Does The Microbiome Hold The Key To Treating Parkinson’s, Autism & Other Diseases? CalTech Microbiologist Dr. Sarkis Mazmazian on The Gut-Brain Axis

28:31So let's say you cohabitate with someone whose microbiome is pathogenic, is altered in some way that isn't healthy. That mixing, for one example, could be that they have an organism or more of an organism that's driving inflammation, for example, right? If now you start being exposed to that organism, you're colonized become or increased in number of that organism, then you may not develop an inflammatory reaction, right? But I want to be cautious about what I'm saying is, you know, I don't want to ostracize particular disease populations, nothing of the sort. These are, you know, probably going to be, you know, when it's all said and done, low likelihood events, meaning that let's say I move in with somebody who has a microbiome driven disease, right?

29:17And I mix my microbiome. It doesn't mean I'm going to get that. It doesn't mean I'm going to get sick. Other factors are involved, such as genetics. And I think genetics are really, really important, meaning that a person could have a dysregulated microbiome, but if they have a healthy genetic landscape, they're probably not going to develop disease, right? And I think we should talk about this gene environment interaction, because I think it's crucial to how the microbiome works. But going back to analogy, if I move in with somebody and I'm genetically vulnerable, but my microbiome was healthy, my microbiome was robust, I didn't show signs of disease, but now that I'm exposed to a harmful organism, that combined with my susceptibility, my vulnerability on the genetic level together may predispose me and I may now start developing symptoms.

30:04Right, right, right. Yeah, that's super interesting. And I appreciate the qualifier because without that, you can just imagine the clickbait headlines that would come from that. I've been very cautious about this. In fact, I resist. There's a lot of hype and a lot of kind of people out over their skis on, in this field, in terms of like how the science is getting translated into mainstream awareness. Correct. And I had contributed to that for many years. I've tried to become much more conservative in the way I extrapolate from the data itself, right? And to this point, it was about a decade ago, I thought about writing an article about, again, the microbiome being a mediator of non-communicable diseases, a disease that we never considered to be transmissible.

30:53And I never wrote that article. Other people now have written articles of that sort. And it's fine. It's fine to put those hypotheses out there. But again, I do worry, right? I do worry that we may be overextending the knowledge base, actually worrying about things that may not happen. But now at least maybe the bright side is once the hypothesis is proposed, then people will test that hypothesis. So we will know. But again, these are gonna be low likelihood events, even if it's true, right? And I have no reason to believe it's true, right? For example, is Parkinson's contagious? There's no real evidence to suggest that that's true.

31:32there's some epidemiologic evidence meaning that you know a spouse of a person with parkinson's is more predisposed in fact neurologists are more predisposed to parkinson's in the general population but there are a number of other potential explanations for that that go well beyond the microbiome after hosting more than 900 episodes of this podcast i have noticed a pattern And that pattern is that the highest performers don't buy into the latest trendy hacks. Instead, they obsess on what actually works, which is always the unassuming basics. And there is nothing more basic than hydration. But here's the kicker.

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35:18What do we know or not know when it comes to the genetic markers that would create that type of vulnerability? There's probably a lot of evidence. There's probably a lot of evidence from the genetic world, meaning all the genetic studies, that have not yet been linked to how the microbiome affects the outcomes of those genetic predispositions. These are really two camps, research areas that are by and large separate from each other. And there may be some conflict between the approaches that geneticists use and people who study the environment, for example, microbiome being a major component of the environment.

35:58and that tension is that genetics, you can explain genetics pretty easily these days, a genetic predisposition to disease because DNA sequencing has become so advanced and the algorithms then analyze the sequence data have advanced so much that we can pretty much get a good genetic fingerprint of an individual and then people do these large genetic studies like in some cases, thousands, tens of thousands of individuals with a particular disorder And then you can then link even low probability genetic predispositions to that disease, right? All that research, a huge, vast amount of work really hasn't been tied to how the environment then modifies those genetic predispositions.

36:43I personally believe that the majority of our genetic predispositions are modified by our environment, right? If you're, let's say, list the top 100 diseases that affect humanity, I'm gonna say 90 % or more are a product of gene environment interactions, not solely driven by genetics, not solely driven by the environment or the microbiome. And by environment, that would include lifestyle decisions. That would include many, many things, right? So lifestyle decisions, let's say, diets, right? And alcohol, drugs, other exposures, but pollutants in the air, things that we can't control, right? I mean, maybe we're sitting in an area where there's arsenic gas that's seeping up from the ground.

37:25That happens. Sometimes we don't even know, right? Heavy metals in our foods, preservatives, many other environmental risks. And I really think these both compound over time. And so maybe contribute to age-related disorders. In other words, we have a historical record in our body of all these harmful molecules that we've been exposed to. We've had the same genetics in our lives. So over after some time, we just pass a tipping point where those environmental triggers just, you know, become so strong that coupled with the genetics, you know, manifest the disease, right? And so, you know, but again, you know, I study the microbiome.

38:00So, you know, the microbiome, I think is a major part of our environmental exposure, right? Just go back to the fact that, you know, hundreds, maybe thousands of molecules in our bodies are come from our microbiome, come from our microbiota. And so they're constantly sending these chemical signals into our bodies and our microbiome is changing based on lifestyle decisions, based on other things in our environment as well. So maybe microbiome can be viewed as a real stat, if you will, for environmental exposures. And technically it exists outside of us. Correct. It's technically not in our body, it's outside of our body.

38:34Yeah, and it's changeable, right? Changeable in a way that our DNA isn't, right? I mean, of course our DNA can be modified in our lifetimes, both in terms of mutations and this other, you know, area of biology called epigenetics, where you're not actually changing the DNA itself, but changing properties of the DNA. And that is linked to environment. But again, these two camps, if you will, really haven't merged in terms of taking what we've learned from all these genetic studies, and then now asking how do those genetic risks, how are they modified by the microbiome? And my hypothesis, something I've written about a little bit recently is that many of us have genetic predispositions, but maybe we don't have disease because our microbiomes are robust.

39:19They're sort of filling in the gaps, if you will, that the genetic vulnerability exposes us to. But if my microbiome then becomes, let's say, again, I've lived my whole life with a genetic predisposition. My microbiome was healthy. I didn't show symptoms, but something corrupted my microbiome. I lost that resiliency. I lost the compensation that my microbiome was providing. maybe now, or it can even go in the other direction where microbiome becomes pathogenic. It's now sending these harmful signals that combine with the genetic vulnerability to result in disease, right? I think, again, this is gonna be the majority.

39:52And I wanna make this point is, I think there's gonna be the majority of the way that our microbiomes interact with us in the context of disease, right? So I think there's only a handful of cases where the microbiome actually will cause the disease. I think in most cases, it's networking or let's say modifying genetic or other predispositions. And so that's where I think the microbiome sort of fits in our biology. Right. Speaking of a pathogenic microbiome, walk me through what led to this discovery that there is a connection between Parkinson's and the gut microbiome. Yeah, this was a hunch that we had many, many years ago.

40:37Again, we study mice, animal models. So much, much easier to test than in humans. But the actual evidence, like most things that we study, the actual evidence goes back decades, in fact, sometimes centuries. And so I won't go in chronological order in terms of what I learned to make us think that maybe there was a connection between Parkinson's. You have to credit Parkinson himself for what he said in 1870, right? That's exactly where I was going, right? It's exactly where I was going. So in 1817, James Parkinson wrote the essay on shaking palsy, where he talked about case studies of individuals that had tremors and gait and posture instability, which is Parkinson's.

41:20It was later named after, he didn't name it Parkinson's. It was named after him, I think a couple of decades later. But then he also talked about the GI symptoms, essentially constipation. And then in one of those case studies, he gave a patient a bowel cleanse, essentially a laxative and said that their motor symptoms or their behavioral symptoms improved. And so this is, you know, the point I'm trying to make is none of this is new, right, to neurologists. It just hadn't been studied. In fact, I've asked many of my neurologist colleagues, like why weren't, you know, why was this gut brain connection not made previously in Parkinson's when you see patients who are complaining about constipation all day long, right?

