Speaking of Psychology - The Mind-Gut Connection (SOP78)

Episode Date: April 10, 2019

Is your gut a second brain? Emerging research is showing that our brains and our gastrointestinal systems may be more connected than we previously thought – potentially holding profound influence over our moods, mental health and sense of well-being. Our guests are Faith Dickerson, PhD, a psychologist who researches the role of infectious and immune factors in serious mental illness, and Emeran Mayer, MD, one of the world’s leading experts on brain-gut interactions in GI disorders. APA is currently seeking proposals for APA 2020 sessions, learn more at http://convention.apa.org/proposals Learn more about your ad choices. Visit megaphone.fm/adchoices

Welcome to Speaking of Psychology, a biweekly podcast from the American Psychological Association. I'm your host, Caitlin Luna. The topic for this episode is the mind-gut connection. Is your gut a second brain? Emerging research is showing that our brains and our gastrointestinal systems may be more connected than we previously thought, potentially holding profound influence over our moods, mental health, and sense of well-being. This exciting new frontier of scientific knowledge has captured a lot of people's attention, yet there's still so much we don't know. Our guests for this episode are Dr. Faith Dickerson, a psychologist who is the head of the Stanley Research Team at Shepard Pret Health System, where she researches the role of infectious

and immune factors in serious mental illness, and Dr. Emeran Mayer, a medical doctor who specializes in gastroenterology. He's one of the world's leading experts on brain gut interactions in GI disorders. Both were featured in the cover story on this topic in the December 2018 issue of the Monitor on Psychology, APA's magazine for members that covers science, education, psychology practice, and more. Welcome, Dr. Dickerson and Dr. Mayor. Hello. Nice to be in the show.

Let's start off with a basic question, Dr. Mayor. What is a gut microbiome and what does it do? So the term microbiome is being used to refer both to the population and relative abundances of microbes. live in our gut, as well as its function, basically related to the genetic material and the ability to generate metabolites and substances that can influence various functions throughout the body. So the microbiome is both the relative abundance of organisms as well as the function of the system. microbiota in contrast is used only to refer to the relative abundances. So what does that do for us in our intestines?

Well, it does a lot. And we're currently in a phase that people think it's involved in just about every normal, healthy function and in a large growing number of diseases. It basically, the most basic function, that's why that symbiosis developed a long time ago, millions of years ago, is that the microbes have the ability to break down opponents of food, mainly plant-based foods, fibers that we don't, that we humans don't have the enzymes to break them down. This was even more important with our ancestors who were not able to cook things and break down some of the fibers. And they produce substances, the most well-known ones being the short-chain fatty acids like butyrate. They then act with these substances or metabolites, they can talk to each other. They can talk to our gut.

and they also can talk to distant organs from the heart, the liver and the brain. So they have a lot of other functions. I mean, they, for example, can metabolize many medications. They can metabolize sex hormones like estrogen and proteoprogynous and testosterone and testosterone. They can deal with substances. So there's many substances that we now, understand are kind of targeted at microbiome, large molecules. So, for example, so-called polyphenols, so the health benefit producing substances that are in many plants, including blueberries

and olives. Infants can break down large molecules called human milk oligosaccharides that cannot be absorbed by the baby from breast milk, but they go directly down to the microbes, metabolize them. So there's many, many substances that we are learning, that we are learning now that would, would, would, would this plays a role. This, you know, this, formally, it's kind of interesting to me always that, that, that people could write medical textbooks without taking this into consideration. that any of our medicines or therapies really work without having taken this system into consideration.

And there's a lot we don't know yet, correct, about what the gut microbiome does and what it can do. This is what people forget. We're at the very beginning of this. You know, we have extremely powerful ways to analyze them. So that's actually made this whole field possible. all sequencing techniques, you know, which used to be extremely expensive, $100,000 per stool sample. Now I can do it for $20. But I think people tend to forget this is a very complex ecosystem with regional differences from the stomach all the way down to the colon.

It's not the same. and we pick up and we measure relative abundances and metabolites in the stool, I mean, that's a mixture of all of those regions. It's kind of, if you look at the world, like extrapolate this to the world, it would be like homogenizing information or mixing blood samples from every country on earth and trying to make sense from these mixed results, what people do in these individual countries or what diseases they have.

