The Gut-Brain Link That Could Change How We Understand Parkinson’s

Could Parkinson’s disease begin in the gut? It’s a question that challenges how we think about brain health, and one that today’s guest has spent years investigating. I’m talking with Sarkis Mazmanian, PhD, a professor of microbiology at Caltech whose research explores how gut bacteria influence the brain. We discuss why the gut has become an important focus in Parkinson’s research and how understanding that connection could open new possibilities for treatment. Here’s what we get into: How the bacteria in your gut communicate with your brain and may influence behavior Why digestive problems can show up years before the movement symptoms of Parkinson’s What mouse studies suggest about the microbiome and autism, and what we still need to learn in people Whether commercial microbiome tests and probiotics can deliver on their promises Ways to support your gut through food, sleep, movement, and managing stress When someone comes into my office, I want to understand their whole story, including what was changing long before they came to see me. That’s what makes the gut connection so compelling in Parkinson’s. If changes are happening years before movement problems appear, could that give us an earlier opportunity to help? It’s a question worth asking, especially when the answer could mean more years of doing the things you love. View Show Notes From This Episode Sign up for Dr. Hyman’s Brainshaping Academy to learn how to nourish the biological systems that support your mental, emotional, and cognitive health https://drhyman.com/products/brainshaping?utm_source=dr_hyman_show&utm_medium=newsletter&utm_campaign=may_27&utm_content=link Get Free Weekly Health Tips from Dr. Hyman https://drhyman.com/pages/picks?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Sign Up for Dr. Hyman’s Weekly Longevity Journal https://drhyman.com/pages/longevity?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Join the 10-Day Detox to Reset Your Health https://drhyman.com/pages/10-day-detox Join the Hyman Hive for Expert Support and Real Results https://drhyman.com/pages/hyman-hive This episode is brought to you Seed, Seatopia, Perfect Amino, Rho, Sunlighten, and BIOptimizers. Make your microbiome part of your daily routine with seed.com/hyman and save 25% with code 25HYMAN. Find a cleaner source of seafood. Check out seatopia.fish and use code HYMAN for free shipping on your first order. Help fill protein gaps at bodyhealth.com and use code HYMAN20 for 20% off. Explore science-backed products at rhonutrition.com and use code HYMAN for 20% off the entire site. Discover why so many people are using sunlighten.com use code HYMAN to save up to $2,100 today and free shipping. Use bioptimizers.com/hyman and code HYMAN for 15% off, special bonuses, and a 365-day money-back guarantee.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  Because the microbiome sort of like tunes our body, all these different systems, it wasn't designed to reverse disease. We're trying to engineer it to do that. Don't wait till you have diabetes before you stop taking, you know, your gut health seriously. Or don't wait till you have any condition because there are things you can do today to improve your gut health, to improve your microbiome health. And the payoff is long-term is your health in the decades that are still ahead of you.

• 0:28Dr. Mark Hyman?

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• 1:10Dr. Mark Hyman?

  evidence. And that level of scientific rigor, it's exactly what led me to join Seed's clinical board, and why I continue to recommend DSO1, and take it myself even after all these years. Go to seed.com/hyman and use the code 25HYMAN to get 25% off your first month. That's S E D dot com slash hyman and use the code 25HYMAN. Your body is not the same in January as it is in July. Less light, colder mornings, more demand on your immune system. And the two things you need most in the winter are the two things the modern diet is worse at delivering, omega-3s and vitamin D. That's another reason why I eat Cetopia. Their food is one of the few foods that gives me both at once. My favorite is their Atlantic salmon. It's delicious, and one serving carries about

• 1:53Dr. Mark Hyman?

  as much EPA and DHA omega-3s as two standard fish oil capsules, which is why I keep my freezer stock with Cetopia throughout the winter. They test each of their suppliers via third-party labs for mercury and microplastics. And their seafood arrives blast frozen, delivered to my door. So a great dinner is always within reach, rather than a trip to the store in the dark. Get your first box at cetopia.fish/hyman and use the code HYMAN for free shipping. Welcome to the podcast. It's wonderful to have you, Tarkus. And I've been a fan of your work and really excited to dive into how the gut plays such a role in our overall health, particularly in our brain health, which we're going to get into today. So thanks for being on the podcast.

• 2:35Speaker 00

  Thanks for having me, Mark. And I as well have followed your work, and I'm happy to be.

• 2:38Dr. Mark Hyman?

  Thank you. So, you know, I want to zoom out for a second and say, you know, I've been on the front lines treating patients for 40 years, and you are an academic physician from the esteemed institutions like Harvard and Caltech, and have really done tremendous research in pioneering our understanding of the microbiome, its role in health, and particularly in the gut-brain axis, and how some conditions like Parkinson's and autism may be connected in part to what's happening in our gut and our microbiome. And I've come at this from the opposite direction, which is seeing patients, you know, being in the trenches and dealing with real problems that people are facing every day. And it's just striking to me how much the gut and the microbiome play a role in our overall health. And this is being, you

• 3:19Dr. Mark Hyman?

  know, borne out across medicine, whether it's cardiovascular disease, or cancer, or metabolic health, or autoimmune diseases, or allergic disorders, and of course, you know, conditions that, you know, you particularly study, like autism and Parkinson's, and I would even sort of say even other neurologic conditions. Kind of our understanding is kind of maturing, and it's clear that there's a there there, that there's something cooking in the gut that is not just about having this inert pile of poop in there that's not doing anything, but it's dynamically interacting with us all the time. You know, I remember sitting on a panel with Stan Hazen at Cleveland Clinic, who's pioneered the work around the microbiome and cardiovascular disease. And I said, Stan, what percent of the metabolites in human

• 4:00Dr. Mark Hyman?

  blood come from the microbiome? And he was like, I don't know, but I think maybe a third to a half. I would like to hear your take on that.

• 4:08Speaker 00

  The evidence I've seen as well, that half of the small molecules floating around our blood are either made by bacteria, or, you know, the precursors are made by bacteria, gut bacteria.

• 4:18Dr. Mark Hyman?

  Yeah, that's an astounding concept. Like, not only, you know, do we have, you know, about, there's many or more bacterial cells in us than our own cells, and 100 times as much bacterial DNA than our own DNA. But up to a third to a half of all the things floating around our blood that are molecules interacting with our biology every second, come from the microbiome, or are derived from metabolites from the microbiome. And I saw this clinically, practicing medicine, treating patients with autism, or people with Parkinson's, or people with, you know, autoimmune diseases, or whatever it was, and depression, or mood disorders, behavioral disorders, ADHD, all the kinds of things that we would see in our practice. And modifying the microbiome by changing diet, by changing

• 5:00Dr. Mark Hyman?

  the microbes in there through herbs or drugs, we were able to see, using probiotics or other things, which are still not studied well enough, but we'd see these clinical changes that were quite remarkable. And, you know, in looking over your research, it's really clear that you're seeing the same kind of signals. You're seeing that there's not just sort of, you know, some of the work you've done, you know, showing that it's not just that, you know, the microbes are sort of incidentally involved, but they're actually maybe causally involved. Like, I would love to sort of have you sort of dive in a little bit of the beginnings of your research, how you came to understand the microbiome played a role, and kind of what got you excited about this, and what you've sort of learned about at the high level around the gut-brain axis, and this whole communication between

• 5:42Dr. Mark Hyman?

  the gut and the brain, including, you know, our nervous system, our immune system, the microbial metabolites, hormones, all these things that start to change as we change the microbiome.

• 5:52Speaker 00

  Yeah, I think just embedded in your question is, is evidence that the microbiome affects so many of our, of the organ systems in our bodies, right? And it's not just, you know, the most obvious ones like the immune system. When we think about the immune system, we think about how we fight off bacteria, infectious agents, you know, viruses, fungi, what have you, protozoan infections. But really, the microbiome impacts our metabolic system, our endocrine system, our nervous system, and just has huge effects on many aspects of our physiology. And so, we became interested in the gut-brain connection largely because of, of, you know, at the time, and close to 20 years ago, anecdotal evidence

• 6:36Speaker 00

  showing that classical neurological conditions, at least conditions viewed as neurological conditions, diseases, if you will, have a GI component, have a gut component. So I think it's well documented, perhaps maybe more in Parkinson's than other cases, that, you know, the vast majority of individuals who are diagnosed with Parkinson's have constipation. They show constipation years, not decades, before their movement disorder, the thing that they were diagnosed with, the Parkinson's. And, you know, that was pretty curious, right? You know, like, why is this brain disorder, you know, manifest in many individuals as GI symptoms? It's true in autism. I think the data is a little bit more fragmented,

• 7:18Speaker 00

  and the phenotypes aren't as clear in autism as they are in Parkinson's. But clearly, many children with autism have some form of gastrointestinal symptom, whether it's abdominal pain, alternating constipation, diarrhea, and what have you. And to a microbiologist like me, this became quite interesting. It was an interesting observation, is that, you know, A, what is the role of the microbiome in these disorders? We're still trying to figure that out. I don't think there's, you know, one answer. I don't think there will ever be one answer, but we're trying to get to some of the clues that help us understand, you know, how microbes shape these outcomes, right? And just what you alluded to is, you

• 8:02Speaker 00

  know, what does that communication look like? How do microbes that live in our gut, the microbes aren't in our brain, right? And our, you know, our colon mostly, but our small intestine as well, how do they signal to the brain? How do they send their cues, if you will, both bad and good? That results in behavioral changes, mood disorders, even death of neurons, as dramatic a phenotype in the brain as one can imagine, like nerve cells actually.