41:59And the answer I get more times than not is that I'm a neurologist. What can I do about their GI issues, right? Which sort of speaks to our medical system and how there's a lack of integration across disciplines. Everybody's siloed in their own respective disciplines. It happens, it's the same in science as well, right? And so, obviously I learned a little bit about that literature, but read mostly about the fact that somewhere between 50 % and 80 % of Parkinson's patients will have clinical grade constipation years before their first motor symptoms, years before they're ever diagnosed with Parkinson's.

42:37And just to be clear and fair, it's not just GI symptoms. They'll have olfactory deficits, so loss of smell, REM behavioral sleep disturbances called REM behavioral sleep disorder, and maybe even like psychiatric issues like depression. so there's this host of of comorbidities in what is called the prodromal phase before the actual diagnosis but constipation is quite prevalent and again you know it was a clean slate of research at the time there was no evidence for or against this hypothesis just this correlation between gi symptoms and and motor symptoms and so we took a a chance and i credit uh tim samson who was a postdoc at the time is now a professor at Emory for just being intrepid enough to just ask that question of is the microbiome involved in Parkinson's?

43:27And we did a very, very simple experiment. We took mice that were genetically predisposed to developing symptoms of Parkinson's and we just cleared out their microbiome, right? It's a very artificial system, right? So there's no sterile microbiology, sterile people or animals, right? But we've just artificially made them sterile and all their symptoms went away. Their gut symptoms went away, their motor symptoms went away, their brain inflammation went away. And that classic hallmark of Parkinson's, which is just to get into the weeds just a little bit. So it's widely believed that Parkinson's is caused by aggregation of a neuronal protein called alpha-synuclein.

44:05So protein we all have, many, many organisms have this protein in their neurons. And when this protein, this molecule clumps, essentially prevents cells from performing their normal functions. And eventually those cells will die because they can't deal with the stress of this like, you know, hairball protein just building up inside. And this is happening in the neurons in the brain. It's happening in neurons in the brain, but it's happening in neurons all over the body, including the intestines, right? And we were one of the first groups to show that in fact, it was happening in the intestines of these animals as well.

44:36And it's not that we did anything revolutionary. We just looked somewhere that people hadn't looked before, right? And so again, that simple experiment, just removing the microbiome, removed this pathologies, alpha-synuclein aggregates, in addition to all the symptoms. And at that point, I actually remember sitting in my office and Tim walking in with the data. I felt like something was happening. I mean, it was clear that something was happening. And of course that experiment doesn't tell us exactly what, it's sort of a go, no go experiment, but this was 2013 or so. And since then we've made a number of discoveries that again, keep reinforcing this hypothesis.

45:13How was that data received at the time? In the Parkinson's world, it's been received quite well, meaning that even neurologists, neuroscientists, people historically working in the field have been very, very open-minded to this hypothesis. Even geneticists who tend to be quite skeptical of the microbiome for reasons that I just discussed a few minutes ago, seem to embrace this concept. Again, it's not a fact yet, right? It's still, you know, well, I'll tell you this. I believe that it's true in mice, right? I believe that this connection between microbiome genetics and Parkinson's is true in many animal systems.

45:54We just haven't shown that to be true in humans yet, right? I mean, again, all that work is currently underway. And so the reason why I believe it's been well accepted in a very traditional research space, neurobiology, neuroscience, is because everyone in that field knew about these GI symptoms, knew about the gut issues, right? I'll give you a contrasting area where there's a lot of skepticism, a lot of pushback, and that's in autism. So the other portion of our laboratories worked on the connection between the microbiome and behavioral disorders, neurodevelopmental disorders, primarily autism.

46:31And there we don't have like the smoking gun. We don't have these connections that are so obvious in Parkinson's in the autism world, or at least in terms of like, you know, the symptomology in an individual with autism. And so we, others have shown in mice, many other groups have shown in people that there's this connection between the microbiome and autism. It's been, again, very, very tough treading in that space. And, you know, I have to say, I'm not, you know, I can see where the skepticism is coming from, right? Because we have, I don't feel as a field, we've done the experiments to even convince myself that the microbiome is fundamental to autism, right?

47:17And the microbiome affects so many other systems, but is it really contributing to this disorder or not? That's still an open question, right? And I feel skepticism is healthy. It keeps us on our toes. Yeah, yeah, yeah. I appreciate that. But the studies that you have done with autism and this four EPS molecule are pretty compelling and fascinating. Like walk through the kind of, you know, the mechanics of how this molecule finds its way into the wrong place. And perhaps, you know, according to your hypothesis has some correlative or causative effect. Yeah, we showed in a 2013 paper that 4-eth phenyl sulfate, 4-EPS that you're referring to, is elevated in a mouse model of autism and is modulated by the microbiome, meaning that based on the microbiome of the animal, it was either increased or decreased.

48:10So that's just a correlation. More recently, we published that, in fact, that molecule in and of itself is able to drive behavioral disorders in animal models, meaning that we set up experimental systems where we can artificially elevate the levels of this molecule, which comes exclusively from gut bacteria. We don't make it, it's not in our diet. Flies, worms, more primitive organisms don't make this molecule. To the best of our knowledge, only certain types of bacteria make this molecule. Why the molecule is made, I still don't know, right? So maybe there's an evolutionary accident. Maybe there's some adaptation that's relevant to the function of the organism.

48:48That's still an open question. But based on that, we showed, based on saying of these experimental systems where we can elevate levels of 4-EPS. We showed that the animals develop many symptoms of autism, but primarily develop anxiety, anxiety-like behavior. And so in addition to that preclinical or animal work, we showed in humans that this molecule is elevated and that particular drugs can lower the levels of this molecule. And so still a lot of correlative studies in humans, but suggesting that what we're identifying in mice, we can actually replicate in terms of the elevation in humans, meaning that a person with an autism diagnosis is much more likely to have elevated for EPS than a person than a neurotypical individual without the diagnosis.

49:36Whether or not... So I do believe based on experimental systems that this molecule is driving behavioral changes, primarily anxiety, but social changes and vocal language changes as well in mice. In humans, the jury's still out on whether or not we've just observed a correlation, an association between the two things or whether or not that molecule is actually driving, any feature of autism, that's still all work in progress. The way my lay person brain understands this is that 4-EPS is a derivative of tyrosine, tyrosine being an amino acid that we get from our food. So we eat food, we protein.

50:17this particular bacteria takes the tyrosine, creates the four EPS, it leaves the gut, it enters the circulatory system, it travels up to the brain and it passes the blood brain barrier. For some reason, the brain lets it in and that's where it's doing its damage, at least in mice. Is this correct? Is this how I understand this? I'm trying to, I realize I'm being incredibly reductive. You could be a scientist, Rich. I'm trying to create a visual image of like how the mechanics of this work, because we're dealing with the epithelial, the gut lining and its permeability. And we're also dealing with the blood brain barrier.

51:00And these are critical sort of walls where decisions are made about what goes in, what stays in, what gets to go out, what's allowed into the brain, et cetera. and part of the dysregulation is around like the wrong things, you know, leaking out and being let into the brain. I firmly believe that's true. And you're right in terms of the way you drew the trajectory of where the molecule is made and how it travels through the bloodstream and into the brain, that's all accurate. So as I referred to several minutes ago is that the fact that microbes have figured out how to get their molecules into the farthest reaches of our bodies, right?

51:39So again, those transporters, those mechanisms to cross the gut epithelium, the mechanisms to cross a blood-brain barrier exist because our body uses those pathways for signaling. I believe bacteria have learned to hijack those same highways to send their signals. And so, as you said, we can trace the molecule from the gut through the circulation. It's actually modified in the liver, goes through circulation, through the blood-brain barrier, into the brain, and we'll go one step further, is that we've shown that particular brain cells are responding to 4-ethylphenyl sulfate. They're not neurons.