So I think that's kind of where we are right now. I would say optimistically even, I think we understand about 10% at best what that system can do, what is capable to do, and what role it may play in various diseases. And I want to turn over to Dr. Dickerson because you mentioned in that Monitor article the idea of bacteria in your gut influencing your behavior

of mental health would have seemed kooky only 10 years ago. And now there's a lot of public interest in this topic. So what do you think has changed? Right. I think a number of things have changed. At least three reasons can account for this interest. One that Dr. Mayor mentioned was that the techniques that we now have to measure the microbiome have really become much more sophisticated and much more.

more practical. The methods that are used, people may not realize, are the same methods that are used to measure the human genome. And we know that these techniques have rapidly progressed over the last couple of decades. So that we now measure the microbiome and the organisms that make up the microbiome with these same methods. And the technical complexity is truly impressive and has enabled this research to take place. I think the second reason that the idea seems less kooky for all of us have to do with the very elegant animal experiments that have been done. And it's important to emphasize that most of what we understand about the microbiome has been carried out in animal studies, particularly with mice. And we can get into some discussion

about how we translate those findings from animals to humans, but to suffice it to say that there are many advantages, obviously, in working with animals, one of which is that one can work with germ-free animals, which do not have these microbes. You can't, you know, really work with germ-free people, but you can work with germ-free mice, and that enables one to introduce these organisms and to study the effects of the organisms in a very systematic way. And obviously, animals can be sacrificed and one can study the contents of their GI tract and the effect of the microbiome on the brain in ways that would be absolutely impossible in humans. Right, right. But I think that the third reason is in some ways a little more distant but also

relevant to this discussion. I think the idea of the immune system and the gut brain access having a role in human behavior and in psychological and psychiatric problems also has to be seen in the context of the larger world of science and particularly of our understanding of genetics. Because it was really felt a number of years ago by many of us that human genetics would really turn out to be more easily explanatory for the psychological and psychiatric problems that people face. And I think that that area of research has been somewhat disappointing. And we don't really have clear answers yet from human genetics about the etiology of complex psychiatric disorders.

And the genetic studies, to my understanding, have not really led yet to effective treatments. So I think with the course of that research, it has enabled scientists and the general public to be more open to other paradigms. So I think that's an important aspect of how this idea seems a little less kooky because we're now open to other realms in terms of our understanding. And as we've said a few times, this is all in the early stages, but I wanted to talk about some of the intriguing findings that have emerged. People with GI disorders have higher than average rates of bipolar disorders and depression. People with schizophrenia often have blood markers that suggest GI inflammation, and people on the autism spectrum have higher

rates of GI problems than average population. So although we know this is in the early stages, what are those findings tell us? Well, I mean, I would make some comments and then turn it over to Dr. Mayor, I mean, I think these associations, they're very consistent and they're very intriguing, and I think they highlight that there is an association among the brain, the immune system, and the gut. But they don't tell us really what's the direction of that association and what is the causality. And again, we're studying these phenomena in animal models, and we can talk to the extent that animal models of psychopathology, have relevance to human disease, but I think they provide a very solid foundation for this area of research. Yeah, I would comment on this with, you know, I've always been a skeptic.

I mean, that's why I'm a scientist. And so, you know, I believe something one once really had a definitive proof for it. And I totally agree with the problem that we have. It's really twofold. One is that the most exciting studies and results about the communication between the microbiome and the brain have come from mouse studies, mouse behavior. Obviously, the mice can't talk. The mice don't have this highly complex brain that we have, particularly the prefrontal cortex.

So it's like comparing a HP hand, hand, calculator with the Watson IBM supercomputer. And the second thing is the mice. So there's hundreds of different mouse strains. There's actually a panel with all these different mouse strains. You can do an experiment in one of these strains with the microbiota and brain and you won't see an effect and then you do it in a different strain and you see the effect. So we don't know which one of these.

So scientists pick the ones where they see the effect. We don't really know if that relates to humans. And I think we have to differentiate. So the brain gut interaction and particularly the interaction of the brain with the gut associated immune system is the biggest part of our immune system that sits in the gut. That's kind of a well-established entity and field of science. We know stress changes the immune function. We know that immune activation in the gut can lead to withdrawal behavior that's often been taken as a depression-like behavior.

