S1 Episode 55: The Gut-Brain Connection

Microbes in your intestine are talking to cells in your brain all the time – and what they say can affect everything from inflammatory diseases to psychiatric disorders. Microbiologist David Artis, PhD, and psychiatrist Conor Liston, MD, PhD, explain the connection between your microbiota and your mind – and how to influence their conversation.

Dr. Phil Stieg: I’m really excited to have two scientific pioneers with us today. Their newly published research is significantly advancing our understanding of the powerful connection between our gut and brain health on the cellular level. Their research has major implications for the development of treatments for autoimmune diseases like multiple sclerosis and irritable bowel syndrome, as well as psychiatric disorders like anxiety and depression. Dr. David Artis is the Michael Kors professor of immunology, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and director of the Friedman Center for Nutrition and Inflammation at Weill Cornell Medicine. Dr. Conor Liston is an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute and associate professor of psychiatry at Weill Cornell Medicine. David, Connor, thank you so much for being with us. It’s a great pleasure to be here. So you’re the two stars that are highlighting the connection between the gut and the brain. I realized that these are animal studies and someday we’ll do it in humans, but what have you found in a nutshell?

Dr. David Artis: The project really began with our knowledge that the gut and the brain speak to each other. And we know that in everyday language—what is your gut instinct, what is your gut telling you? But we’ve never understood the molecular mechanisms and the cellular mechanisms that underlie that communication. Very recently Conor and I identified the relationship between the microbiota that colonized the intestine and how they influence brain development and function. The microbiota is made up of viruses, bacteria, fungi, and parasites. We acquire those very early in life and they are our partners in life on changing constantly every day from our first breath to our last. We know now that the microbiota can influence many different diseases, inflammatory diseases like arthritis, fungi bowel disease, multiple sclerosis, metabolic diseases like obesity and diabetes. We understand more recently the impact of the microbiota on cancer. And also, as we’ll talk about today, on the impact on your psychiatric associated diseases.

Dr. Conor Liston: Understanding how the microbes in our guts interact with the brain has been quite challenging. And it’s a question that I wouldn’t have dreamed really of pursuing, except that I have this amazing immunologist collaborator here at Cornell who really made this kind of work possible. I think it’s, it’s the kind of work that you need expertise in both neuroscience and immunology and microbiology to pursue.

Dr. Stieg: The gut-brain connection has been known for centuries. Going back to Hippocrates. What took so long? Why are we finally asking these questions now? We’ve had some technology to do this in the years past. What happened?

Dr. Liston: I think one of the big challenges to tackling that question is that it really requires a different kinds of expertise, the kinds of expertise that you get as an immunologist and a microbiologist focused on understanding the immune system and, and the microbes that populate our guts, but also neuroscientific expertise. And, uh, without those two kinds of expertise that don’t usually exist just in one lab, it’s quite challenging to, to pursue these questions and make progress on it.

Dr. Stieg: So it’s a stroke of luck that the two of you have found each other? Or I’m presuming this is happening throughout the United States. There’s other centers like this?

Dr. Artis: Biomedical research and medicine traditionally has been somewhat siloed. You’re either a neuroscientist or you’re an immunologist, or you’re a microbiologist or a physiologist or, or whatever it is. Where we are seeing the new technologies bring us is that these silos are breaking down. Conor and I are extremely fortunate. We happen to have met each other somewhat by chance, a number of years ago, and developed this interest in broad technologies from diverse fields that would normally not speak to each other to ask questions that have never been properly addressed before.

Dr. Stieg: One of the important things that that I’m hearing is that it’s the technological advancements in terms of our understanding of the molecular profile. It’s not just identifying which bug you’ve got in your gut, but it’s what molecular profile of that bug. And those are extremely variable from patient to patient or from animal to animal?

Dr. Artis: They can be quite different between any given individual human or animal. So you and I, Phil share certain aspects of our microbiotas, but when we go deeper and deeper in the sequencing, we will find individual differences. You and I have more similarities to each other’s family members than you would have to mine. You have more similarities to your dog than you would to my dog. And so certainly we’re just beginning to understand how dynamic and diverse these communities are.

Dr. Stieg: The two of you have made a significant discovery about the gut-brain connection. Can you characterize that for us?