52:13Neurons may also be responding to this molecule. We haven't excluded that. But we know that there are cells called oligodendrocytes and their biology, their actual maturation is regulated by this microbial molecule. So what oligodendrocytes do, just in a nutshell, is they myelinate our neurons, our neural axons. So what that means for, let's say, the non-neuroscientist is think of the electric wire in your house. It's coated with a rubber coating, right? To allow long electrical impulse to travel and not dissipate. Our neurons do the same thing. They send projections sometimes many, many inches, if not very long, two or three feet.

52:52And so that that signal isn't reduced or doesn't dissipate over time. We have this myelin sheet that codes the long axons. That's what oligodendrocytes do. So they actually create this myelin and this ability for neurons to send their signals over long distances. And so when oligodendrocytes don't develop properly, there's a reduction in the ability to myonate neurons, and that just changes brain function. It's called connectivity, meaning how different regions of the brain are talking to each other. A lot of this is regulated by oligodendrocytes, right, because of their ability to myonate neurons, and this micro molecule regulates oligodendocyte biology.

53:33So we think we have a handle on how at least this one molecule is working. There's many others that we haven't studied. And everything I just described was done in mice, but it tracks very, very well with human studies because this changes in myelination pattern, changes in connectivity, how regions are talking to each other in the brain, all that's been shown in people, right? So in observational and brain scan studies, we know that that's true in autism and a lot of other neurodevelopmental conditions. So we think we're on the right track in terms of understanding how the molecule is working.

54:03And with respect to Parkinson's, is there some kind of analogous mechanism that's similar to what you laid out with autism? Yeah, and I wanna also preface this by saying that what I described some endogon autism is probably one of multiple mechanisms. It's working in concert with many other things, yeah. Yeah, and there are probably other things that are happening in parallel that have nothing to do with 4EPS, right? And so there's probably multiple ways to get to the same outcome. And so likely true in Parkinson's as well. So one of the mechanisms that we've shown in Parkinson's is, so going back to aggregation of this neural protein, alpha-synuclein, this is, I think, maybe a more famous example is A-beta, amyloid beta in Alzheimer's.

54:51So again, these clumps that form in the Alzheimer's brain, it's something very similar is happening in Parkinson's, right? So again, highly and widely believed to be the causative pathology of Parkinson's is aggregation of alpha-synuclein. So what we showed is that there are bacterial proteins which can induce alpha-synuclein aggregation in the intestines. So bacteria that are elevated in human Parkinson's, we can take those organisms, put them into mice, and those organisms can now induce aggregation of alpha-synuclein when previously there was no aggregation. And produce similar symptomology in those mice.

55:28And the origin is the gut, right? Because we're not adding the bacteria or the bacterial protein to the brain. The bacteria reside only in the intestine. And in this case, unlike 4-EPS, the bacterial molecule that's essentially triggering this pathway that's setting things in motion stays in the gut, right? It just starts a cascade of events in neurons of the intestine where alpha-stochin aggregates. And once alpha-stochin aggregates, it sort of self propagates itself. So there's this, it's called the amyloid hypothesis or the pre, sorry, the more accurate, the prion hypothesis where a protein misfolds, it forms these clumps and then it causes more of that same protein to form clumps.

56:06So it just sort of spreads, right? And so once the, you know, so like, you know, horses out of the barn, if you will, in the intestines, this protein aggregation can make its way through the intestinal neurons up the vagus nerve, which connects the gut to the brain and into the brain and then spreads throughout the brain. So it's not the bacterial protein that ultimately causes the disease, it's the bacterial protein triggers this cascade of events and the neuronal protein then results in disease. And so we've shown this a number of different ways in animals, adding bacteria, adding the protein, you know, doing all those different permutations.

56:40perhaps some of the best evidence for this is that we developed a compound that can drug this pathway, that can inhibit the bacterial protein from associating with alpha-synuclein in the intestine. And what's unique about this drug compound, this molecule, this drug molecule, is that it's gut retentive. It actually never enters the circulation. It's only active in the gut. And this drug works, at least in mice. We don't own people. Wow. And so not only is the cascade started in the gut, but we can inhibit the process in the gut and then see improvements in behavior, see improvements in brain pathology.

57:16So from a therapeutic perspective, the goal is to identify that specific microbe or bacteria and find a way to target it such that you either kill it or you shut it down or you prevent it from engaging in that process that leads to all the kind of cascade of events that you don't want. That's exactly right. And to the best of our knowledge, and going back to the fact that this is almost likely not the only, almost certainly not the only way that the gut can be involved in Parkinson's is that when we now look across human populations, people with Parkinson's and compare them to, you know, household controls, population controls, this organism and this bacterial protein that I just mentioned is found in about 18 to 20 % of Parkinson's.

58:03And so I think, you know, that suggests that the mechanism we identified It can't be singular. Either there's redundancy, meaning that, you know, in something over 20%, there's a similar pathway that's happening that we just don't know, or there's something entirely different that's happening, or certainly that the gut is not involved in, you know, some potentially even large portion of Parkinson's. And that's all again, work in progress. Talk a little bit about the relationship to the vagus nerve with Parkinson's. because I know that if you have that nerve cut in surgery or you have your appendix removed, you become less likely to develop Parkinson's.

58:43Like what does that tell us or not tell us about the mechanisms of this disease? So there's - Like why not just, anybody who has a predisposition to Parkinson's, shouldn't they just get their vagus nerve cut? Or what is that? There's probably a lot of bad things - There's consequences to cutting your vagus nerve. So the vagus nerve, again, it's this bundle of neurons that go from the brain to many, many different organs. And so when you cut the vagus nerve, there's a lot of side effects to that. Like just the strongest of which are like digestive effects, but affects breathing, affects heart rate, affects a lot of other things as well.

59:15And so vagotomy, which is severing the vagus nerve, is likely not the best way to solve that problem. But what you're referring to are a number of studies, initially from Europe, where they have really good medical records, better than we have here, that showed that people who are vagotomized, a vagus nerve was cut many, many decades ago as they age were protected from Parkinson's, statistically protected. It doesn't mean that none of them got Parkinson's. It means that they were less likely to develop Parkinson's over the years. And the reason why they were vagotomized, I think this is also quite interesting, is oftentimes the vagotomies were done to control peptic ulcers.

59:52So stomach ulcers that would lead to cancer. Because people thought this was a consequence of stress. So why do we have ulcers, right? is because we were stressed. We now know we have ulcers because of helicobacter pylori, because of bacteria, right? So it's a sort of funny link back to gut bacteria themselves. But again, so this is not standard these days. So people with stomach ulcers are not vagotomized, they're given antibiotics, right? And so, but again, there was a population of people and as you just rightly referred to, epidemiology is suggesting this is the case. In mice and rats, I think it's absolutely conclusive that the vagus nerve is involved in mouse models of Parkinson's.

1:00:30None of this is our work, but people have set up experimental systems where they can trigger the initiation of Parkinson's-like symptoms in the gut in mice and rats and show that starting in the gut, that pathology, that symptomology can then migrate up to the brain and the mice develop symptoms of Parkinson's. And then if they cut the vagus nerve in the rodents, they basically see the GI symptoms, but they don't see the brain disorder. They don't see the motor and the movement disorders. And mice and humans, rats and humans are obviously very, very different, but I think there's enough fundamental biology linking us.

1:01:08Again, they only have their vagus nerve looks just like our vagus nerve, it innervates the same organs as our vagus nerve does. So I think there's, I don't see a reason why mice and rats would be that different in this particular case than humans. Yeah, I mean, that leads to my next question, which is we see so many interesting things in the study of mice and rodents. So few of those things seem to apply to humans when you kind of move up the phylogeny. Like what is the, like... Why is it that it seems so clear in mice and yet this question mark lingers over the human animal and why can't we perform some kind of studies that would create greater clarity?

1:01:51Yeah, I have a pretty advanced thoughts on this one. And so the vast majority of the basic biology studied in rodents does translate to people, right? And so for example, there's dozens of examples. I'll just use the vagus nerve, right? So again, a lot of vagus nerve biology was first studied in mice and rats. And a lot of that has translated to people, meaning that the vagus nerve works very similarly in the two different species, right? What hasn't translated, and what I think you're referring to is drug discovery and drug, you know, the actual efficacy of drugs, right? The vast majority of FDA approved drugs were at some point in their development, you know, tested in rodents, right?