And many studies have looked at this. And actually, I would say there's some studies that prove causality from the brain to the gut and to the immune system. and vice versa. The problem with the microbiome, we don't have that yet in humans. So it could easily be, and I'm going to tell you a study that I think in some way supports that it could easily be that all these changes we see in gut microbial composition and function and metabolite production in patient populations with different brain or psychiatric disorders are a consequence of the output of the brain, of the disease to the gut,

which we know changes a lot of functions, has effects on the environment that these microbes live in, but also directly on the microbes. Or if there's really primary changes in the microbiome that either started in infancy or are related to intake of medications, many of which modulate the microbiome and then generate signals that they contribute to the, to cause the brain disease. So this, and just give you one example, there's many studies now in mice, monkeys, humans,

that psychological stress can change the relative abundance, for example, a decrease in lactobacillin, a change in triptophen metabolism that's related. to this lactobacillin. And we recently completed a study with Jeff Flackner at University of Buffalo that showed that the patients who underwent, these were patients with IBS that underwent cognitive behavioral therapy. We looked at the responders versus the non-responders. And the responders showed not only changes in the brain, but also in the relative

of abundances of microbes in the gut. So clearly an improvement at the brain level can have an effect on gut microbial composition. So I think we have to be really careful until we have these longitudinal interventional studies before we can say there's really a causality in one direction versus the other. Yeah, I wanted to talk about a recent study you interviewed about in nature microbiobiology, and that was about the link between gut bacteria and depression. So in that study, it was of 2,100 adults, and it found that people with depression had different groups of gut bacteria than people without depression.

So what are your thoughts about that study as well? Yeah, so it's, again, it's a nice study because it's a large study. It's also has the same limitation because it's a it's it's an association that that's been shown. There's a lot of variation that goes into a study like this. It's not like mice. If you study seven mice, seven term free mice and characterize abnormalities and metabolites and then relate this to behavior. Here you have a tremendous variability. in terms of genetics of the participating subjects,

and the dietary habits, the medications that they're on, co-morbidities, that all could play a role here. And as I said, I mean, the gut-brain interaction is very sensitive to a lot of factors. Stress is one that we understand quite well. So it's limited by that. I mean, the association that they found with certain taxa and depression and quality of life is interesting. It does not, you know, prove causality in any way. And it's there's some similarities with, so there's a few of these depression studies in patients with major depressive disorder.

the findings that they have are not necessarily all consistent. There's some, this fecalibacterium shows up in several, in most of them actually. That's interesting. And I think it's definitely something that should be followed up in mouse studies. But I would look at this really with, still with a significant skepticism that it proves a causal relationship. Yes, I think I'm, you know, I'm really, as we've touched on a bunch of times, is that there's all this intriguing research, but before we get carried away, there needs to be more research and more work done in this space. Dr. Dickerson, I know you've been doing a lot of research with bipolar disorder. So can you talk about what you found in your work? Yes, our studies are different and present a different look and a different way of investigating this topic.

The study that was most recently published last fall in the journal bipolar disorders was not of the microbiome directly, but was a clinical trial of probiotics. and probiotics have become very popular. They're widely used and advertised as having health benefits, which they may have. And probiotics are microorganisms that are introduced into the body for beneficial qualities. So they're compounds that contain actually live organisms that are thought to have a health benefit. So in all of this research, our ultimate goal obviously is to improve the symptoms and the lives of people, and in my case, patients who have psychiatric disorders. So what we did, again, based on our concept of the gut brain access, is we studied individuals who had been hospitalized for mania. And mania is a very acute psychiatric condition.

Most people are probably familiar with the idea of it. Patients are very activated, unusually so, with rapid speech and flight of ideas and behavioral activation. And this syndrome, this condition can be very disruptive and can lead people in a psychiatric hospital where they can get treatment. So what we did, it was based on a previous study that we'd done that hadn't been a clinical trial, but just observing patients, is that we enrolled people who were hospitalized for mania when they were acutely, psychiatrically ill. And after they were discharged and they were more stable shortly after discharge, we enrolled them in a trial where they were randomized to receive either a probiotic compound. as a supplement or something that looked like the probiotic but was not the probiotic. So this is a standard design of a randomized controlled trial. And the idea that we had based on our previous work was that the probiotics would reduce

intestinal inflammation and would help with their clinical course. The study that this was based on showed that a patient. admitted to the hospital for mania had elevations in inflammation and that the level of the inflammation was predictive of whether or not they were readmitted in a six-month follow-up period. So we thought that one way maybe to reduce inflammation and to help with this outcome would be to administer probiotics. So probiotics are pretty acceptable to patients. It wasn't that hard to recruit people for the,