Dr. Artis: One of the remarkable series of findings that we made involved, the collaboration between psychiatry, neuroscience, microbiology, immunology and chemistry, to begin to understand how the molecular mechanisms operate between the gut and the brain. First, if you deliberately manipulate the microbiota, you can change the behavior of mice, their ability to learn, and to experience fear. And we can talk a little bit more about that. We went on to show that there was a dramatic effect on subsets of neurons and other cells that are resident in the brain. So signals derived from the gut were directly impacting cells in the brain. We also went on to identify with our chemistry colleagues in Cornell-Ithaca, a subset of what molecules that we call metabolites are made in the gut and make their way through the, through the blood, into the brain and can influence specific cell types in the brain itself to recondition them and influence their ability to form memories and undergo learning.

Dr. Liston: And one of the things that really stood out to me as really interesting from this series of studies was that there was this narrow developmental window early in life. So a specific time early in life, when these signals from the gut microbiota were required for regulating the kind of normal developments of the brain. And if those signals were absent, the brain did not develop normally. And those effects could actually be permanent throughout the life of the organism. And I think that was, was quite surprising to both of us when we first saw that, that you could intervene very early in life and, uh, and rescue these problems with learning. But intervening later, say at the age of five or six in a person or in young adulthood was not sufficient to reverse these deficits. So it really emphasizes this, this role for signals, uh, from the gut in regulating brain development early in life,

Dr. Stieg: We suggested earlier, however, that there is a relationship between your microbiota and some psychiatric disorders like depression, are we forming links now? So if we look at the microbiota and we look at the, uh, the clinically at the patient, can we draw any conclusions about relationships?

Dr. Liston: I think we’re moving in that direction. So one of the big challenges with any kind of research like this, where you have an association between one thing and a disease on the other hand is testing. Whether those two things are actually causally linked with one another. And I think the research that is coming out of David’s lab and my lab does suggest that these signals are important for a very basic function that is relevant in many psychiatric conditions. This kind of learning that helps you to update information in your brain about how stimuli in the environment are related to threats. This seems to be very sensitive to these signals.

Dr. Stieg: Well I know you’re interested in the inflammatory cells of the central nervous system called the microglia, and you have some data about that that I read in your paper. Can you tell us what’s going on there?

Dr. Artis: One of the pathways that we identified links, the microbiota that are resident in the intestine with cells that are resident in the brain in particular, there is one cell type, as you’ve said, called the microglia. There are many others as well, the astrocytes and others that we know were impacted by microbiota derived molecule. So certainly there will be an immunologic component to this too. And a good example is multiple sclerosis where we know that’s an inflammatory disease of the central nervous system, but we know the meninges or another compartment of the brain is highly populated by immune cells. And we’re just beginning to understand the relationship between the microbiota and the meninges. We are really at the beginning of a new era of where neuroscience, microbiota science and immunology are coming together. And there are new technologies whether through imaging or sequencing or the ability to genetically manipulate the microorganisms themselves. We were able to do things that were simply not possible a decade ago. And I feel like we’re in a great place right now to make groundbreaking discoveries.

Dr. Stieg: Your study has great import in terms of its application to diseases in the psychiatric realm, such as autism, post-traumatic stress disorder and depression. Can you describe what you’ve found and how you think it relates?

Dr. Liston: We were interested in a specific kind of learning here, which we call fear conditioning and extinction learning. It’s a big term, but the basic idea is simple. You can think of a soldier at war. The meaning of like a loud, crashing sound outside is different at war than it is back here in New York City, where a loud crashing sound is less likely to be a bomb and more likely to be a car backfiring or someone dropping some construction materials outside. We need to be able to unlearn all the associations and learn new meanings when we, when we change our environments. And what we found in this study was that mice that had been treated with large doses of different kinds of antibiotics that eliminated most of the microbes from their guts that these mice had this particular deficit in that kind of learning. They were unable to learn new meanings for, for stimuli in their environments. And we saw a similar effect in what we call germ-free mice, mice that were born in sterile conditions and don’t have any microbes in their body.

Dr. Stieg: I don’t want anybody to be confused here that we’re thinking antibiotics are bad if you’re taking antibiotics. Do you think there is a relationship between antibiotics and excessive antibiotic use and, say, post-traumatic stress disorder?