1:02:34And they showed efficacy, meaning that they solved the problem that they were trying to solve. And then as those drugs were developed, about 90 % of them never worked in humans the way they worked in rodents. So we're pretty good, I think, at understanding basic biology in mice and then showing that we can replicate the basic biology. What I think we do a very poor job of is taking drugs that are developed in rodents and making them work in people. I'm happy to elaborate on that. I think there are some pretty good examples why I think this is... I think we've essentially set ourselves up to fail, right?

1:03:13in terms of drug discovery using the mouse models that we currently use, right? And so the vast majority of biomedical research relies on specific strains of mice, inbred genetically identical clones of mice, right? And so you do this because you want to replicate your own data, you want a group of mice to all behave the same, so you can actually make a discovery, right? And so we are not clones of each other as humans. And so we've essentially set ourselves up to fail because we're essentially saying that one person's DNA is gonna extrapolate over 8 billion people. And that's certainly not the case, right?

1:03:51But what I think we do even a worse job of is accounting for the environment that these animals live in, right? And so you and I were exposed to many microbes, infections, stress, other environmental impacts on our bodies throughout our lifetime. And there's, as we talked about a few minutes ago, a cumulative impact of our previous exposures, whether they're microbial or toxins or heavy metals, whatever they may be. And so animals in a laboratory live in the same cage, in the same box their whole lives. They have very little to no environmental exposure. We help filter the air that they breathe, right?

1:04:31They're eating sterile food most of the time, drinking highly purified water. And so their bodies just don't have that historical fingerprint of, you know, all the damage that's been done. They don't drink alcohol, they don't eat fast food, right? Unless we give them a Western diet. And so, you know, you couple that with the fact that we're not modeling genetics properly and we're not modeling their environment properly. We're seeing a narrow sliver of human biology in these animal models, right? So going back to the basic biology translating is, again, the wiring is the same, the organ systems are the same.

1:05:06So that part translates, right? But then we expect a reaction from these animals to a drug and we figure out some condition to make it work in a mouse, right? Sometimes even contrived, like very, very high doses, for example, right? And then we go out into a very wild human population, very diverse human population. And most of the time the drugs don't work, right? So I think we should be doing a better part on the front end of diversifying our animal models of not using these genetically identical environmentally limited, restricted model systems, I think we should go out and do population studies in people or in animal populations and use that data to develop better drug.

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1:07:29I would suspect that it's even more complicated for someone in your field when you're thinking about therapies or interventions that are micro-based, because you'd be introducing a microbe into a microbial environment that's not nearly as diverse or complex as the human being. So you'd be less likely to extrapolate anything meaningful from whatever impact that has. Yeah, that's absolutely true. But I think there are workarounds on that. And so what we're doing, part of our research program now is develop animal models that are just more reflective of human lifestyles. So again, diversifying the animal models that we're working with.

1:08:12But then the other aspect that gives me a lot of hope is that the regulators, the FDA, is quite bullish about microbiome-based therapeutics, right? Because again, the purview of the FDA is to ensure safety and tolerability of drugs, right? I mean, it's not their primary concern of whether or not the drug works. They're just the gatekeeper to make sure we're not harming people by putting experimental drugs in them that make the drug is worse than the actual symptom that we're trying to treat, right? And the FDA's position, I think, has been very clear and consistent for the past decade is that taking a micro from one human being, putting another person is a low risk proposition, right?

1:08:53So they're very lenient about giving investigational new drug designation to human derived therapies. They have really educated themselves the last decade. So they've called me out three, four times, all before the pandemic. And essentially, these were like learning lessons for them. And I wasn't the only person, they invited many other people out just to sort of bring scientists in. And so they're learning what's on the cutting edge. And what they've done more recently in the past few years is actually develop guidance, like written guidance and guidelines for how do you develop probiotics? How do you develop organisms that come from humans?

1:09:32And again, this is not something that they feel is risky because if let's say I were in a chemistry lab and I develop an entirely new molecule, and I believe it's going to bind to a particular receptor or affect a particular cell type that's gonna improve a disease outcome. But that drug has never been in a human being. There's a lot of risk that as soon as you do, something bad's gonna happen, right? It may or may not, we don't know, right? But that's what they try and protect against. They don't see this risk in the human microbiome because essentially civilization has done the safety trial over millions of years.

1:10:04Yeah, yeah, yeah. What we should be doing more of, and me and my lab are certainly not the people who would do this, is taking organisms. and instead of, and I'm gonna actually argue against myself here, instead of testing them in mice for five, 10 years, go directly to people, right? I think the vast majority of time, the worst thing that's gonna happen is it's just not gonna work, right? But we learn from that, right? As opposed to doing these intellectual, you know, gymnastics in animals and figuring out how they're gonna work and then seeing if they're gonna actually work in people, just go directly to people because, you know, the worst thing that's gonna happen is people are gonna get like some diarrhea or bloating, but again, that's majority of time, they're gonna have nothing's gonna happen.

1:10:44Yeah, yeah, yeah. Low risk, but with this added extraordinary value proposition that it's a very targeted remedy that goes directly to the one thing that you're trying to address. Like I've heard you talk about SSRIs, like Prozac, for example, like only 1 % of it, like actually, you know, passes through into the brain and does anything. Whereas if you can really crack this knot and figure this out, it's the difference between carpet bombing your body with something and like a very strategic drone attack. Yeah, I think that's true for all drugs, to be honest with you, right? Is because ultimately it comes down to effect size.

1:11:25Like, so how potent is the activity of the drug? Whether that drug is a molecule, whether that drug is a living organism, right? Meaning that if it's really potent and to your point specific in doing what it's gonna do, you're gonna see an effect. right if it's not if it's let's say the effect size is weak right meaning that a person has to be super healthy a triathlete or something right for it to actually work then you're going to see a very weak signal in the clinic and you know and probably not going to be able to develop that drug that's the same with with with pharmaceuticals right i mean pharmaceuticals their effect size really matters right and that's why the vast majority or that's one of the reasons why the the vast majority of drugs that are FDA approved work in less than 50 % of their patient population, right?

1:12:09There are drugs making billions of dollars that work in one out of 10 people with that disease, right? But they're still making billions of dollars, right? And so I think, you know, again, there's a lot that you can learn by going directly into the clinic and again, very low risk in terms of safety. I think we should just be doing more of it. It would stand to reason with these discoveries that you've made around Parkinson's and autism that there would be similar revelations with other neurological disorders. Talk a little bit about what that landscape looks like right now. I would say in my personal opinion, there's a lot of research going on Alzheimer's.

1:12:48We work on Alzheimer's disease. I think the likelihood that someday we'll have microbiome-based therapeutics or diagnostics or modulators of Alzheimer's is probably very low, right? And I think that's for a couple of reasons. The initial data don't look as strong for, let's say compared to Parkinson's, but also Alzheimer's is a very difficult disease in and of itself, right? I mean, there's a lot of damage that's done in the Alzheimer's brain prior to our ability to really know if that person is having cognitive issues, right? So I think it's hard to turn that ship around. um i think something like depression is um an area where the human data really look compelling meaning that it's not just that the microbiome is different in a person with major depressive disorder versus a person who doesn't have depression but the signatures the way the microbiome changes appears to make a lot of sense right so one of the strongest pieces of evidence in the microbiome of people with depression is that this is an interesting topic we can talk about as well.

1:13:56Our microbes make neurotransmitters. Like the vast majority of neurotransmitters that our neurons make, gut bacteria make those as well. What they're really doing, we don't know, right? But a lot of the bacteria that are differential in a person with depression and a person without depression are these neurotransmitter producing bacteria. And there's also a lot of evidence showing that there's study to study, you know, a lot of correlation between the types of organisms that are either up or down in depression versus a person without depression. And so that signature speaks a lot to me, right?