• 8:29Dr. Mark Hyman?

  Wow.

• 8:29Speaker 00

  Again, that's, that was really very fascinating for me, and very understudied 20 years ago. I would argue it's still quite understudied now, right? And so, we looked at these problems from the lens of the microbe, right? And tried to understand what are the organisms that are at play in these different conditions? What are the signals that they're sending? What are the, you know, human cells that are receiving those signals? And then how do they mediate various different outcomes? Again, change in behavior, you know, movement disorders, cognitive impairments, what have you. I think we made some headway. I think we understand a few of those signals, but the microbiome is not one thing. It is many,

• 9:14Speaker 00

  many things, many hundreds, if not thousands, of organisms and molecules. So we have a long way to go. But I think there's, you know, very little argument in my mind, that at least in animal models, that there is a causal role for the microbiome in these, you know, classical brain disorders, right? And we know that because we can just manipulate the microbiome of animals in ways that we just simply can't do. It's not ethical or feasible to, you know, people. And then get, you know, very solid, reproducible, rigorous outcomes. And so, whether or not, to what degree that translates to humans, I think, I feel that, and we are still trying to figure that out, because again, we just can't do

• 9:58Speaker 00

  the invasive experiments in humans that we can in animal models. But I think that has to be the next step, right, is to try to understand to what degree the gut, or in our particular case, the microbiome in the gut, is signaling to the brain. Because, you know, I think the upside is potentially enormous, right, is if we can

• 10:21Speaker 00

  Help people with class one neurological outcomes, you know, brain disorders, if you will, by treating their gut. And I think this is one of the, so the, the north stars of our research is we don't try to get drugs into the brain. It's very hard. I mean, that's, I think, the classical approach, right? We just try to, you know, manipulate what we can, what's accessible to us. That's, that's in the gut. And then the body does the rest in terms of communicating that signal to the brain.

• 10:47Dr. Mark Hyman?

  It's so important, what you just said, that the signaling from the gut happens through a lot of different mechanisms.

• 10:53Speaker 00

  That's right.

• 10:55Dr. Mark Hyman?

  And you kind of alluded to a few of them. It can be direct microbial metabolites that maybe bind to different receptors and had different effects. It can be through inflammatory signaling or hormonal signaling.

• 11:07Speaker 00

  The nervous in the gut communicates to the nervous system of our brain through the vagus spinal nerves, other neuronal connections.

• 11:15Dr. Mark Hyman?

  Yeah, we, we kind of, that, that whole second brain thing, we, I think we've known about for a while. And I think it's such an important piece of this. So I didn't mean to leave that out. But, but it's these other pieces that are sort of new in, in thinking, right? Okay. Well, we know that the nervous system in the gut and the nerves in the brain, we, we can map them out. They're well understood in traditional medicine. But the idea that there's some strange metabolites from your microbiome that are changing your biology in ways that create demonstrable disease, it's not something the average doctor actually even thinks about.

• 11:42Speaker 00

  And, and, you know, we'll take that, that data that we talked about a couple minutes ago, and, you know, what percentage of the molecules in our blood are microbial origin? I can't quote you a number, but, you know, there are a, a large number of molecules in our brain that come from our gut microbiomes, right? And we certainly know this in animals, because again, we can just do, do those refined experiments, uh, but through extrapolation, through experiments like, you know, looking at postmortem tissues or C, you know, or CSF. I think there are very strong clues that, and Stan's work is some of this, as Stan Hazen, who you mentioned, you know, contribute to some of this, is that there are micro molecules like floating around our brain. But what do they do? And the vast majority of which, you know, we don't even know what they are, let alone what they're doing.

• 12:27Dr. Mark Hyman?

  So saying for brains is may not be a, a wrong statement. Yeah, I think it's kind of hard. I, I, I, I remember Rudy Tanzi talking about this, that there are discoveries in Alzheimer's brains. And he's one of the leading Alzheimer's researchers in the world at Harvard, who, who, who has described this phenomenon of microbial compounds in the brain, or even microbes in the brain, that potentially come from the gut. And, and it's such a, it's such a hard leap to think about, how does that happen? Because, you know, we think about the gut as this tube, it's impermeable, except for nutrients. And yet, that's not necessarily true. I think your work, particularly in the autism models, have been fascinating around how, you know, you see increases in gut permeability, you see

• 13:08Dr. Mark Hyman?

  increases in immune signaling, you see, uh, you know, other metabolites potentially having effects, particularly, you know, some of the metabolites that come from the microbiome having an effect in an adverse way on brains and kids, like in autism. Can you talk more about how, how sort of that work came about and what, what you learned?

• 13:27Speaker 00

  Our, our work is grounded in, in, in animal models, particularly mouse models. And so, um, I have to say, there are caveats, obviously, to animal models. They're not, they're not humans. But we try to reproduce the human condition to the best of our abilities. This work started many years ago with a collaborator, Paul Patterson, who was here at Caltech. Paul was quite interested in the role of the environment on behavior. Um, and I'll fast forward, you know, hopefully I'm not doing a disservice to the decades of work that he did, but I'll just fast forward to, to how we got involved, is he had looked at epidemiologic data showing that an infection during pregnancy resulted in an increased risk of that child having, having autism. And he modeled this in mice, essentially

• 14:11Speaker 00

  gave pregnant mice the flu. And then the animals had not just behavioral disorders, which he had characterized and continued to characterize. But when we started working with him, we looked at the gut. And we found the permeability that, that you mentioned, the inflammation in the gut that you mentioned, and, and other GI symptoms. And we found changes in microbiome. And we thought to ourselves, this, this is probably more than just a coincidence, because of that emerging literature in people, that, that the gut was involved in, in, in autism. And so we started digging. Uh, we went into, uh, you know, looking at immune, the immune side, you know, and I think there's still a lot to be done and other people that are, that are doing that. In terms of profiling, what are those immunologic changes? We got really interested in, as you mentioned, metabolites,

• 14:53Speaker 00

  the small molecules. And that, and again, we're just explorers, right? So we go, we, we look for things. And, and when something looks interesting, we, we, we dive in and try to follow, uh, those leads to try to understand really mechanisms of action, like really what are, not just what's there, but what, what are, what are those molecules doing? And so we did something called a metabolomic screen, which basically is a profile of molecules, right? In, in these animals. And we're comparing the animals that had the behavioral, uh, uh, conditions, uh, behavioral deviations, if you will, similar autism to those that didn't. And we found high levels of a particular class of molecules, are these like small phenolic molecules that sort of look like amino, they come from amino acids, kind of look like amino

• 15:38Speaker 00

  acids, reminiscent, they're not neurotransmitters, they're sort of reminiscent of neurotransmitters. And one of the molecules that we discovered that was highly elevated in the mice that showed behavioral symptoms was a molecule called four ethylphenylsulfate. And I won't go into the details of it, but just as one example, this molecule was 40 fold elevated in the mice that had behavioral, uh, uh, changes. Um, and then when we looked in the literature, the molecule was almost identical to a molecule that had been shown to be elevated in human autism and the urine of human autism. And we thought to ourselves, and this, this can't just be a coincidence, right? That the molecule that just stands out in our animal

• 16:19Speaker 00

  data set is a molecule almost identical to one that's, that's elevated in people. And again, you know, from a scientist's perspective, that was enough for us to put our, our, our resource and effort into trying to understand what that molecule is. And I'm just using this molecule as one test case, right? To really give us a, an example of how, how these connections work, these gut brain connections work. And so over the years, we, you know, through, you know, with help from lots of collaborators, found the bacteria, the bacterial genes that produce these, these, you know, this molecule and these, this class of molecules. And, um, then started asking ourselves, all right, are they just there? Or are they doing something? Right? So then we set up these experimental systems where we can, you

• 17:00Speaker 00

  know, you know, control the levels of, uh, production of, of, uh, for ethanol sulfate and related molecules in the gut. And then we can behavior test the example, right? And so this is now sort of the, you know, again, it doesn't rise to the level of causality, but I'd say a contribution to behavioral deficits. And we showed that if we, again, we de novo discovered this molecule, but if we then, you know, artificially elevate the levels of the molecule in, in mice, because again, we can engineer bacteria to produce those molecules, those mice had very potent signs of, of anxiety, but they also had, um, uh, speech, uh, issues or, or, or changes, changes in social behavior, social

• 17:44Speaker 00

  changes in repetitive behavior. And those are conditions, again, there's no, mice don't get autism.

