric nervous system. So, in nervous system that’s kind of wrapping around our gut it’s not visible when we do an endoscopy or during surgery because it’s sandwiched in between the layers of the gut. Then we have these endocrine cells, hormone producing cells that are dispersed throughout the gut at least 20 different types of hormones. These hormones are being released in response, for example, to food. Also, one of the particular important cell, the serotonin containing cells in the gut 95% of the all bodies serotonin is located in the cells. So, even though we think it’s important to treat the serotonin in the brain with drugs like Prozac the great majority of this neurotransmitters that are located in cells within the gut. And then we also have the largest portion of the body’s immune system located in the gut just underneath the epithelial layer that separates the inside of the gut from from the outside. So, it’s a remarkable accumulation of systems they’re in the gut, which is within microbes of these microorganisms that are not human cells but are very micro- microbial cells. It’s been found so you can look at this brain gut microbiome axis from a from a microscopic level. You have the brain. You have the gut. You have the microbes. But you can also look at it from the interaction of a lot of very complex systems, each of which has been studied and characterized on its own so most psychiatrists have never thought about the gut or the microbes and have explained all the psychiatric diseases on the same level of the gastroenterologist have studied the gut for decades and have never thought about the brain or the microbes until very recently. So now we’re putting these together. We know that – that all of these cells interact with each other and there’s the immune cells and there’s the nerve cells. The microbes they all speak the same language because they have signaling molecules that are shared so have been involved during evolution of the microbes have very similar chemical substances by which they communicate with each other but also with us. So, the system the brain-gut-microbiome axis is essentially a very complex network of players all of which speak the same language and all of which in some ways interconnected. That’s important because if you trigger this system from the brain level, so there’s a molecule called corticotropin releasing factor or hormone CRF secreted by specialized cells in the hypothalamus, the brain region and when that happens, it triggers a cascade of events that goes by the sympathetic nervous system to the gutcells it influences the microbial behavior the chemicals that the micros produce act back on us and on sensors in the gut, and the signals go back into the brain. So, that’s one simple example of how this system can be triggered from the brain, and it can also be triggered from the gut-level. Those portions of the food that are not being absorbed in the small intestine and get into the large intestine where the microbes – most of the micros live, they break down into molecules that the human body then can absorb but also in many of these molecules have signaling functions, so they can act on multiple receptors in these gut cells. For example, stimulating serotonin release so the microbes have a big role in stimulating serotonin release, which then through the vagus nerve, this big connection nerve connection – connections we have between the gut and the brain. This serotonin can activate the nerve fibers that go back into the brain so food can engage the brain gut microbiome communications and just like a brain stimulus such as stress or emotion can do it. The consequences of this thinking of these multiple communication pathways are that this basically is not an emotion that will not have the gut microbiome component to it. So, even though, we think it’s just all in the brain or it’s for many people an emotion is something psychological. It’s really a engagement of the entire system with a gut component which is a contractions which are specific for each emotion but also now we know with a microbial component plays a role in feeding back the gut activity back into the brain. So, multiple players that all interact that probably cannot function in isolation. Probably one of the big reasons I think we’ve had difficulties in developing new and effective drugs for many like psychiatric disorders or common gastrointestinal disorders such as irritable bowel syndrome, is the fact that we have never seen the interconnectedness of that big network of big or regulatory network. Most drugs have a small effect that many side effects because all these other players in the system react to a drug in a way that we had not intended to. So the story that chronic gastrointestinal symptoms, functional gastrointestinal disorders with equally psychiatric disorders and there hasn’t been any breakthrough in therapies despite a massive effort to identify individual cells either in the brain or the gut without looking at the rest of this complexity.
- TRACEY:
- Yes. Absolutely. It is such a complex system. I like how in your book how you talk about the vagus nerve as being the information highway. Sort of you – you lean to the California Highway. I call it the 401 if you’ve been to Toronto. It’s moving at lightning speed though as we all wish the traffic would move here.
- EMERAN:
- So, the vagus nerve. there’s different ways that the signals from the gut can reach the brain. So, one is through the vagus nerve – the nerve bundle that essentially connects the brain to all our organs. There’s a special branch that goes to the lungs, to the heart, to the kidneys, but the one that goes to the G.I. tract is probably the greatest importance. It has the sensors that can encode different kinds of signals in the gut. It can encode if the hormone is released in these gut cells, it acts on the vagus nerve. If immune mediators like cytokines are released, and it acts on other receptors on the vagal afferent sensors. So, it’s basically collecting on the milli-second, milli-second basis 24 hours a day. Any information – subtle information – that goes on that comes from the gut and its microbes. So, mostly likely also during sleep will receive signals from the microbes that live there, and constantly send it. What’s interesting about the vagus nerve it’s a two directional highway because one portion, the smaller portion, which is really a fraction of the entire nerve sends signals from the brain to the little brain of the gut, the enteric nervous system. But most of the information goes the other direction. So, it goes from gut to the brain. Most of this information we don’t perceive consciously, but there’s pretty good evidence that are backgrounding motions so when you wake up in the morning and somebody asks you, “How do you feel today?” That is almost certainly influenced in part by the signals that the vagus picks up in your body and you know to a large degree from your gut and sends into limbic or emotion modulating regions within the brain. I mention this in my book as well. I mean there used to be a surgery for the most effective search report Peptic ulcer disease and surgeons with cut that nerve completely. Its remarkable that this was actually compatible with life, I would say. But what’s been forgotten that many of those patients had developed very strange symptoms after that surgery so the ulcer disappeared, but they developed very strange symptoms, and affecting their emotions and I think today we can understand why that happens because you deprived the brain of a major input that comes from the gut.