1:14:28Meaning that why is it that a person with depression in one geography, in one part of the world with a different lifestyle has the same microbial fingerprint as someone on the other side of the world with depression, right? You know, this doesn't happen in autism. This doesn't happen in Crohn's disease. This doesn't happen in allergies. That they're just huge study to study variation, right? Not so much in depression, And so I think in terms of this gut brain area, right? And there's other, let's say, inflammatory metabolic disorders that I think the microbiome has a strong likelihood of impacting.

1:15:02Again, we work very little, I'd say, on depression because I don't think the animal models of depression are that good. But I think from what I've seen, the human data really suggests that we can potentially modulate depressive activity by using the microbiome. And the other piece of evidence, and this is conjecture, is that there is exceedingly little evidence that there's damage in the depressed brain. So unlike Parkinson's, unlike Alzheimer's, and even a little bit of evidence in autism, much less than neurodegeneration, obviously, that there's actually like some physical change to the brain, right?

1:15:41To the best of our knowledge, there's no physical change in the depressed brain. So it means like the wiring is still there, right? All the components are there. Maybe it's just a chemistry problem. Maybe just the molecules are in balance. That to me gives me a lot more hope that we can actually modulate those outcomes. Is it a chicken and the egg thing though? I'm imagining, given the bidirectionality of the communication between gut and brain, is it possible that something's happening in the brain that then is signaling the gut to activate those microbes and create those neurotransmitters? or is there clarity around it beginning in the gut and traveling up to the brain?

1:16:20Yeah, I think it's gonna be case by case. And I don't think we have a good handle on in what scenarios, under what circumstances, it's let's say gut first versus brain first. And I'll throw another wrinkle in there, going back to genetics, right? Is our genetics shape our microbiome, right? So it doesn't have to be brain reshaping what's happening in the gut, but a person's biology, their DNA, and the way their gut functions, the way their immune system or their metabolic systems function, reshape the microbiome. So there is a lot of, you know, our bodies influencing our microbiomes to potentially be different than, you know, another person.

1:16:56So, but then the question still completely wide open is, what do those changes actually mean? So I'd say we're quite good at measuring the changes. We're not that great at understanding how those changes affect biology. And that's where model systems like animals come in, you know, because we can test hypotheses in mice that in most cases are either not feasible or not ethical to immediately test in people. But conceivably you can imagine a world in which we understand these mechanisms better and the gut flora in really precise terms. And we find a way to shut down that mechanism that's happening with that particular strain of bacteria or eradicate that strain of bacteria or introduce some other microbe into the gut that crowds that out or overrides it somehow and problem solved, right?

1:17:49Like it sounds like that's possible. I'm sure that's unbelievably simplistic and it doesn't take into consideration a million factors, but that's the future that I'm imagining where you have these very precise interventions that are very specific to one thing that almost aren't interventions at all. You're just introducing something natural into your gut microbiome and it sets in motion a series of events that rectify that dysfunction. I entirely agree. And I think the strategies to accomplish what you're proposing, some of which is already being done, right? But the strategies are already being built.

1:18:33So you may be familiar with the fact that, you know, the current go-to microbiome-based therapy is a fecal transplant, right? So a wholesale transfer of one person's microbiota into another, healthy to a disease, for example, right? There's probably been 50 ,000 fecal transplants done in clinical settings, you know, safety records, impeccable, right? You know, my view is the fecal transplants are the go-to therapy because we don't know what about the microbiome is therapeutic. So what you're talking about is more research, getting to the point where there are specific organisms with defined properties that you can say, all right, this is an organism that's potentially therapeutic and then matching it to an individual who may be receptive to the beneficial effects of that particular organism, what we in science call personalized medicine, right?

1:19:22I do believe this is the future. I do believe that once we have more research and we know what are the particular ingredients in a fecal transplant that may be, you know, that therapeutic, you know, effect, right? But the reason why I'm just really excited about this, in addition to the fact that this is what I do, but is the fact that, again, I wholeheartedly believe that the vast majority of human disorders where the microbiome has evolved involve the person's genetics, involve a genetic predisposition, like a vulnerability coupled with a microbiome vulnerability, right? And as we sit here today in 2024, it's still very, very hard to correct the person's genetics, right?

1:19:59But we certainly can change their microbiome. We can introduce particular organisms. We can get rid of their entire community and put in a new community. So if there are two levers to pull, today we can pull the microbiome lever. We still can't pull that genetic lever, right? And so again, if a person has genetic predisposition, their microbiome is not healthy, they have disease. If we make their microbiome healthy, maybe it overcomes or compensates for that genetic predisposition. You find the healthy donor or the super donor and you collect their sample or whatever you call it. And you ship that to the very Tony fecal transplant clinic where you recline in a nice chair and you're given a nice tea or something.

1:20:43And you take these in capsule form, I suppose. Mostly capsule, but then there's enema. There's enema, right. And an NG tube, nasogastro. But is there not a colonization problem? Like, would you have to, like, it's not a one treatment thing, right? Like, what does it take for this new population to take hold and make a difference? Context specific, and again, largely unknown, we're at the cutting edge of research. Context specific, meaning that if it's an acute gastrointestinal infection, right? That one treatment seems to solve the problem, right? But again, that's like when I have a bacteria growing in my intestines, that's making me very, very sick, causing stomach pains, bloody diarrhea, like loss of weight, lethargy, right?

1:21:32It's called a clostrum difficile infection. It's quite prominent. I think 30, 40 ,000 people a year will get this. And it can be fatal, right? In those cases, fecal transplants have a 93 % effectiveness rate, better than any FDA approved drug for C. diff, cost room deficit infection. So in that case, one treatment is enough. We know this, this is a fact, right? Because essentially you're putting out a fire, right? But in more chronic disorders, what we've been talking about for the past few minutes, neurological disorders, think about allergies, think about autoimmune, like multiple sclerosis or rheumatoid arthritis, where these are lifelong conditions, it's still unknown how many treatments a person needs to have.

1:22:15I think, again, there's exceedingly little data, so I'm speculating, but I don't think one treatment is going to be effective. My rationale for that is that, again, your lifestyle, your genetics reshape your microbiome. So I can, you know, I have an autoimmune disease, right? So if my microbiome were cleared out and a healthy microbiome were put in and maybe my symptoms went away, I believe sooner or later, my lifestyle, my genetics are gonna reshape that healthy microbiome back into something that's pathogenic, to make somebody that's not healthy anymore, right? So I do think that, I guess that long-term you're gonna need resupplementation, right?

1:22:55But not different than taking a pill a day, right? Maybe even easier, right? Or an injection every couple of weeks or so, right? And so again, these are chronic disorders, I believe have to be managed with chronic therapies in most cases. It also stands to reason that this might be a field where AI could be helpful because you're dealing with just so much data and just, you know, innumerable number of strains and different types of microorganisms. And, you know, I don't know that our brains have the capacity to understand the complexity of how all of these things are interacting with each other to determine what's causing what, what's correlative, and what is something that we need not pay attention to.

1:23:34But if you could apply some kind of super intelligence to study the interactions between all of these things, it seems like that could be a helpful diagnostic. Yeah, it's happening in real time as we speak, because again, the ability to generate microbiome data is accessible to most clinicians and most scientists, right? So, you know, I can have my microbiome seek within literally within a couple of days. I mean, I have access to the technology. I can know what's exactly in my microbiome and really generate large data sets. And we can go even beyond just the microbiome. So, you know, oftentimes we wanna know not just who's there, which is what microbiome analysis tells you, because again, you're sequencing DNA.

1:24:17So it tells you the organisms that are there. We like to know what they're making, like what are the molecules they're producing. So you can look at RNA, which is made from DNA, which is one step closer to understanding what are the products of the microbiome. And then, you know, a more recent technology that's been layered on to microbiome analysis is metabolomics to look at what are the molecules, the really the business end of the microbiome. So you generate all of these data sets, right? But what happens is, again, this is how science unfortunately works, is there are a lot of piecemeal studies, like self-contained studies, where I can have even thousands of people in a study, right?