• 17:49Dr. Mark Hyman?

  And what language do mice speak?

• 17:52Speaker 00

  You can just drop them with these ultrasonic microphones, right? And so, so you don't know what they're saying, you know, or trying to decode them.

• 18:01Dr. Mark Hyman?

  Sometimes when you're craving something sweet, the answer isn't necessarily to have more willpower. It's worth asking what your body might actually be asking for. And one thing I paid attention to was whether I'm getting enough protein throughout the day. Protein is important for satiety, for muscle, for providing the essential amino acids our bodies need. And that's one reason Perfect Amino's has become part of my daily routine. I take it every day because it's a simple way to supplement my protein intake with all nine essential amino acids without adding a lot of calories. I especially like having on days when I'm traveling, working long hours, or just know that I haven't gotten enough protein from food. It's a small thing, but for me, it's become an easy part of my everyday routine. If you're looking for help to fill protein gaps, go to bodyhealth.com

• 18:42Dr. Mark Hyman?

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• 19:24Dr. Mark Hyman?

  Ro uses liposomal delivery to support nutrient recovery, protection, and enhance absorption. If you're looking to put on another layer of protection this winter, start here. Go to rhonutrition.com and use the code HYMAN for 20% off site wide. That's the code HYMAN, R H O, nutrition.com. There's speech pattern, there's sound pattern. Yeah, I get it. I'm just teasing.

• 19:46Speaker 00

  There are stereotypical vocalizations that animals make, and they do this in particular, just to go, go into a little bit of detail. I do think it's interesting, but, um, is that, you know, in a, in a courtship, uh, paradigm, or in an aggression paradigm, if you put animals into those, into those contexts, then they vocalize, right? And so you can, it's such an induced vocalization and then see how different are different groups of animals in their speech patterns, if you will, right? And so again, they don't, they speak mouse, as you said. But, again, we can see, you know, are there changes on the baseline, right? And so, again, I also want to emphasize, you know, you know, there is no mouse model of autism. Mice don't get autism, right? But we can model certain behavior.

• 20:31Dr. Mark Hyman?

  Their behavioral correlates, like their behavioral correlates of autism in mice. And, and you see those rise when this level of, uh, for ethanol sulfate rises. And it, it, how is that not causal? If you, if you, if you kind of like have a normally behaving mouse, you give it this, somehow induce this levels of production of, uh, this, this molecule, and then it induces these behavioral changes. And then you dial it back and they go away. How is that not causal?

• 20:59Speaker 00

  We don't know what's actually elevating those levels in people, right? And so why, why do people have high levels of fourth penal sulfate, which we then showed in the subsequent papers. So again, once we found this in mice, then we looked in, in, uh, human tissue, feces, and serum, and we found that elevation. That primary change, we don't know, right? And the other aspect, which I also alluded to, is, you know, would you, in science, you know, to, to get You know, to be able to make confident claims, you really have to make systems very simple, right? So to go into these reductionist models. And so, again, we're working in an area that's where we can make, you know, causal contributions or causal claims about

• 21:42Speaker 00

  very specific things. But then when you zoom out, like, again, this molecule was produced by this bacteria, gets to the brain, it affects brain function. But when you zoom out, right, into a person, there's no one molecule, there are hundreds of molecules, right? And then that person has infections, that person has lifestyle, you know, changes, you know, dietary patterns, their genetics are super important, right, in how it manifests. So it can't, I don't think it rises to the level causal in humans, because that's molecule at identical levels in two different people could have two different effects, right? For example, I could have a genetic vulnerability, for example, that makes me

• 22:22Speaker 00

  predisposed to adverse behaviors. If that, you know, a certain molecule is elevated, you have a genetic landscape that doesn't make you vulnerable, you could have high levels of that molecule, but you don't manifest behaviors, right? And so, again, I'm, I think it's important to be rigorous and, and also know the context in which you're working, right? So, again, the data show that that molecule is important, this class of molecules are important. In whom are they important? In, you know, what else is going on? Those are the blind spots that we still have.

• 22:52Dr. Mark Hyman?

  I mean, that's such an important point. Sarkis is that, you know, they're such heterogeneity in the population, and the genes load the gun, but the environment pulls the trigger. So the same insult might not cause a problem in one person where it might cause a problem in another person. And we see this all the time in medicine, and we try to label people with these categories of illnesses like autism, but these are, there's no such thing, there are autisms, and there are Alzheimer'ss, or Parkinson'ss, whatever the plural is of that. And, and I think, you know, we're so used to these sort of very narrow disease classification systems that we miss the reality that, that these conditions are quite heterogeneous, even though they may manifest the same way symptomatically, they causally might have

• 23:35Dr. Mark Hyman?

  very different patterns, and there might be variable factors that are including genes and environmental factors, and that there are no two cases that are exactly the same. And I see this as a doctor practicing medicine in the trenches, that, you know, I'm humbled by the fact that, you know, how little we know. And then actually, you know, by listening to the patient, you will learn a lot. I think William Moulter said, listen to the patient who has the disease, rather than the, think about the name of the, whatever the disease that the patient has. And I think that's, that's really important. And I think, I think with autism, I've seen clinically so many cases where we've looked at the gut microbiome, we've seen abnormalities in there. And I remember one of my professors was a pediatrician named Sidney Baker, and he, he was an incredible pioneer in this field and treated thousands

• 24:20Dr. Mark Hyman?

  of kids with autism. And he used to talk about, you know, if you've seen one kid with autism, you've seen one kid with autism. And when we looked at these kids' gut, whether it was symptomatically, or just looking at their stool, or even things like organic acid testing, which looks in some ways at the microbial metabolites that come from the gut that are in, that metabolize by the body and excreted in the urine, and we can measure those things. And we don't completely understand how they all interact or what they do, but their signals are there. When you see these things, it correlates with, with these symptoms. And when you treat them, these kids often will get better. And I've seen many kids in my practice who, when you, when you optimize their gut health, and you get rid of the bad bugs, you put in good bugs, you deal with the leaky gut phenomena. I think, you

• 25:01Dr. Mark Hyman?

  know, because there's this complex web of interaction between the gut microbial environment, between the immune system and the gut, and the nervous system, and the rest of the body, it's such a complex web. And so you're, you're right, you're trying to tease that one molecule here or there, and it may not be the whole story. But it, but, but the truth of the matter is that there's something going on here that, that traditional medicine is missing when it comes to understanding how the microbiome plays a role in, in, in kind of psychiatric, in neurological, and even, you know, a host of other conditions that I mentioned earlier. So that's why your work is so important, because it's kind of teasing apart, like, how this all sort of interacts.

• 25:36Speaker 00

  Yeah, I mean, especially for something, for a condition like autism, right, where there isn't a, you know, a blood test or a brain scan, right, or using behavioral assessments, which can be quite subjective. Many of the behavioral assessments require parent reporting, right? Parents tend to be, you know, not the most accurate in terms of being able to recall what happened a week ago, a month ago, a year ago, right, in their environment or to their child. And obviously, there's the very strong emotional, psychological component to this as well, right? And so I think that makes the problem even more difficult

• 26:16Speaker 00

  to solve, right, is because the definition of autism is not one thing, right? And, and again, it's, it's subject to, to a lot of noise based on, I mean, just like data noise based on the observer and, and, and the reporting. And so now we're trying to take what is likely a biological, heterogeneous biological group, and superimpose on them the ability to assess their biological state with a heterogeneous set of tools, right? So that really compounds our ability to know really what's going on, right? And I think that's, that the autism

• 26:58Speaker 00

  field would really benefit from is, again, like, like a biomarker, right? Like one, if there is ever such a thing, and there may not be, right? I mean, I think autism could be quite, quite, you know, different in the fact that, like, multiple etiologies, which are like this comp trigger, if you will, all converge on a set of behaviors that we call autism, but the origins are all different, right? They just manifest in the same way. But if we had something reliable where you can track it, you know, with, let's say, a blood test, and that tracks with behavior, right, then I think we can start asking those questions of, okay, you know, as you've talked about in your practice, when I treat the gut, what do I see, you know, objectively, what can I see confidently changing that

• 27:43Speaker 00

  individual, right? And so I think, you know, obviously, other conditions, we have better, a little bit better understanding. And, you know, again, these objective biomarkers, you know, like something you can measure that is independent of, let's say, placebo or independent of opinion or recall, right? And that makes, that allows us to make headway faster when you have those, those sets of endpoints or those reliable outcomes.