the study because we know they're generally safe. So what we found was that in this trial that took a number of years to do, as you can imagine, to recruit the patients and to follow them for the six months, a period after hospital discharge, we found that those who were receiving the probiotics, that we only found out later when we broke the blind, so to speak, that the ones who were receiving the probiotics were significantly less likely to have a relapse, to have an exacerbation of psychobiotics. psychiatric symptoms in the study period, the six-month study period. So this was a proof of concept, as it will be considered, of the role of inflammation

and reducing inflammation, again, through the use of a probiotic compound to improve psychiatric outcomes. That's all very fascinating. And, of course, yeah, go on. If I can make a comment, I mean, this is definitely one of these examples of a very important study done in humans and sort of going towards a mechanism rather than just an association. And I think it sort of goes along with, you know, with our earliest study on this topic

of probiotics and brain function or activity, what we showed that the regular intake of a probiotic in healthy young women change the connectivity. of a whole network within the brain that was activated by an emotional recognition task. So we have not followed this up in a psychiatric population, but it certainly for us was a proof of concept that the signaling from the gut to the brain induced by a probiotic actually does happen as it happens in mice. So I think this mania study, but Dr. Dickus, is really, that's the kind of studies, I think, that we need to move this field forward.

I think it's really an iterative process, understanding how some of these processes may work in animals, then human observational studies, testing them out in clinical trials, where, again, we aim to minimize any potential harm that patients would be exposed to, and then to circle back, again to other research realms. In this study, you might say, well, this is one study. It's one hospital. You know, you had a pretty good sample size, but again, you'd really need to replicate it to do the study again.

And in fact, this particular trial is being replicated at the University of Texas, where they're recruiting now for a similar study. and in the University of Texas study, unlike ours, they're actually getting measures of the gut microbiome. We had measures of the oral microbiome, which is kind of another chapter. But I think that we need to continue these studies with slightly different populations. We're also performing a trial now, also funded by the Stanley Medical Research Institute, in which we are performing a very similar study this time instead of starting with patients who are acutely manic, we are starting with patients who were admitted to the hospital

for bipolar depression. Because for people who have bipolar disorder, in fact, the depressive aspect of the illness is often the most disabling and does also result in hospital admissions. So we're doing a similar trial, but starting with people who are acutely depressed in the context of their bipolar disorder. So we're, you know, just recruiting now and enrolling people and they're taking their study minutes and we don't know which they're taking. And that's the kind of the excitement and the mystery of a clinical trial is really not knowing how it's going to turn out as the study is underway. And Dr. Mayor, I want to turn to you to talk about a book you wrote called The Mind Gut Connection.

And in the book, you described the gut as having capabilities to surpass all other organs and even rival the brain. and that it stores 95% of all serotonin in our bodies, that hormone and neurotransmitor that regulates mood. Because our guts have direct connections to our brain through nerves, what happens when our brains and our guts are not in sync? Yeah, so this statement, it's not related that I'm a gastroenterologist, but it's partly related to the fact that I've studied these brain gut interactions for the better part of my career for the last 40 years. and what has become during that time what has become known is as it just said I mean it's it's the biggest endocrine organ in our body it's the biggest immune it's the biggest portion of our immune system it is the main storage site for for serotonin it has its own so-called enteric nervous system which you know has has been called the second brain even though it's really the first brain so

One of the questions is why is that? And well, the reason is during evolution, this gut brain of gut nervous system axis was really the first system of regulation. And then the microbes, the algae, came into this, what was originally just a floating digestive tube with a nerve net around it. And so this interaction between the microbeholder, some type of microbeholder, this very complex system in the gut with all these modules. And the brain is one of the most ancient biological systems in our body and has been maintained in virtually every life form from, you know, fruit flies to cockroaches to large animals to whales. It's almost ubiquitous. So you almost can say this is part of evolution and this close connection, which has really been neglected for a long time. I mean, it's really amazing to me.

It took the microbes to stimulate the interests of people in the brain gut communication because, you know, people have been studying this for a long time. there's a lot of evidence that for this bidirectional communication in the brain regulating any of these other systems in the gut and the gut sending signals by multiple communication channels to the brain. So I would almost say this is like the main axis homeostatic, the main homestatic system within our bodies that has been around for the longest time and we're now just recognizing its importance in health and in disease. And I understand that stress can have a huge impact on a person's digestive health.