1:24:54But I can report the data set in one study and it's very, very hard to know because of both methodological differences and the results, how much this study correlates with another study, right? Again, all this is done manually. I think the microbiome space at large is a really good playground, if you will, for AI because we're generating massive data sets across a number of different conditions. I think it's hard for people to see those patterns, but I know a number of groups that have already made really nice breakthroughs taking publicly available data, data that's generated even sometimes years ago and seeing things that were just not obvious.

1:25:37Right, right, right, right. Yeah, I had Tim Spector in here and he was sharing about the Zoe app and that allows for kind of this mass experiment where they're just collecting so much data on people and their lifestyle habits and their genetics, et cetera. And he has this hope that from that, they're gonna be able to divine kind of hidden truths around how the microbiome is operating and contributing or not to certain conditions. Yeah, I think it's the future. I mean, the present and the future. What are some of the studies that are underway right now that have you excited or what is the ultimate study?

1:26:18Like if you could design the perfect study to help resolve some of these questions that you have that would enlighten us, what would that look like? I would test the concept of causality, right? To what degree are changes in the microbiome contributing or even causal to some of the disease that we're talking about, right? And I think this is virtually impossible in diseases of aging or even like autoimmune diseases, which tend to manifest in adolescence or early adulthood, right? Because so much has happened in our lives. So much information, data was lost because we weren't tracking people, their diet, their exposures from infancy.

1:26:59and so the dream experiment that i would do is either in autism or in type 1 diabetes where the diagnosis is very early in life within the first five years right and so i and i would i've implored large funding agencies to do these types of studies where you follow at-risk pregnancies right so a person a family with a child with autism the next pregnancy is highly at risk for developing autism, right? And so, and same with autoimmune disease like type one diabetes. So you follow the pregnancy. So you collect as much data from molecular data from the mother as possible, as well as metadata. Like, you know, did they get sick?

1:27:40What were their diets on and so forth, right? But you actually are looking at the microbiome, looking at their blood metabolome. And then now track that infant over time, right? From birth through the first several years, how did they, what is the development of the microbiome? What was their immune profile throughout this? What were their sort of neurological endpoints in addition to behavioral data, in addition to symptomology, right? And some portion of those individuals are gonna develop the disease and some portion are not, right? But now you have this rich data going back to the beginning, to the in utero development, right?

1:28:16So again, you're capturing all that historical data, which is hard to do when you get a person diagnosed with a disease at the age of 20 or later, right? So to me, that's like the dream experiment. Again, we do this, it's FASA, we do this in mice all the time. These are the studies that I think we need to do in people. And that really gives us, I think, both that longitudinal, what happens before what type of data, but also now insights, potentially windows into when and how to intervene, right? So if one hypothesis is that a child with autism versus a child without autism and it's somewhere along the way, their microbiomes diverged.

1:28:56Like, you know, the autism population, they went in a different direction, right? If we knew when and where that direction was, maybe we can steer them back towards what's healthy. Again, a hypothesis. And allow you to figure out what are the variables that you don't need to worry about versus the ones that are the most important, yeah. That's right, that's right. And again, our ability to not just capture a lot of data, which is not just molecular data, but you're using wearables. There are people developing camera systems and software to track behaviors inside a person's home, right? To know what types of behaviors are they exhibiting, right?

1:29:36So just marry that rich data with the molecular data. And again, the two problems that have really faced us are data storage. When you collect that much data, where do you actually put terabytes of data, right? And that problem is solved or solvable. And then the AI portion that we can now go back in and analyze just large, large, large multimodal data sets. It's not just like large data sets of molecules, but molecules and behaviors and immune profiles and who they talk to. And did that person have an infection when they met with them? I mean, just think about like how complex and rich that data is.

1:30:13We can actually start mining that now. Yeah. There might be some privacy concerns with a little bit of that. It's sort of a voluntary surveillance state in order to do that. But we are signing up for that world where, I got wearables and I'm tracking all different kinds of things and those tools are only getting better and better and better and the diagnostics that go along with it are getting better. So I think it is an exciting time and it feels like it's accelerating really quickly. Yeah, I mean, the privacy issue is a significant one. I feel like we've given away a lot of privacy over the last several years.

1:30:50I mean, just think about how much information is available on our cell phones and who has access to it. Who do you think is listening on that thing right now? I get solicited for advertisements. I mean, this has happened more than once, I'm sure it's happened to you or your listeners as well, where I mentioned something I haven't talked about in years. And all of a sudden there's an ad popping up on my newsfeed. All the time. I mean, this is not a coincidence. I know, it's scary. Let's talk about cravings and appetite because this is just mind blowing stuff. What do we know and not know about how the gut microbiome is influencing the foods that we crave?

1:31:29An area we've worked on a little bit very recently, we have active projects in this. So I'll take one step back. In terms of food craving, some of the initial work came from obesity studies, right? And so historical data in mice, some human data as well that the microbiome, and I think it's, you know, I'd say it's pretty solid these days in terms of evidence that the microbiome is involved in obesity, right? And the original hypotheses were, and I think rightly so, is that this was a metabolic influence, meaning that microbiomes extracted more or less calories from food or had different molecular byproducts that were resulting in obesity.

1:32:14And that certainly is happening. But what was an offshoot, and I think quite unexpected for the researchers who did this work, was that when you change the person's microbiome while you were studying obesity, you're actually changing their feeding behaviors as well. Their appetite was changing and their food preferences were changing. And so this emerging concept that again was a byproduct of the original hypotheses that changing person's microbiome changed their behavior, right? And so what we, and dovetailing on all of that work, what we've shown recently is that a mouse's microbiome affects their desire to eat palatable foods or hedonic feeding, if you will, like sugar, right?

1:32:56There's one example of high fat foods, right? And it's pretty interesting, the data. And so we published this last year, another group published this after us. and so we feel better about our data as well when it's validated, is that when you remove a mouse's microbiome, it actually desires more of these hedonic foods, of these palatable foods. It doesn't eat more of its chow. It just eats more sugar when you present that than a mouse that has a complex microbiota, right? So something about an animal's microbiome is suppressing their desire for sweets or junk food, if you will, right? And so again, broad sweeping changes, but again, linking the microbiome to this behavioral effect.

1:33:40So in fact, in the studies, the way we do the studies, we don't see obesity, we don't see metabolic changes. We're just seeing feeding change. We're just looking the first like few hours, after changing an animal's microbiome. Well, not just the feeding changes, but also the energy that the mouse is willing to expend to get the sugar, right? Isn't that an added kind of wrinkle to the whole thing? the intensity of... We haven't exclusively ruled out the energetic component because it's sugar, but we've done enough, we've done experiments like sucralose, right? Where there's no calories. No, I mean energy in terms of like the motivation of the mouse, like they have to press this button and you're able to calculate like they're going for it.

1:34:21Like they're gonna keep pushing that button. Like they're willing to go out of their way that as a measure, I guess, of the intensity of the craving. That's exactly right. So the word is motivation, right? So how motivated is the animal? How hard is it willing to work for that sugary treat, right? That behavior is modulated by the microbiome. That's fucking crazy. Yeah, it is. And we've recently identified a set of, again, these are mouse species. They're not, you know, these same organisms do not exist in people. A handful of organisms that are mediating this effect. And so we're at the stage where we know, at least we have candidate organisms.

1:34:56And so now we wanna know, how is that signal being sent to the brain? And how are these organisms actually telling a mouse that it craves more sugary treats than a mouse that doesn't have those organisms, right? And so I think once we unlock that biology and it may be novel biology, it may be other systems that were already known, but just we didn't know that the microbiome was accessing those systems. Once we know that, then it allows us to intervene, right? And then there's, and so you're asking about feeding and but I think what's interesting and maybe just extrapolating further is a lot of the circuits, the neural circuits involved in feeding are involved in other hedonic behaviors, like alcohol abuse, gambling, smoking, right?