• 28:07Dr. Mark Hyman?

  But when a kid, when a kid goes from being nonverbal and not connected and having all these, you know, classical autistic features, and then they go away, or they dramatically improve, it's not, it's not like you need a biomarker to figure that out. If a kid says, is not talking, and then starts talking, that's a pretty good biomarker.

• 28:24Speaker 00

  What defines talking, right? So number of words in a given amount of time, you know, the complexity of the language, the, the, the size of lexicon, right? And so, but I would.

• 28:36Dr. Mark Hyman?

  I mean, going from not talking to being fluent, I would say is a pretty good biomarker. And I've seen that happen. I've seen that happen. And it's like, something is going on. And it's often when you treat the gut, or when you get rid of things like gluten, or when you do, you know, kind of these weird sort of manipulations of the body and its sort of ecosystem, sometimes things will just click into place. And so I think, I think we were chatting a little earlier, how, you know, a lot of the autism field feels like this is a durable problem. Like, it's genetic, it's non-modifiable, it's fixed, and it can't be changed. And I think, you know, well, your work shows that that clearly can. When you take the germ-free mice, and those have no microbiome, and you put in the poop of an autistic person or mouse, I don't know how you exactly did it, and

• 29:18Dr. Mark Hyman?

  then that germ-free mouse becomes autistic. That's a really interesting finding, right? Can you talk about that?

• 29:24Speaker 00

  I can. But again, you know, the caveats are that it's an animal study. I want, before I talk about our work in terms of showing the contribution of the microbiome to autistic traits in mice, just going back to your point about, about language, you know, the, what you described to me is something I've heard many dozens, if not hundreds of times, right? People who've treated the gut, because again, I just hear these, these stories, right? The gut, and, and, you know, to, to the people who are observing them, clinicians, parents, you know, other caregivers, what have you, to them, it's black and white, right? Is that this child, you know, was a certain way for years, and we improved their gut

• 30:07Speaker 00

  function, and they're no longer the person we've known for years, right? And so it's hard to argue that point, right? But I would say, Mark, in, and you tell me as a clinician, right, you know, that translating those observations into clinical results is challenging without those quantitative metrics, right? Without being able to actually put numbers around what you're, what you're seeing, right? And it's not, again, it's not that people, you know, I don't disbelieve, it's not that it's an issue of belief, it's an issue of, like, I don't know, the, the language scientists and physicians speak in terms of saying, okay,

• 30:48Speaker 00

  now I believe what I just heard, let me, based on that information, make a set of decisions, right? So that's why I think, again, you know,

• 30:58Speaker 00

  Trust me, I like to push the envelope, don't get me wrong, right? But at the same time, you know, it has to be, whatever claims we make, we have to be able to validate it and substantiate it in ways that are objective, right? And so, again, so I think there is value in being able to find those, those metrics. And maybe it is something like just recording, right? And, and especially these days, right? Because you could sort of really deconstruct language in ways that are, that are, you know, quite sophisticated, right? And put numbers around that, those, those parameters. I think then scientists will say, okay, I believe now there's a change from before and after, right? That, that gut intervention. And let me now dig in to see what the, what the biology is.

• 31:39Dr. Mark Hyman?

  Yeah, that's a great, that's a great point. But I think, you know, when I, when I'm thinking about these kids and I've seen literally hundreds of these kids along the whole spectrum of neurodevelopmental disorders. And there are common themes, like these kids all have a lot of oxidative stress and you can measure that with, you know, lipid peroxides or 8-hydroxy-2-deoxyguanosine, which is a DNA adduct, like a damaged DNA byproduct. They have low glutathione, they have impaired methylation. They often will have problems with the microbiome, which you can measure. And then there may be things that aren't like well-accepted, but they're things like urinary metabolites of, of a deer rabbit at all, which is a fungal metabolite or other, other metabolites from microbes that we can measure.

• 32:24Dr. Mark Hyman?

  And that they change when the behavior changes. So the oxidative stress comes down, methylation patterns improve, glutathione comes up, we see, you know, the, the, the microbial metabolites change. These things we can observe and I, or we see, you know, intestinal inflammation improve. So there, there are subtle markers, like I had one kid who was autism, he had high calprotectin, eosinophil protein X, which are biomarkers of gut inflammation. Well, he didn't fully have colitis or ulcerative colitis, but he had something cooking in his gut. And so we, we normalized his microbiome by, you know, giving, I don't remember what we gave him, I think we had to give him rifaximin and, and any fungal, flucanazole to kind of reset the bugs and probiotics, which are sort of not absorbed antibiotics and any fungal and, and probiotics. He, he got better and, and those numbers came down.

• 33:08Dr. Mark Hyman?

  So there, there weren't like an autism biomarker, but they were things that we use in medicine to measure function in the body that are, that are a little bit more tangential, but seem to be kind of moving in tandem with these kids. When they, when they're bad, they're worse and when they're better, they're better. And so, I mean, that's, that's what I've seen clinically and I know it's not, it's not, it's what do we call anecdotes? And I think, you know, the, the plural of anecdotes or anecdata or something. And, and I think that the whole phenomenon of N of one studies, I think is really interesting because that's, I think where we're going to start to learn more. If we can start to be more rigorous about these N of one studies where we, we, the person is essentially their own control before and after. And it is, it is a messy problem because these are, you know, this whole, our whole

• 33:51Dr. Mark Hyman?

  movement of medicine from being reductionist and specialty-driven to being more understanding the body as a system or network and the microbiome is the most important example of that in human biology. You know, the, the labels and the ways we describe anything don't match the, the observations anymore. And so we have to change our theories when, when our theory doesn't explain our observations. And that's, that's kind of where we are in medicine, but the clinical practice hasn't quite caught up with where you are in your research, unfortunately.

• 34:17Speaker 00

  And I think it will, right? Because, you know, at the end of the day, the clinicians who are, you know, are on the front lines, obviously they want to do the right thing for their, for their patients and, and they'll try, you know, they'll, they'll use the tools that are available to them, right? But again, there, there's a certain, you know, threshold of evidence that they need before they say, all right, I'm going to start implementing this, right? Again, some people are just going to be, you know, more, you know, pioneering, if you will, right? And, and, you know, take calculated risks, right? But, you know, I think mainstream medicine is, tends to be very, very conservative. Again, and you would know, you would know better than I, I would.

• 34:55Speaker 00

  Going back to, to the, the studies that we did, so we did a number of different, right? Is, we had been, you know, one of the places that we started is we had been previously working on an organism, a gut microbe that had very potent anti-inflammatory effects, something I worked on early in my career. And this in and of itself, I think was a, was quite a, a sort of a sea change, if you will, and how we view microbes, is that we had discovered an organism that actually dampened the immune response, that actually balanced the immune system, right? Because, again, you know, we all think of the immune system as something that becomes activated once there's an infection. The goal is to then clear the infectious agent and our immune system evolve to do that, right?

• 35:40Speaker 00

  And in most cases, it does it quite well and actually does it without us knowing in, in many cases, in most cases. So what we discovered was an organism that actually did the opposite. It actually helped the immune system fight off infections, it actually helped the immune system not become overactivated. So again, you alluded to autoimmunity, but what is autoimmunity? It's when your own immune system is attacking your body, right? That it thinks there's an infection or it becomes activated for some, you know, usually unknown reason. And then there's, over time, the chronic immune activation leads to tissue damage. If it's in the brain, it's multiple sclerosis, if it's in the gut, it's Crohn's disease, right? It's in the, you know, joints, it's rheumatitis, so on and so forth, right? And so the organism that we had discovered actually was protective against these autoimmune

• 36:24Speaker 00

  or allergic conditions because it dampened the immune system. And so now fast forwarding to the animal results that I described a few minutes ago, we found elevated levels of inflammation in the gut of these mice. And so our, our hypothesis was, well, let's put in this bacteria that dampens the immune system and see if we then get behavioral improvements. And we actually did, right? And so, once we added this organism, the name of the organism is called Bacterium fagellus, it's in about 30 to 50% of the healthy human population. Generally can be in pretty high numbers in, in most people. It's a healthy organism, a healthy gut bacteria, right? Or gut bacteria that is about healthy people.