So how is our gut different when we're stressed and when we're relaxed? Well, you can almost say, you know, a turn that I used in my book, The gut is sort of the other side of the coin of an emotion. Any emotion, be it related to stress or not stress, will be reflected in changes in multiple gut functions, range from the simple thing, the contractions in different parts of the triadrack, the regional transit times, secretion of mucus, fluids, immune activation. When you stress, all of these functions are altered. When you stress acutely, it's an adaptive response. It goes up and then it settles back to its normal level. In chronic stress, it's different.

It becomes maladaptive. So many functions become not just maladaptive for our own health, but also to the microbes that live in it. And as I mentioned earlier, so no one of the NFAPE, has been particularly well studied on this. You know, one of the main stress mediators released by post-gangionic sympathetic nurse in the gut. It also goes up to concentration of noopenephrine in the gut lumen. There's certain microbes that actually metabolize the form of noopenephrine that's released inside the gut and make it more active.

and it's been shown that this noopinephrine in the gut can modulate the behavior and the gene expression of a large number of microbes. First it was shown for pathogens. It makes pathogens more aggressive and more virulent. But it now also has shown for symbionts, so for the good guys in our gut, it changes their behavior. So you could almost say if you're chronically stressed, your gut is completely different in all its function and the alteration in the microbes will produce substances

that get into your bloodstream and obviously some of them will reach the brain. Stress also increases the permeability of the gut. It's been referred to in the lay media is the leaky gut. So the leaky gut doesn't just happen in response to unhealthy food item like fat and sugar, but also really well studied in response to acute severe stress and chronic stress. With that mechanism, you get immune molecules into the circulation. So you can say, you know, when you're stressed, don't just worry about. but your heart and your blood pressure and the way it feels unpleasant,

but you're doing something fundamental to one of the main regulatory systems in your body. Yeah, and it's been reported that hunter-gatherer tribes have more vibrant diverse gut microbiomes. How does that compare with the average Americans gut health? I mean, can they be compared? And what can we take away from that? Yeah, so there was a pivotal study. which was done a couple of years ago where they compared

they took one of these hunter-gatherer tribes on the Orinoco River, the Yanomami Indians and looked at their relative abundances and richness, diversity of their gut microbiome and compared those to they did the study both in adults

and in infants and they compared it to a population in North American cities, both again adults and infants, the remarkable thing was that there was a, I think it was about a 40% decrease in the richness and diversity of the gut microbiome in people living in North America. And that was even more intriguing that this was not only seen in the adults, but also in the infants.

So it's not something that you lose, these bacteria as you grew up and have an unhealthy diet, you start out, we start out with that compromised diversity. So we've lost many of these organisms very early on. And during a period, it's obviously said that the first thousand days of life are so the most important for the maturing of the gut microbiome and its interactions with the immune system. So we start out very early on in life, and it's probably plays a role the transmission from the mother to the infant to the newborn, with a compromised microbial ecosystem, which has obviously, you know, major implications because people like Marty Blazer and this book, Missing Microb has shown this pretty dramatically. this decline in the diversity and relative abundance of certain organisms has been going on for the last

hundred years or so and is continuing. So when you look at any other ecosystem, if you diminish the complexity and diversity of an ecosystem, it will lose its resilience and resistance against perturbations and diseases. So this is something I think we really have to worry about. Does that have anything to do with being in a world that's too clean? I think that's part of it. It does pretty many factors. It's obviously dietary.

I mean, these Yanomami Indians have obviously a very different diet. It is, even though they live in the middle of the jungles surrounded by all these wild animals, it's a predominantly plant-based diet with multiple different types of plants that they consume. And it's medications, antibiotic consumption in infants and in pregnant mothers is extremely high in the West. And there's other medications as well. So there's multiple factors. The hygiene hypothesis, so that's, you know, the excessive cleanliness and hygiene that we have in the Western world.

and it's pretty obvious if you travel to one of these places in the developing world, how dramatic the difference is, just in food preparation. And that's being implicated in a compromise training of the system early on in life during those first thousand days. So that our immune system does not see potential mild pathogens and does not really learn. to differentiate between self and non-self. And the increase in allergies and hypersensitivities and autoimmune diseases has been proposed that this hygiene hypothesis is really the explanation for it. Yeah.