1:35:38And so I think there's the potential that this research will allow us to think about something broader than just feeding, but maybe think about addiction and sort of other learned behaviors, maybe negative behaviors that we may be able to intervene in, in a, as we're talking about in a very natural way. Yeah, it's very exciting. The idea that you could modulate cravings by altering the microbiome in some way is fascinating. And just the idea that, we're not necessarily as in control of our thoughts as we may believe. I wanna touch on sentience in a minute, but I also wanted to share like what might be the dumbest idea ever and just tell me if this is ridiculous.

1:36:24but in the most simplistic terms, is there any truth to the idea that, on this adage of like you are what you eat, like if you just eat McDonald's all day long over a long period of time, you're seeding your microbiome with biota that is in that food. And on some level, perhaps creating a new colony of gut flora there. Is there any evidence to suggest that that in turn could create a cycle of craving for that food because those microbes want more of that McDonald's food because that's what they like, that's what they are, that's what they need more of, which is why when you try to quit fast food or some analog of that, you have intense cravings that only subside over time and can be supplanted when you start eating healthy food.

1:37:16And then all those healthy foods that you thought you hated, suddenly you have a taste for and you, maybe the cravings aren't as intense, but like you do look forward to them because you are seeding your gut flora with something new and healthier for you. Yeah, I don't know of any ever, it's an interesting hypothesis. I mean, that's like my kind of like lay person's, you know, operating theory. Yeah, and you seem to be a believer in the microbiome, right? I definitely believe in that. And I know like my idea is like as rudimentary and as perhaps as dumb as possible, but like, do you think that there's, could be any truth in that?

1:37:52I've learned to not exclude any hypotheses that involve the microbiome. Can I go to Caltech and study this with you? I think the experiment would be actually quite straightforward in mice because again, we can feed them whatever we want and then measure their cravings in really rigorous and accurate, mathematically accurate ways. I don't know of any evidence for or against this hypothesis. so it's testable. If it were, first of all, and I think it'd be in just a subset of people, right? I mean, just like any other vulnerability, some of us are just more or less prone to repetitive or addictive behaviors, right?

1:38:32Whether or not eating a particular food makes you desire that type of food more, and if that process is mediated by the microbiome, I would say it's completely unknown. And again, I don't see any literature, but I can see other ways to explain that, right? It could just be entirely behavioral and neuronal, right? Meaning that our circuits are being - Creating a pathway. Yeah, and being reinforced, right? So I feel a certain way when I eat, maybe I feel good. I personally do not feel good when I eat fast foods, but I think a lot of people would, right? Comfort food and other ways to sort of improve mood.

1:39:11And so the reason why I bring in mood is that, if I eat something or I drink something, and it makes me feel good, then that's reinforcing a neuronal circuit. And every time I do it, I'm going to want more of that. So I can see entire pathways that have nothing to do with the microbiome. But Rich, you're welcome to our round. Okay, good. Anytime. And you can do the work. You may have to take a break from the podcast. Can I just tell your students, like, here's what I want? I don't tell my students what to do. Anyway, I'm just kidding. The implication that the microbiome plays this important role in all kinds of metabolic systems and this link with Parkinson's and with autism and perhaps other neurological disorders and the impact on mood and anxiety and your stress response and cravings and anxiety, like begs the question of just how sentient we are.

1:40:13It's an affront to our sense of self and kind of an assault on the ego to understand that we're not always at the helm in a very interesting way. Like we are this scaffold and we're host trillions of these organisms. And in a certain way, you can make the argument that at times they're in control of things that we delude ourselves that we're handling ourselves with our own sentient minds. Yeah, I think the microgram is part of the complex, you know, being that we are, right? And they're a component of it. And whether or not they're directly influencing our thoughts or modulating our thought process, right?

1:40:58Tuning it up or down or, you know, or, you know, response to an environmental stress, as I mentioned, or some reward behavior, right? I eat or drink something that makes me feel good. And they're just modulating how good I feel. They're not dictating how good I feel. I would probably be more conservative, even though I've written pieces that suggest that my mom is completely in charge. That was naive of me when I thought that way. There is no self. I think it's a continuum, right? I think we have a contribution to that effect, right? Yeah. Like whether it's a mood disorder, whether it's some other behavioral disorder, whether it's like a disease, right?

1:41:41But I know microbiome in our environments have a contribution as well, right? Yeah, sort of likened it to the Wizard of Oz, like this big machine, this front that you see, but then behind the curtain is like some microbe just pulling the levers and turning the dials. Or, you know, it's a distributed system though. There's lots of microbes all over the place that are all jockeying for a say. That's right. And again, it's gonna be different in different people, right, for, you know, whether it's genetics or their lifestyle. But, you know, again, I think at the end of the day, they're a piece of this biology, of this, you know, behavior, these responses, but importantly, a modifiable piece, right?

1:42:21One that we can control, even today, we need to get better learning at how to control, you know our microbiome make it healthier for example or allowing us to change you know have you know you overcome mood disorders for example right but again much easier to do that than to alter our genetics or alter our lifestyle right and so i'll give you a really simple example is you know there's a huge percentage of people with diabetes who don't need to take medication who can just eat a little bit better, have a more active lifestyle and can manage their blood glucose. Type two. Yeah, type two. Or pre-type two.

1:43:01We live in a society where I think people like to take pills, right? As opposed to change their lifestyle. So again, I just wanna be complete and rigorous about this. There are other levers to pull like lifestyle. Like you don't have to change a person's microbiome and certainly very hard to change their genetics, but lifestyle changes can be therapeutic as well in a lot of contexts, right? For mood disorders as well. I mean, sleep, exercise really help with mood and affect. And so there are other levers to pull, but I feel like the microbiome again is one of multiple ways that we can intervene in these processes.

1:43:35But even though I have said this in the past, I don't think in most cases, microbiome is causing a human disorder, for example. I think it's just contributing to it either positively or negatively. What are some other best practices if we wanna protect our gut health and make sure that we're not dysregulated in ways that we have some agency over. I think gut health is linked to health in general, right? And the four aspects of which, which I suspect you and many of your listeners practice is healthy diet. And we can define that quite specifically, exercise, getting good sleep and managing stress.

1:44:18You know, if you do those things, you have a healthy gut, you have a healthy microbiome, you have a healthy body, you know, overall. In terms of what is going to affect your microbiome the most, at least the data that we have today is diet, right? And that's intuitive, right? You know, the microbiome digests the vast majority of the molecules we put in our body, the food that we eat, right? We essentially live off the byproducts of our microbiome. So I've seen data that suggests 90 % of the actual molecules that we put in our body as food are modified by our microbiomes and then enter our body.

1:44:51Only 10 % of the actual molecules in food are what our body actually sees, right? And so, you know, the microbiome is, you know, they have first dibs at what we're eating and their change, their behavior, their structures are changed by our diet. And so in terms of effect, I think the diet's gonna have, you know, the largest impact on our microbiome. And a lot of data suggesting that particular types of diet, you know, plant-based diets and really diverse foods correlate with a healthy microbiome and a healthy body. The wider the diversity of plant foods and the more fiber rich those foods are, the better off you're gonna be by and large, yes.

1:45:30Our body is quite good at digesting protein, quite good at digesting fat, but we've essentially outsourced the ability to digest fiber to our microbiomes. And there's very good reasons for that, right? not to get in the weeds too much, but the chemical bonds of proteins are pretty simple. And we have enzymes like trypsin, chemotrypsin that can break down those bonds. Similar to fat, we can digest a lot of our fats with enzymes that we have in our own genomes, right? So essentially like take fat and protein, break it down into its molecular components, its pieces, and then our body uses that for fuel and energy.

1:46:08But for carbohydrates, the chemistry is so complex that we would need so many enzymes to break down all the different types of fiber that we eat, that our genomes would have to be much larger than they currently are, right? And so again, that's why I said, we've outsourced that to our microbiomes because the vast majority of carbohydrate degrading enzymes are not in our own genomes, but on the genomes of our gut bacteria, right? So really the fiber helps. And again, the data to suggest that a diverse fiber rich diet correlates with a healthy microbiome is quite robust, right? So again, there's thousands of studies where people have taken microbiomes, largely from feces.