• 37:06Speaker 00

  And it, it, you know, when we treated mice with this, with this, you know, let's say I call it next generation probiotic, the mice improved in their autism-like quote-unquote symptoms. So they said, okay, well, it must be the immune system there, right? Because that's how we've been studying this organism. Turned out it wasn't because we knew the molecule made by the bacteria that dampened the immune response. And when we put in a bacteria that was missing that molecule, the organism was still able to improve behavioral outcomes. And we didn't see much change in the, in the inflammatory patterns in the animals. So again, a good, you know, maybe story, like your initial hypothesis could be wrong, but that's, you know, a long way.

• 37:49Speaker 00

  So find something because organism, regardless of its ability to modulate the immune system, was still providing behavioral improvement. So we wondered, well then, why is that?

• 37:57Dr. Mark Hyman?

  What was it? Yeah, what was it?

• 37:58Speaker 00

  And so our best guess, we don't know for sure to this day, but our best guess is that in addition to dampening the museum, we found that the organism actually helps repair that leaky gut feature that we talked about, right? So, you know, what does the gut do, right? The, you know, just very basic, the gut lets nutrients in and keeps toxins out, right? Or excretes, you know, waste from the body as well, right? Again, overly simplified. When that discrimination of knowing what to let in and what to keep out is broken down, then harmful things get in, we consider 40PS and other molecules to be in that category that are elevated because the leaky gut. And so we showed in animals and we showed in, in cell cultures that this organism was able to reseal that barrier. So think of this as like a zipper, right?

• 38:42Speaker 00

  That is then, you know, zipped up or, or sealed by this bacteria in ways that we still don't understand. But once that happens, once the gut is repaired, less of these toxic molecules get out of the gut and into the circulation. So they're effectively, their concentration drops and they're no longer inducing these behavioral variations.

• 39:03Dr. Mark Hyman?

  That's amazing.

• 39:04Speaker 00

  But I mean, again, it just, it just tells you, and I think this is to your point, but in, in a way, in an experimental system, well, again, we know exactly what those variables were. That person didn't go out and eat a cheeseburger, you know, while we're treating them or take an antibiotic, what would you have, because we can, again, you know, very carefully control the environment. And we know it's because of this, of this microbe. But, you know, again, maybe this is an example of what you were talking about, that you, you know, we know we're treating the gut in this particular case. The organism does not travel to the brain, right? But it then short circuits that flow of these, of these neuroactive, these neurotoxic molecules and the consequences is improvement.

• 39:44Dr. Mark Hyman?

  You know, you brought up the concept of a leaky gut and this is something that I used to be laughed at when I mentioned in academic circles a few decades ago. And now here you are talking about this as a sort of established fact. And I think We do now understand that the gut is a semi-permeable membrane that allows hopefully just nutrients and things that we want in and keeps bacteria and toxins and food fragments out. But when that is interrupted, it can dysregulate things in multiple ways from allowing microbial metabolites or the signal molecules to get through, or actually just activating the immune system, or irritating the nervous system in the gut that irritates

• 40:26Dr. Mark Hyman?

  the brain nervous system. So there's so many mechanisms by which it can cause neurologic disruption and systemic disruption. But you know, you kind of highlighted this particular story of your science, which is that you added a bacteria that had an effect, which is to help seal up this leaky gut that had then consequences in terms of the behavior of that animal. You've also done the opposite, which is you've taken poop from an autistic kind of model of mice, and you put it in a germ-free mice, and you've induced abnormal behaviors. So it kind of works both ways, right?

• 41:02Speaker 00

  Again, our microbiomes, your, mine, and the vast majority of people, we have somewhere between 200 and 500 different species of bacteria, depends on how they're computationally counted. And, you know, it's really the balance between those organisms that mediates, you know, the balance between health and disease, right? And so, again, all bacteria not bad, all bacteria not good. Some can be good in certain contexts and bad in other contexts. It's, you know, it's pretty complex, right? But, you know, again, we think of infectious agents as something that comes into the body and causes a disease. The microbiome's impact on our physiology isn't something from the outs, usually is not something from the outside

• 41:47Speaker 00

  coming in, right? It's that the ratios of the organisms that were there are altered, right? And so when you do these wholesale depletions, like antibiotic treatment, or one other thing we do is we grow these mice in these bubbles, these sterile chambers, right? But there's no microbes in there. So you know about like, people with like SCID mutations or impaired immune systems, like the boy in the bubble, right? We can grow mice that way. So there's, you know, the genetic side of food environment is identical, they just have no microbes in there, right? So really clean systems, artificial, because there's no germ-free humans, right? But we know exactly what's in or not in those animals, right? So when we do these manipulations, we're getting rid of everything, the good and the bad ones, right?

• 42:30Dr. Mark Hyman?

  Yeah.

• 42:31Speaker 00

  Oh, you know, the next level, which we and many other people are now moving towards is how do we think about recreating natural situations? Well, we're not just removing all the microbes, the good and the bad ones, or we're just putting in the good ones, or we're just putting in the bad ones, right? But we're, you know, reproducing this imbalance, if you will, right? And so one of the ways to do that, and there's probably a number of ways, right? But one of the ways to do that is then take fecal material from humans with a particular condition, and then put them into the animal models, right? And there are caveats to this, right? You're putting human microbes into mice, and you're looking at, obviously, all the mouse readouts that we talked about. But this is much more natural

• 43:13Speaker 00

  in terms of reproducing the human condition than anything we do when you just start off with mice, right? For a number of different reasons. A, mouse and human microbes are vastly different, right? Number one. Number two, the mice that we work with in biomedicine and academia and pharma industry, what have you, they have very depleted microbiome. And this is sort of a tangent, so I'll leave it there.

• 43:35Dr. Mark Hyman?

  Because they're eating that crappy industrial mouse food instead of like wild mouse food, right? It's like humans. I've been a big believer in infrared saunas for a long time, but I really came to appreciate mine when I was dealing with mold exposure over 10 years ago. My Sunlighten sauna became part of my daily routine at that time, and I felt better every time I used it, so I never stopped. I'm still in it almost every day for circulation, recovery, and managing stress. And a big part of that reason is simple, it just feels good. All I have to do is get in, sit down, and I'm supporting circulation recovery and my ability to manage stress. Now, Sunlighten's built on that with a new Amplify Red. More intense heat plus red and near-infrared light working together for cellular energy and recovery in one session. Sunlighten has been working with infrared technology for

• 44:20Dr. Mark Hyman?

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• 45:05Dr. Mark Hyman?

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• 45:34Speaker 00

  Right. But it's really a commercial thing. So the animal vendors have depleted the microbiome just so they can have a reproducible standardized microbiome, right? And so, but again, what has that done? It's divorced the function of that microbiome from the things that we're looking at in mice. Again, this is endemic, it's pervasive in biomet. It's a huge shortcoming, right? It's something that we're working to try and, you know, improve, but it's, we're not going to change, right? The way experiments are done. So that being said, right, is, you know, how can you make, or how can I make, mouse models more reflective of human biology, right? Again, we have a couple of levers to pull. And when you make these germ-free

• 46:16Speaker 00

  animals, right, again, they're, you know, they give you results, they're animals that we test, but they're also a tool, right? They're a tool because now you have no mouse microbes, again, a completely sterile mouse gut, so you can transplant the human microbiome into those animals without competition from the mouse organisms. So what does that allow us to do, right? Again, in addition to studying microbes, is to say, right, if I take poop, a source of microbiota from a person, let's say with Parkinson's, and, you know, a household control, a spouse, or a population control, right? And I put these organisms, these entire groups of organisms, right, into mice, now I can say, what are, what's the outcome in

• 47:00Speaker 00

  that animal, right? Do they have symptoms of Parkinson's? Or is the mouse that received the Parkinson's microbiome, does it have worse motor symptoms, or worse movement disorder, neuroinflammation, GI symptoms, than a mouse that got a human microbiome from a person that didn't have Parkinson's, right? To me, that's a much fairer comparison, number one, right? It's closer to humans, which I think is very important, right? But it also allows you to, again, as I said, recapitulate, reproduce that natural state, right, of an imbalance in, you know, the organisms that were there, right? I think this is, you know, I personally, this is a very, very powerful tool, right? And the reason why, it's not