And I want to get both of your thoughts on companies that are offering to map your gut flora. So Dr. Dickerson, do you want to start off with that one? Right. I think that while that's an intriguing idea, it seems somewhat premature. I don't think the results would be easily interpretable. We don't really have standards by which to judge these results. It seems like, quite honestly, it might be a little bit of a waste of money. Maybe benign, unless people were told something about their health that was alarming or actionable in a way that would be, would be. damaging to them. But I think, I think at this point it's really premature. Although, you know, one can see that it would be kind of intriguing to do it, you know, given that we're all kind of learning more about this microbiome and kind of intrigued and have no way to measure it ourselves. You know, it's not like we can look inside our gut and figuring it out. So I think it's intriguing, but premature at this point. Yeah. My common on this is, and I have to disclose that I am

on the advisory boards of several of such companies, the leading companies in this area. And I still have a certain degree of skepticism as well as enthusiasm for something like that becoming really a routine test that instead of getting a blood test, where you look at 10 substances in your blood, 10 measures, and then make predictions about your health.

I think this has the potential to go much further than that. And clearly, you know, in combination with genetic testing. So we're definitely moving into a future with these technologies that are now available in the supercomputers that can make sense out of the data will pretty fundamentally change. Medicine, diagnostics, health assessment, risk assessment. But we're still in the middle. of this process. You know, there's one company, actually not involved with it, that postulates in their

advertising that you can, if you have type 2 diabetes, metabolic syndrome, that you can tailor your specific diet that's good for you and that does not worsen the syndrome, that you can basis on an assessment of the gut microbiome. That, you know, that needs, it's based on a lot of high quality research papers in both animal and humans. But it needs to be determined or needs to be seen in the next few years, which one of these approaches turns out to be good enough. So they're going to be adopted by insurance companies.

and so that if you ask me what the likelihood is that this is going to happen, it's going to happen. I think I would say it's probably close to 70% as all right now. The way it says it's, but we're not quite there yet. Yeah, I think it's an example where the technology at this point is ahead of our complete understanding and the interpretability of the data. But I think the technology is there, and once there's more knowledge, potentially these methods, would be informative. But I think now it would, you know, if one did it more out of curiosity and not putting much faith, so to speak, in the results, I think it would be interesting, but not really as a diagnostic or therapeutic tool.

And can people do anything to improve their gut health? Well, that's always an interesting question. I mean, we know from studies, some of which have mentioned in this podcast that diabetes is associated with aspects of the microbiome and obesity. We haven't mentioned antibiotics yet, actually. Antibiotics have a major effect on the microbiome that I can tell you a study we've done about antibiotics and patients with mania. But based on what we know so far, I think we can assume that if patients have a healthy weight, and if they have diabetes, if their diabetes is in control, and if they avoid unnecessary antibiotics, that that's likely to improve their microbiome.

Again, we don't know quite in what direction the microbiome affects these conditions and vice versa, but we do know that there are some ways that people can, in general, improve their gut health. Yeah, I would say also this question about gut health, so people always want to know this, what can I do for my gut microbial health and my gut health? So we always assume that the two of them are interrelated. But, you know, in terms of probably the best thing that you can do is you stay away from unnecessary intake of medications and particularly antibiotics. And I do want to emphasize unnecessary because obviously antibiotics are life-saving in any conditions.

And to be on a healthy diet, I think we know from even long before the microbiome science coming on the horizon that a largely plant-based diet has the greatest benefit on cardiovascular brain function, metabolic diseases. So part of that beneficial effect of the diet, for example, is mediated by the microbes. but not all of it. We know that so many effects on metabolic health are not mediated through the microbial metabolites that are generated from a plant-based diet. What the ratio is between a direct effect, for example, of health-promoting food on our gut,

like all the things that are being absorbed in a small intestine, and not metabolized by microbes, as opposed to what role the microbial-generated products, by-products from our diet is, I think that needs to be determined, but it's two ways, I think, that you can affect God-Tales, diet directly and diet through the intermediary of microbes. Yeah, what about foods like yogurt, you know, kimchi, kombucha, sourcrow? they get a lot of tension for being good for us because they're fermented foods. Do those have any impact on your gut health, the Jep's system?

Well, one thing to say at the outset is the many products that are promoted and sold, for many of them we really don't know if they contain the active organisms that they claim or the concentration of the organisms. And that is a major issue because most of these products are not really regulated by the FDA. so it's hard to know. I would say that if these organisms are present and present in a sufficient quantity, that they may be beneficial.