Dr. Liston: I don’t think the science is there yet for that. I absolutely agree. Antibiotics have done tremendous good for people. And I want to emphasize that neither one of us is encouraging people to not take antibiotics when they’re sick, but there’s a bigger problem of a lot of people taking antibiotics when they don’t really need them. And if you don’t, you might just want to exercise a little more caution in whether you take these because they have, they have lots of effects that, that, that we might not be thinking about.

Dr. Stieg: And to be clear, the work that you’ve done is on animals. Is there any data in humans about, or is it anecdotal—about changing the gut microbiota and an impact on their psychiatric disorder?

Dr. Artis: There are certainly associations in the scientific literature, particularly in children with autism in subsets of patients with schizophrenia, older patients, where the composition of the microbiota has been altered. There are yet to be large-scale clinical trials to deliberately manipulate the microbiota and test the effects of that on psychiatric symptoms. But I think it’s certainly an area that will require future study. When we think about changes in the microbiota, there are certain aspects of lifestyle that can have perhaps the most profound effect on the composition of a healthy microbiota. The first as a healthy diet and a balanced diet, the second is exercise and general wellbeing, and it’s everything your grandmother told you: it’s eat well and look after yourself. And I think that would be a message I would send to everybody.

Dr. Stieg: It’s not really then, you are what you eat—which is important, but it’s also what your gut does with what you eat. And it creates these molecules, as you said that, and I’m presuming that they get reabsorbed through the gut, they get into the blood and they go to the various organs where they’re utilized appropriately. That leads to the question, are we going to start regulating everybody’s gut microbiome once we understand what’s good for you?

Dr. Artis: One could envision a scenario in the not too distant future where a routine visit to your physician might not just involve blood work and other regular readouts, but a microbial or microbiota profiling that may become part of our standard of care. And I hope that that will, in the near future, will become part of our analysis of patient wellbeing. Should we be considering manipulation of the microbiota, and how would one go about doing that? We have much more work to do before there will be a therapeutic phase of that.

Dr. Stieg: What tips can you give me to leading a gut healthy diet that will also translate into being a brain-healthy diet? Because that’s what I’m most interested in.

Dr. Artis: Eating a healthy diet, a balanced diet composed of lots of fruits and vegetables, and maybe reducing the amount of red meat that you’re consuming. Maybe high fiber exercise has a major impact on the composition of the microbiota. Lower levels of stress, have an impact on the composition of the microbiota, all of the things that your grandmother told you many years ago.

Dr. Stieg: As a psychiatrist, do you see this healthy diet cutting down on inflammatory agents as a direct effect on the gut, thereby transferred to better brain health? Or is there also a direct effect on the brain?

Dr. Liston: There’s, there’s definitely a direct effect on the brain as well. Exercise is a great example of a really simple intervention that people can take for themselves and improve their brain health and their quality of life and their stress levels. For example, we know that exercise can change the rate at which new neurons are being generated in the brain’s new nerve cells. And those effects seem to be important in conferring. Some of the mental health benefits of exercise, and it’s really simple intervention as well.

Dr. Stieg: One of the fears that I have is the commercialization of this whole concept. What can you say to us about where we are? I feel, in talking with you that we’re really early and we shouldn’t see any commercialization.

Dr. Liston: We are really early. And I agree with you. I think we need to exercise a lot of caution or jumping into intervene on the microbes in our gut and try to manipulate them before we know how to do it properly. I think there are some exceptions where the science has advanced further. For example, the treatments of particular kinds of infections in the guts. Cluster and endothelilal colitis. That might be one example where the science has progressed further, but in many other cases, I think that the public interest in the opportunity to change our microbes in our gut in order to improve our health has perhaps grown a little faster than, than the data has.

Dr. Stieg: David and Conor. Thank you for being with me. I think for me, the carry home message is how young this field is. And I think that you have responsibly reported where you are. We’re still at the animal level. There is great excitement, I think, and I believe about what you’re going to be able to do in the next couple of years and how we’re going to be able to treat psychiatric diseases by modifying the gut microbiome. Thank you so much for taking the time to elucidate and clarify a lot of the information for us.

Dr. Artis: It was a great pleasure. Thank you Phil.

Dr. Liston: Thanks for having us.