• 47:42Speaker 00

  just us, there's like 50, 60 papers in the literature from labs all around the world that show that you can transplant some human phenotypes into mice just by moving the microbiome from humans to mice, right? You're not changing the genetics of the animal, you're not giving them chemical exposures, not even putting them on like processed, you know, ultra-processed foods or anything else, right? You're not giving them infections, you're just moving the microbiome, right? And in doing that, you can see, again, increased movement disorders in if the mouse is, you know, colonitis with a Parkinson's microbiome, increased behavioral deficits if it's colonitis with a microbiome from a person with autism. We've done this in multiple sclerosis, but it's been done in depression, it's been done in rheumatoid

• 48:27Speaker 00

  arthritis, right? So it's been done in a number of conditions, right? And so then, I think there's just two things. A, it You know, I think it advances the concept that microbiome change is meaningful. Right? We're not just measuring the change in in humans. We're actually putting that microbiome to the test, albeit in an animal. Right? But now gives you a an experimental system that you can take apart in ways that we can't. Humans and really get to underlying biology, right? Learn things that the that the typical mouse that the world, you know, scientists use, that that information you just can't get because it doesn't have that human microbiome with that original change in the ratios of organisms that were there the entire time.

• 49:12Dr. Mark Hyman?

  Well, I don't know if you intended this or not by your work, but I I know there are people out there in the frontiers of medicine who are taking healthy microbiomes from healthy donors, if there is such a thing, and and using it in patients with Parkinson's or with autism. And they're actually seeing changes. And I've I've heard enough case reports where I'm like, oh, this is fascinating. Because when I when I hear, you know, one story, I go, okay. When I hear two or three or four of the same story, I go, oh, and there's maybe something paying attention worth paying attention to here. And and, you know, I'm not suggesting in any way that anybody go out and start doing poop transplants from healthy kids to kids with autism or people with non-Parkinson's presentations with people with Parkinson's. I'm not saying that. We're not ready for that yet. But it's an interesting phenomenon that that we're seeing out there

• 49:56Dr. Mark Hyman?

  that people are are desperate with these conditions and they're trying to do something. And and sometimes it's working and it might have to do with what you're talking about. But but, you know, we've had other scientists on the podcast, neurologists, talking about Parkinson's from a different perspective, environmental toxins, which is a whole different thing. So, like I said earlier, these are heterogeneous conditions. I mean, they they're not one cause for every case of Parkinson's. There are many causes and many triggers that can cause the same downstream symptoms, including toxins, including changes in the microbiome. So I think it's just this whole area is so fascinating. You you kind of dove a little bit into the Parkinson's area. I I think, you know, you know, we do see this and it's well understood in traditional medicine that people with Parkinson's tend to have gut issues. They tend to be constipated.

• 50:39Dr. Mark Hyman?

  You mentioned often years or often even a decade or more before they get any symptoms of Parkinson's. And you're suggesting this isn't necessarily just a correlation, but there there may be some causative factor here in the microbiome that's changing things over time, causing inflammatory or toxic damage in the brain that's leading to a Parkinsonian presentation. Is that is that kind of what you're where you're pointing at?

• 51:01Speaker 00

  We think so, right? So so then the the idea that Parkinson's patients, the majority of Parkinson's patients have GI symptoms is is not new. In fact, it goes back at least 200 years. Right? I I often quote the Essay on Shaking Palsy written by James Parkinson himself in 1817, where he talked about GI issues in individuals that that he was studying. And neurologists know about this because many of their patients will come in. And in addition to their movement disorders, talk about their their GI symptoms. And again, I think there's a lot, there's very large epidemiologic studies now that show that this is the case. But again, I think there's still a chicken and the egg question mark is, you know, which comes first and which one is affecting which? Meaning, is it is the disease starting in the brain and affecting the gut?

• 51:45Speaker 00

  Is the disease starting in the gut affect the brain? Obviously, different people, it could be the different paths, right?

• 51:50Dr. Mark Hyman?

  It may be maybe you're the wrong question. It may be both.

• 51:54Speaker 00

  But it might, it's it's, I would venture to guess it is both, but it's different in different people. Right? Some people, it could be brain.

• 51:59Dr. Mark Hyman?

  Yeah.

• 52:00Speaker 00

  Others, it could be in the gut, right? So this has evolved into into something that's now called the brain first versus body first hypothesis in Parkinson's, where again, I think the data are just much more solid than other conditions about this GI GI comorbidity in a brain disorder. What's really fascinating is that people who have, if you look at someone who was diagnosed Parkinson's and you look back at their medical history, oftentimes you'll see that they either were treated or reported GI symptoms, years, if not decades, before their their movement. That's what made them, you know, go to see a movement disorder specialist in the first place. Right? And so, again, it's a temporal argument.

• 52:44Speaker 00

  It's not, it's not, you know, causal, but it suggests that maybe something started in the gut first. And in, you know, it, that's where it initially began. And then over time, you know, you know, migrated to the brain. And what I mean by that is this, and this is part of that that gut first hypothesis or body first hypothesis, is that there's the trigger for Parkinson's, which could be an environmental toxin, which could be a bacterium, which could be an industrial chemical, a heavy metal, a number of different things, right? Or a combination of of these, right? Because it's interesting, because a lot of the environmental toxins that are implicated in Parkinson's actually affect your microbiome. And so I think.

• 53:24Dr. Mark Hyman?

  Yeah, I was gonna say that. If you hadn't said that, I was gonna jump in on that because that that is right. I think that's a very, very important observation that toxins also affect the microbiome.

• 53:32Speaker 00

  Yeah, is it is it that the toxin affects the microbiome, which affects the body? Or is the toxin affecting the body directly and bypasses the microbiome? Again, and we don't have those answers, right? But that being said, so if you, you know, again, look at, you know, again, let's just call them just trigger, all those triggers, maybe the trigger's in the gut, right? Because, you know, we ingest a lot of things, right? I mean, our skin is relatively inert. Obviously, we inhale molecules, but the vast majority of the molecules that contact our body, that go into our body, come in through our gut, right? And so that's where the trigger is. And so this hypothesis is that that initial, you know, pathology and by pathology in Parkinson's, it's aggregation of a neuronal protein called alpha-synuclein.

• 54:14Speaker 00

  Right? So for those who don't know, alpha-synuclein is a neuronal protein. It's found, again, expressed by our neurons, our nerve cells. It has a function in those nerve cells. But what's interesting about this protein is that it it tends to clump. And when it clumps, it builds up into cells. And if the cells can't get rid of the clump, eventually the cells die. That's the neurodegeneration part, right? The nerve death part of of Parkinson's. Similar, different protein, but similar concept in Alzheimer's disease. And so the hypothesis goes that there's a trigger where the nerve cells are dying first in the gut because of alpha-synuclein aggregation. And that's why you're seeing the constipation first. Because again, you know, neurons help us think and sense and and all the other, remember.

• 54:59Dr. Mark Hyman?

  Motility of your gut is dependent on the nerves, right?

• 55:02Speaker 00

  That's right, right? And so, you know, our our intestines, as you just said, you know, push contents through because our nerves are telling our gut muscles to contract. It's called peristalsis, right? So if those nerve cells die, then the muscles, you know, contents sit, takes longer. That's constipation, right? And so again, this is the hypothesis. And what is, you know, again, the extrapolation of that is that that's why the constipation comes first because the nerve cells may be dying in the gut first in some people before they start dying in the brain. So the question then is, how we started the conversation, is how does that signal get from the gut to the brain? It could be a number of different paths. I think inflammation is is is one of the the most likely, but the nervous system itself is another one.

• 55:46Speaker 00

  Because what's very interesting about alpha-synuclein, this neuronal protein that aggregates that clumps, is we know that that protein can move from neuron to neuron to neuron, right? And so it can actually like a, maybe there's like a highway of nerve bundles. I mean, we know there's a highway of nerve bundles connecting our gut and our brain. Maybe, you know, alpha-synuclein is just using that highway. It started, you know, it was triggered in the gut, but is using that highway to get into our brain. And that's why, and that process takes years. And that's why the movement disorder comes years later because that process has to migrate to the brain and then kill enough neurons in the brain for the movement disorder, right? So again, this is a hypothesis.

• 56:30Speaker 00

  I think there's a lot of evidence in people.

• 56:32Dr. Mark Hyman?

  It's interesting.