Yeah, I would say I would agree with this. I think the, I would probably say that 90% of the commercial available products, supplements, and, you know, various pro and prebiotics are not based, or not evidence-based, for example, confirmed by the gold standard, a randomized clinical controlled trial.

So you would never be allowed to sell a medication with this limited amount of evidence. And I'm sure that a big portion of the benefits that people derive from taking different types of probiotics and prebiotics, you could consider a placebo. response. So it's nothing bad. It's actually placebo response is always good.

But the actual health benefit I mean my recommendation to patients is start out with naturally fermented products as you said the kimchi and the yogurt and the

rather than taking pills with probiotics and in just your prebiotics with a high variety of plant-based foods, which are all full of prebiotics, instead of taking, again, taking pills with prebiotics, with a single prebiotic, if those things are not available, for some reason or another, if you're in the North Pole, and you may benefit from taking, you know, some of these substances in pill form. And Dr. Dickerson, in that monitor piece, you talked about psychobiotics. Can you explain what those are?

Right. Psychobiotics are organisms that when ingested in adequate amounts, live organisms when ingested in adequate amounts, produce mental health benefits. So again, we haven't established absolutely that the ingestion of live organisms does produce mental health benefits, but in, theory, something like a probiotic compound, if it were to be a determined and established in evidence-based trials, that it was helpful. That would be an example of a psychobiotic. Kind of an interesting combination of a term here. And so I want to get both of your takes on this. So what is needed to continue research in this field?

Is it more funding, more grants? What do you both think? I'll start with you, Dr. Dickerson. Well, certainly we can always use more funding. And a new area of research, like the one we're discussing, it falls among and between our usual research silos. So here we have a gastroenterologist participating in this podcast. I'm a psychologist. It falls, to some extent, in complementary and alternative medicine because these are not established medications.

per se. So there's always the question of funding of who is really taking the lead in this area. And as often happens, there are a number of different traditional research silos which are moving ahead. So again, definitely grant funding. I also think there are regulatory issues. It hasn't been absolutely and fully established. What is the role of the FDA? How much oversight, They need and do have. These are new kinds of compounds to be tested that don't fall in the categories of traditional medications. Prebiotics were mentioned a while ago. Those are not live microorganisms, but do serve to promote the growth of healthy organisms in the GI tracts.

So the regulation of prebiotics, the regulation of probiotics. these regulatory issues for human subject trials, I think also need to be better clarified. And there are some barriers here into performing this research with clinical patients. What do you think, Dr. Amir? Yeah, I mean, I would agree with this. I think, you know, just make one comment on the kind of research that's needed. I think that's very important. And this is already happening to a certain degree.

So for the human studies, and I personally believe that it's the best approach to do something in humans first to really characterize that it plays a role and then go back to the animal model and look at the mechanism. I think that's somehow more rewarding than starting with relatively artificial animal models and then only a very small fraction are translatable into human populations. A good example, intractable seizures. We, for example, have known that a ketogenic diet is beneficial, is therapeutic. And then a study came from an investigator at UCLA, Elaine Scha, that showed that this ketogenic diet changes the microbes to produce metabolites that are responsible for a change in the seizure threshold. So this is like this reverse translation. I think that's one. The other one in human studies, we need large numbers because you have a lot of variables now that you can measure from the microbial abundance, the metabolites, genetics of the host, and then various other parameters, clinical parameters.

You need very large data sets to do that. And so it will require consortia, most likely in. international consortia that can generate 10,000 subjects, data from 10 subjects. And that's probably one of these two approaches that you go to the reverse translation and you go to very large data sets and then use artificial intelligence to extract patterns and identify predictors. to me that's really the most promising approach. And the NIH, for example, has taken that approach.

So we're involved in a study, in a cooperative study on cognitive decline. What this is exactly being done with a consortium of U.S. and European investigators collecting data on patients. Thank you so much for joining us, Dr. Dickerson and Dr. Mayor. This has been a really wonderful conversation. Thank you. It's a pleasure to be on the show. Thank you very much.

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That's K-L-U-N-A-A-R-A-A-A-P-E-A-A-R. speaking of psychology is part of the APA podcast network which includes other great podcasts like APA journals dialogue about new psychological research and progress notes about the practice of psychology you can find all our podcasts on iTunes stitcher or wherever you get your podcast you can also visit our website speaking of psychology.org to listen to more episodes i'm kately luna with the american psychological association