- TRACEY:
- Can you explain a little bit to us about how this gut-brain-microbiome axis may be playing a role in IBS or depression and what exactly is happening?
- EMERAN:
- Let’s start with IBS where we know that the great majority of patients have clinically being involved and of the brain and the gut portions of the microbiome is a recent addition to this. At the gut level and that’s kind of the main clinical presentation – chronic abdominal pain and discomfort associated with alterations in the bowel habits. One way to explain it and there’s in the great majority of patients a spectrum of brain related disturbances seen from, you know, in a mild forms of a more anxious behavior and more worrying behavior all the way to an excited disorder. I perceived from our research and our clinical experience would say it’s not IBS patient that does not have the brain component as well. It may be very mild. So, how does it work? It’s a good question because we still don’t know what comes first is that you’re born with a greater stress responsiveness that generate signals that go from the brain by the vagus nerve and the sympathetic nerve to the gut and make the gut contracts in different patterns change because its influence is chronic change the composition and the metabolites that your gut microbes produce, which sends signals back to the brain. We already know from these cross-sectional studies that look at the brain with brain imaging we see evidence for increased stress responsiveness and increased sensory processing. We go to the gut level, we see increased contractions and secretions of the gut. If you go to the microbes now there are several studies out in the conflicting results still, but there’s an alteration so-called dysbiosis of gut microbes, which could either be just simply secondary to the signals the gut gets from the brain and because of the increased stress responsiveness of the brain. Or it could be something that’s related to previous infections like post infectious IBS. The only thing we know right now is that all three components are involved in IBS possibly to different degrees in different people. So, I think we’re still a little away from being able to answer that question, what comes first? And it’s even possible that both, that IBS is something that could be triggered from both ends of the brain gut microbiome axis that some subset of patient’s primary brain disorder in another subset is primarily a gut disorder.
- TRACEY:
- In patients who experience depression, what do you think is happening there in the axis?
- EMERAN:
- So, with depression you know there are some interesting studies and there’s even a recent human study. Most studies have come from mouse models that have looked at depression -like behavior. I won’t have the time to get into what this exactly is but obviously, the mouse doesn’t have the same feeling of depression but it shows the behavior that we interpret as being depressed. We know that it’s often associated with constipation in many patients and most likely based on the brain-gut axis. I think we can say that this is constipation is in part related to the signals that the brain sends down that the depressed brain sends to the gut. But then there’s also what we know now of today about the serotonin system, which has been implicated to a large degree in depression now that we know most of the serotonin sits in the gut and very close to the vagal nerve endings that’s transmit that signal to the brain. We can almost certainly say that depression also involves the gut serotonin system. If you take patients with depression of a major depressive disorder and look at their gut micro biome ah it’s altered, you can separate patients and healthy people based on your gut microbiome composition. If you transplant these gut microbes from depressed patients into mice, the mice will develop this depression-like behavior as I mentioned earlier. These researchers have also identified the chemicals that these depressed microbes produce both in humans, but also after transplantation into the mouse and these metabolites of the signaling molecules by themselves can induce depression like behavior. So, we know that even though the brain plays a big role in depression in and certainly inexperience, there’s something in the microbes and molecules that are produced that can transfer a depressive trait simply based on microbial transfers. So there something at the microbial level that is clearly altered in a way that can transmit almost like an infectious disease the depression from one organism to another.
- TRACEY:
- In your book, you describe the toxoplasmosis gondii and I thought that was such an incredible story.
- EMERAN:
- We’ve been talking and in discussion mainly about the microbiome and its benign symbiotic of microorganisms that we live with. But this fascinating stories in the world of parasitology of microorganisms that have phenomenal skills and knowledge of our nervous system that they utilize for their own purposes. So these parasites have a much greater knowledge and ability to influence the human nervous system that any neuroscientists or any psychiatrists has and it’s pretty based on the fact that you know the microbes have evolved over billions of years’ and have developed the knowledge and a communication signaling system that’s been the basis of our nervous system. So, they’re the ones that have basically transmitted the genes for our nervous system to develop and if you take this example of toxoplasma for successful reproduction. It has to get into the gastrointestinal track of the cat in the best way to get in there or the only way to get in there is it has to be transmitted by something that the cat eats and digests and then it gets into its small intestine. And mice and rats are obviously the most natural food for cats. Or used to be the most natural food and normally will be very difficult or not very efficient way of transmitting these organisms and closing the lifecycle. If the cat would have to catch these animals because they have this inborn stress response – fight or flight response. So, whenever a mouse sees a cat, he runs away. So, what happens when the mouse gets infected is that organism gets to the brain of the mouse and changes the fear response circuitry within the mouse and also changes the circuitry that has to do with sexual attraction. And so, now instead of running away from the cat the mouse feel sexually attracted to the odor of cat urine so, the mouse will actually move to the cat and greatly enhancing the chance that’s being eaten and the organism can reproduce in the cat’s intestine. Both disabling the stress response and increasing sexual arousal are two feats yet that our neurobiology has not been able to do. Would be very successful drugs. But we’re far away from that goal. So, a good example of what microbes can do.
- TRACEY:
- Absolutely fascinating. Thank you so much for explaining no of this to us today.
- EMERAN:
- Okay. It was a pleasure. Thank you.