• 56:33Speaker 00

  Almost, it it's almost irrefutable that this can happen in mice because again, we can trigger these events in the gut and see pathology in the brain. So it can happen. And that's where the frontier of Parkinson's research, at least in terms of gut brain connection, is, is to try and understand, you know, is there a gut first origin in some case of Parkinson's? And if, Mark, I think this, you know, again, you know, I I mean, it there's very important knowledge, but I think this is really an opportunity, right? As as I mentioned earlier, it's much easier to intervene at the level of the gut than it is to intervene at the level of the brain.

• 57:09Dr. Mark Hyman?

  Yeah.

• 57:09Speaker 00

  Right? So if we can identify people, identify them early enough in their disease, I think there's a good chance in the next five, 10 years, we'll have interventions. So hopefully, this is an aspiration. Hopefully, stop Parkinson's in its tracks in the gut.

• 57:22Dr. Mark Hyman?

  Yeah, it's so it's so important what you're saying. And I think that that the the whole sort of understanding of how.

• 57:30Dr. Mark Hyman?

  You know, these neurological conditions are not just brain disorders. They're systemic disorders that affect the brain. Martha Herbert, who's a pediatric neurologist, wrote a paper about this called autism. Is it a systemic disorder that affects the brain or a brain disorder? And her hypothesis is it's a systemic disorder. And I clinically observed that, too. And whether it's with Parkinson's or autism or any host of a number of conditions, you know, you can't leave the gut out of the equation. It's almost like, you know, functional medicine, which is what I practice, is sort of the clinical application of this approach of systems or network medicine. We always start with the gut. It's like, whatever you're doing, like if there's a problem, generally start there and see if you if you help normalize the microbiome as best you can, which is hard to do,

• 58:15Dr. Mark Hyman?

  but you can, what happens? And often people will have pretty significant results. And even without any digestive symptoms, which is kind of the other thing that people don't understand is you don't have to have digestive symptoms to have dysbiosis or imbalance in the microbiome that causes systemic effects. And I just, I recently had a kid who with Asperger's slash sort of on the spectrum autism, and he had pretty bad behavior and very hyper and trouble with, you know, language and in school, kind of reading, writing and stuff. And he, it turned out he had very high levels of folate receptor antibodies, which were triggered by a cross reaction to casein dairy. And, and this is sort of well described in the literature.

• 59:00Dr. Mark Hyman?

  And, you know, the treatment was a form of folate called Lucoverin to bypass this step and to activate this brain folate receptor. The kid also had fungal overgrowth in his gut. He also had gluten sensitivity. He also had leaky gut by objective measures that we tracked. And so we just kind of treated all these things. And the mother sent me a text, well, my kid's normal. What is this amazing? You know, and I, you know, we don't see that every day, but it's, you know, it's not, and it's not that every kid with autism or ADD or Asperger's has this particular pattern. It's just that, that there's a way in to understand these things on an individual basis that takes into account that the gut plays a big role, that these things play are all interacting.

• 59:41Dr. Mark Hyman?

  And so I think that your work really highlights that, that these are, that both you can, you can have bad bugs creating bad metabolites, creating bad things in the body, or you can actually induce, you know, improvements by putting healthy microbiomes in animals that are predisposed to abnormal conditions like autism models or Parkinson's models. So it's, it's kind of like, it's pretty, it's pretty amazing research. Your work is pretty amazing.

• 1:00:07Speaker 00

  Can I ask, so how long in your practice for those cases where you have seen improvements? How long does it usually take?

• 1:00:13Dr. Mark Hyman?

  It can be, it can, it can be days. It can be days. It can be quick. Like, it's not long. Like, it depends on what's going on. Sometimes there's more durable problems. Sometimes kids have other issues. Sometimes there's heavy metals or sometimes there's, there's things that are hard to treat. But when it's the gut and that's the problem and you reset it, it's quite, you know, it's quite amazing. And there's often some trigger, right? Like you said, maybe there's toxins that cause changes in the microbiome, or maybe there's gluten, which causes a leaky gut. We know from Fasano's work at Harvard that that, you know, increases onulin that causes increased permeability in the gut. So there's enough there, there in the literature to kind of put the dots together. And, you know, the art of medicine is really what I do.

• 1:00:55Dr. Mark Hyman?

  The science of medicine is, is, is great to kind of inquire and to dig in and to tease apart these things. But at the end of the day, people are suffering out there. And, and this doorway through the gut, you know, is, is kind of interesting. And I'd kind of like to spend some time hearing your thoughts about, you know, what's happening out there in the space of, of quote, treating the microbiome, testing the microbiome, probiotics, you know, personalized probiotics, symbiotics, prebiotics, you know, polyphenols. I think that's a whole nother category. So I think, you know, we're sort of, I feel like at the beginning of this dawn of the microbiome era, even though I've been doing this for 30 years with the training the gut, it's still like, it's still kind of like a very, it's a very complex area. And I think we're just being to understand it.

• 1:01:40Dr. Mark Hyman?

  So I'd love to hear your thoughts about, you know, for people listening, well, what do you do? Like, how do you, how do you create a healthy gut? And how do you deal with maybe finding out if your health issues are caused by your microbiome? And then what do you do about them if you find them?

• 1:01:52Speaker 00

  I'll start with, with sort of the commercial approaches, right? So you go online, you can find a number of different companies that will, you know, for some amount of money, test your feces, you know, test your, you know, you send a fecal sample, they'll test your microbiome. And then they'll recommend a set of probiotics because they'll say, okay, you deviated from what is quote unquote, healthy profile, microbiome profile, and we can get you back, back on track. I don't believe any of that, to be perfectly frank. And I'll say that just simply because I know the literature, I know the state of the art in the field, and there is no one way, there's no way to look at a microbiome and say, you're healthy or you're not healthy, right?

• 1:02:38Speaker 00

  Absent like some like obvious pathogen or some obvious toxin, right? Which is not what we're talking about here, right? And so, so, you know, I'm, I'm more than skeptical. I think I just, I just don't believe that that's possible because I don't, the science doesn't back that up, right? So what are the things that we can do? I think the things we can do are largely what your grandmother would have told you anyway, right? Is eat a healthy diet, make sure you get a lot of sleep, good quality sleep, right? Exercise. There's a lot of literature I'm sure you're familiar with on, on exercise and the microbiome, right? Elite athletes have, you know, very interesting microbiome configurations. And then the other one that I don't think enough people talk about, but there's a fair amount of literature as well, is managing stress.

• 1:03:22Speaker 00

  So stress, this is the brain to gut connection, right? Changes your, your gut profile, right? So if you can do all those easier said than done, then that's, you know, I think, you know, the baseline. And those are foundational and durable ways to keep your microbiome healthy, right? So again, if you're eating plant-based diets, diverse plant-based, you know, diet, lots of, lots of fiber, you're feeding, you're giving your gut microbes the things that they love to eat, they're going to flourish, right? And again, you know, sleep, exercise and stress. In terms of, of actual like supplements or, or let's just call them interventions, right?

• 1:04:03Speaker 00

  I think using, using human milk oligosaccharides, it's another way to feed your bacteria, things that they, they like. You mentioned polyphenols, bacteria love to feed off polyphenols, right? You know, like in, you know, green tea or coffee, right? But other, you know, certainly other, other sources as well.

• 1:04:24Speaker 00

  What I'm, I guess maybe more on the fence about are probiotics, right? I mean, this might be the frontline. This might be like the most obvious, right? But, but the vast majority, almost all probiotics that are commercially available to us were developed decades ago. They cut their lactate gas back there. They come from milk and dairy products, right? They don't come from the human gut. They, they haven't, you know, evolved to be able to network with our bodies in ways that are indigenous, are, are, you know, native gut microbes do, right? There are a couple of products now on the market that are human gut microbes that are commercially available, right?

• 1:05:05Speaker 00

  And so I think those are more likely to be able to, you know, have an effect size, have, have an impact on our biology. But I think this is the future. And, and I know more and more of these, you know, let's call them again, next generation probiotics, these human derived organisms, not dairy product organisms are going to come online. And I think that those are going to have a better chance of improving gut health and then obviously beyond the gut immune metabolic neurological improvements as well.

• 1:05:37Dr. Mark Hyman?

  I mean, there are now prescription poop pills for C. diff, right? So you can, you can actually take a quote, a human poop pill, right?

• 1:05:45Speaker 00

  There are FDA products for, for C. diff, right? But I see, I, so what we're talking about in terms of C. diff are clusterium defecile infections, right? And so these are like these blooms of organisms that really cause lots of, of gut damage. And they often are resistant to antibiotics or they can become resistant to antibiotics. And so what I think the medical literature is very solid on, I think it's like 50,000 or more fecal transplants for, for C. diff, clusterium defecile infections, is that when you replace the microbiome of a person that has this infection with a healthy microbiome, the fecal transplant therapy is better than any F, any other FDA approved therapy, any antibiotic.

• 1:06:28Dr. Mark Hyman?

  Dramatically, dramatically.

• 1:06:30Speaker 00

  Yeah, over 90% success, right? Which like most FDA approved drugs don't work in 90% of the people that take them, right?

• 1:06:35Dr. Mark Hyman?

  Not even close, yeah.

• 1:06:37Speaker 00

  It's more like 40, 50%, right? And so I think that's a success story. It's a clearly a success story, right? But that, that environment of, you know, like this bloom of a, of a weed, if you will, right? You know, that's, that's killing all the flowers around it. That, that's a unique situation, right? Again, C. diff infections or a handful of other, uh, uh, bacteria infections that were essentially putting out the fire with a fecal transplant. You know, I think it's, it's a miracle. I think it's a success story, right? For, for the microbiome research. I'm not sure how much that translates into autism or Parkinson's or, or Crohn's, right? Because those studies are being, you alluded to them, right? And we still haven't like cracked that code, right?

• 1:07:21Speaker 00

  We still don't know what the, you know, what is the optimal donor? How much do we have to dose? How often do we have to dose? Is, do we need durable colonization? Like, you need to really change someone's microbiome? Or can you just put it out and everything goes back to normal? All that's still being, still being figured out, right? But the basic biology, the basic system of an infection versus a chronic condition are also very different, especially when you're trying to reverse an outcome, right? So again, let's just go back to Parkinson's. I'm going to contrast this with something you said previously in autism. That's why I asked about that, the time component. It was for this reason, right? In Parkinson's, again, there's Death of neurons in particular brain regions like the substantia nigra pars compact, right, there's, there's, once neurons are dead, there's just no going back unless you're

• 1:08:06Speaker 00

  gonna put stem cells into the brain or something, right? Nothing in the gut's gonna make those, those, those nerve cells. So there's, there's actual damage, right, to the brain, like something is, you know, for lack of a better term, broken in the brain, right? So you gotta fix that. Nothing you do in the gut is gonna, is gonna change that. Um, in autism, I think, conditions are a little bit different. There, there is no obvious damage in the autistic brain, right? To me, that's more of a chemistry issue than, than a pathological issue.

• 1:08:35Dr. Mark Hyman?

  Oh, there's neuroinflammation on these kids' brains, right?

• 1:08:37Speaker 00

  Well, you can see an inflame, but again, inflammation is toggled back and forth, right? You can turn on-

• 1:08:41Dr. Mark Hyman?

  Right, it's modifiable, right?

• 1:08:43Speaker 00

  Death of neurons is, is, is, is a one-way, is a, is a cul-de-sac, right? And so, so, anything that's modifiable, I think now puts it into the context where a gut, or let's say other interventions, we'll talk about the gut, you know, has a chance of, of improving or reversing symptoms, right? And so, again, you know, the stories I've heard very similar to, to the ones you're, you're recounting here are that, you know, gut interventions tend to have within days or weeks, really dramatic improvements in acute behaviors. You mentioned aggression. I think that's a very obvious one, right? Is that you can see this, you know, aggression or irritability phenotype change pretty rapidly.

• 1:09:24Speaker 00

  What I'd like to see are longer-term studies on some of those same individuals in a, you know, like, clinical setting where we can measure as much of those objective, you know, endpoints as possible. What I'd like to see are longer-term studies because, you know, if a child is irritable, they're not learning in, in class, right? They're not developing relationships, right? Same with, I would put anxiety in the exact same category, right? If a person is anxious, which is prevalent in, in autism, right? Or they have attention issues prevalent in autism, right? They're not learning, they're not building social bonds or, or relationships. And if we remove, and this is a question, right? If we remove

• 1:10:05Speaker 00

  those constraints, right? If I'm not so concerned about my GI issues, or I'm not held back by my anxiety, or I can focus better, right? Over time, do I now improve on some of those other core autism traits? It, you know, do, again, my relationships are, are they getting better? Is my cognitive, um, uh, ability improving as well, right? So I think you kinda need to remove that veil, if you will, first, and, but then it takes time to learn. It takes time to develop, you know, those social skills, right? And so, so again, I think that's still a gap in the, in, in, in at least the medical literature is what are the long-term benefits, right? Not just the acute benefits, like aggression, what are

• 1:10:49Speaker 00

  the long-term benefits in terms of, of social engagement, cognitive improvement? Um, again, just learning in school, so on and so-

• 1:10:57Dr. Mark Hyman?

  Yeah, well, this, this whole field is so fascinating to me, and I think, you know, your work is really looking at how the future's really about, you know, personalized approaches, it's, it's targeted, it's, it's not just shotgun approaches, take this probiotic and everything's fine. So it's, I think, that, that's, that's kinda, I think, what we're gonna learn more and more about is how do we create personalized medicine in general? And how do we create personalized microbiome treatments and personalized treatments for different conditions and deal with the multifactorial nature of things? It's not just one thing sometimes. So it's, it's kind of, it's kind of an amazing moment to be in medicine, I'd say. And, and I think, you know, for people listening, the basics go, right? Stay away from drugs that hurt your gut, like don't overdo antibiotics and acid blockers, you know, try to breastfeed

• 1:11:39Dr. Mark Hyman?

  if you can, try not to have a C-section if you can avoid it, you know, for a baby. You know, do, do eat a wide variety of plants, like somebody says 30 plants a, a week to actually get a diverse level of microbiome support from fiber and polyphenols. That all works. And I think, you know, there are, there are doctors out there like me who are kind of on the edge and doing things experimentally, but we try not to do things that are harmful and try to be supportive. And, and, and we do see remarkable changes across a spectrum of diseases by, by treating the gut. And your work has really been a lot of the leading light in helping us see that there's a, a there there, that there's something actually going on and, and kind of proving unequivocally that, you know, this is not in people's head, that this is probably in their gut, so.

• 1:12:24Speaker 00

  Yeah. Again, you know, our microbiomes are like a, a, an organ, if you will, right? You know, and, and they're just, it is foreign, it is a foreign organ, but it has the metabolic capacity, the microbiome has the metabolic capacity, the liver has the same mass as the, as the adult brain, right? I mean, this is an organ in our body, it just comes from, from the environment, right? And, you know, one of the things that I, that I, I, you know, when people ask for advice, I say, what can you do about your microbiome? Again, I think there's, you know, as we just talked about, I think there's a number of things you can do. But I always try and tell people, get ahead of the problem, right? Is the microbiome is not a pharmaceutical, it's not a drug. It may be someday, but it isn't today, right? So we still, there's a lot that we still need to learn about the microbiome to turn

• 1:13:07Speaker 00

  micro, the microbiome into drugs or to drug the microbiome directly, which is something we didn't talk about, but I think is also quite interesting, right? But because the microbiome sort of like tunes our body, all these different systems, right? It wasn't designed to reverse disease. We're trying to engineer it to do that, but it, it wasn't designed to do that, right? So by getting ahead of the problem, what I mean is, don't wait till you have diabetes before you start, before you start taking, you know, your, your gut health seriously, or don't wait till you have, you know, any condition before, cancer, what any condition, right? Is, you know, there are things you can do today to improve your gut health, to improve your microbiome health. And the payoff is, long-term, is,

• 1:13:48Speaker 00

  you know, is your health in, in, you know, the decades that are still ahead of you, right? And so I think prevent, and that's something we don't do well enough in this country, but the microbiome is, is a, an avenue, or is a test case where I think we can prevent a lot of adverse health outcomes in later years by taking care of our microbiomes now.

• 1:14:07Dr. Mark Hyman?

  Well, that's a, that's a beautiful place to stop. Thank you so much, uh, Sarkis, for your work. Everybody who's listening, want to learn more about his work, you can go to Sarkis, S A R K I S dot caltech dot E D U and learn all about his research. Um, I hope you get lots of funding and get lots of support because what you're doing is so important. And I think the faster we can learn about this, the better we can do a job of helping people recover from some of these really tractable chronic illnesses that often start in the gut.

• 1:14:36Speaker 00

  Thank you, Mark.

• 1:14:37Dr. Mark Hyman?

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• 1:16:04Dr. Mark Hyman?

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• 1:16:49Dr. Mark Hyman?

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