1:46:47So, you know, it's easy to get stool samples, looked at people's microbiomes. And in the majority of those cases, the disease population has a less diverse microbiome than the healthy population. So the more organisms you have correlate, microbial organisms you have correlate with health, right? So that's one piece of data. The other piece of data is that people who eat plant-based diets and diverse plant-based diets have more complex microbiomes. So if you put those two things together, complex diet leads to complex microbiome, which associates with health. What about fermented foods? Not an area that I'm terribly familiar with, but I'm a little bit more skeptical.

1:47:29I would put that, again, in my personal mind, I would put that in the same category as probiotics. Again, these are largely organisms that don't come from humans that are in fermented foods. So they're likely not evolved to network with our bodies in ways that the microbes from our own body, you know, that originate in our own bodies or live exclusively in our own bodies. It doesn't mean that they have no effect. It doesn't mean maybe they even have in certain people, you know, pretty potent effects. but I'm in the camp of human evolved organisms, likely being the area that, the aspects that we should look at in terms of the microbiome that we can leverage.

1:48:05So small effect sizes may not give us the therapeutic effects that we're looking for. We need something more potent. And I just surmise that the organisms in our body are gonna be more potent. Mm-hmm. If somebody is listening to this and they're like, sure, I can increase the amount of fiber in my diet. I can increase the plant diversity, but I have no idea if my gut microbiome is adequately diverse. Is there a test? Like how could one determine the current state of affairs? I was reading an article just a couple of days ago that there are 170 companies that will analyze your microbiome for you for a fee, right?

1:48:47And again, I think that's based on the technology they're probably gonna, and I don't know the vast majority of these companies, I suspect that the majority of them will do a pretty good job in analyzing your microbiome. In terms of interpreting that data and giving you actionable outcomes, there I'm quite skeptical. I don't think the field is at the point where we can say, based on your microbiome, if you eat this food or you take this probiotic, you're going to shift your microbiome from an unhealthy state to a healthy state. I think we need a lot more data to get to that point. So the profiling, the cataloging, I think we're gonna do a good job at, I'm not sure that the outcomes that we're looking for would come from these microbiome based studies.

1:49:35It doesn't mean people shouldn't do them, but I would say, take it all with a grain of salt. And it's maybe a rough benchmark for health. Again, you're looking for very obvious things. So for example, if you get your microbiome sequence, I think maybe this is a good use of microbiome profiling. If you get your microbiome sequence and you have a large amount, proportional amount of an organism that's clearly bad for you, right? Then maybe you should do something about your microbiome, right? I think the vast majority of cases, you're gonna look at microbiome profile and you're gonna say, I'm not sure exactly what this means.

1:50:11Right, like how am I supposed to interpret that? But I suspect it won't be long before you can marry the results of your genetic testing with the results of testing your microbiome and get a better understanding of, well, I have this, I'm high risk for this and I'm seeing an elevated level of this over here in my gut and that's an indication that I need to rectify something. I hope so, based on our conversation. How far away are like, so you, speaking of businesses, I mean, you have a couple companies that you founded that are working on these problems and creating therapies, therapeutics, interventions.

1:50:53Paint the picture of five years from now and perhaps even like the utopia that you're aiming for. Like, what does the world look like if we have the breakthroughs that you can reasonably anticipate us having in the upcoming years? And what would that look like in terms of how it changes healthcare and the practice of medicine? and personally how we live our lives. Yeah, I think that maybe two lines of thinking, though in theory, the sky's the limit, right? But two lines of thinking is if we are able to identify, as you were just alluding to a second ago, gene environment interactions, like how our personal genetics interact with our personal microbiomes, we may get pretty good at preventing certain diseases.

1:51:44I'm not sure we can treat or reverse many diseases. I hope so. You know, and I won't exclude that possibility, but I think it's a lower bar, a more reasonable goal, if you will, to say, you know, I set my sample to 23andMe, I'm at risk for type 2 diabetes. Is there something I can do microbiome-wise, but also health-wise, as we talked about, to prevent that day where actually my blood glucose goes above a certain threshold where I'm diagnosed with diabetes, right? So I think the preventative aspect is the way to go. But I think that the other axis to think about is just the psychological part, is that when people are taking something that they feel is natural, that they believe is going to make them healthier, then that might prompt them to live healthier lifestyles.

1:52:30So it's sort of a cascading event. I think you probably know a lot about this since this is certainly, I speak in personal experience as well, right? Is that it's like exercise. Like once you exercise and you see some benefits, you're more likely to eat better, right? And so I think that the microbiome offers that window, if you will, or that opportunity to begin a healthier lifestyle. And again, it did for me. You shared that the FDA has really become an ally. Is there a sense that the conventional medical establishment is coming around as well and is supportive and receptive to the work that you're doing and your colleagues are doing?

1:53:07They are, but they're, you know, from a big pharma perspective, right? So again, thinking about who's really going to develop these drugs, right? You know, I don't think big pharma is yet sold on the microbiome. And I think there's some very good reasons for that. And so it's going to be smaller companies. It's going to be, you know, maybe even health food companies, not traditional pharmaceutical companies are going to make the biggest breakthroughs. And again, I don't think regulatory issues are going to stand in the way. I don't think manufacturing is going to stand in the way. and certainly not societal acceptance.

1:53:40I think society would welcome these types of natural approaches. But for them to become more mainstream, which is not exactly what you asked, but maybe thinking about like, you know, forward looking, you know, to what degree is this, is the microbiome being leveraged to actually treat disease? There's gonna have to be buy-in from the big pharmaceutical companies. And I suspect, I don't know, and there's not one answer, but I suspect they will take a conservative approach over time. And until there is, for better or for worse, a revenue stream that is attractive to them, they're probably not gonna jump in, right?

1:54:17And so, and again, I think there's some, beyond not to be too cynical, right? Beyond just the financial component, there's some really structural reasons why big pharma isn't completely sold on the microbiome. For example, is there's no precedent for an organism or therapeutic that's alive, that's a living drug. And so pharmaceutical companies don't even know how to wrap their minds around it, let alone a business plan, for example, is you may know that most pharmaceutical companies are not developing new antibiotics, even though antibiotic resistant bacterial infections are a huge problem and a growing problem.

1:54:56The reason for this started about 20, 25 years ago that pharmaceutical companies just started shutting down the microbial genetics division or the antibiotics division is because, you know... Infectious disease are one of the few things that modern medicine could actually cure. And by curing, again, I'm gonna be cynical, by curing - I know where this is going, but go ahead. They've lost customers, right? So they wanna treat chronic disorders. They don't wanna cure anything, right? And so one business model is, well, and there's some recent precedent for this that I'll touch on a minute is, is the drug something, let's say it's a live organism, is it something you're gonna have to take every day and you're gonna have to keep buying capsules?

1:55:38Or if you take it one time, is it gonna colonize, right? and give you lifelong or many, many months or years of benefit. And the one time is that business model work. Yeah. And I don't know. So there have been breakthroughs in genetic medicine recently, where it is one injection, one treatment that solves a genetic problem. These are like highly penetrant and where you know the gene mutation is causing that there's very little environmental contribution. Again, this is the very small percentage of human disease is like monogenetic, highly penetrant, genetically caused diseases, right? And so there are some therapies that have come out, you know, in the past few years, you know, they're like tens of thousands, hundreds of thousands of dollars for one treatment, right?

1:56:23And so maybe over time, there'll be more of a business model for the microbiome. But again, that's like, that's one of my multiple reasons why big pharma is still not interested. Sure, sure. But will they be and when they will be? I don't know, I can't speculate. But I think if the customers are there and the effects are there and the benefits are there, that's an opportunity. Yeah, I'm a former lawyer, so I can't help but think about the intellectual property. Can you protect a strain of a microbe strain such that it would be something that a larger company would feel comfortable making a giant investment in?

1:57:05Yeah, the current way to do it, which may not be the best way to do it is to genetically modify that organism, to make sure that it's doing something that wasn't happening in nature. You may know this from your, I know you're a recovering lawyer, but I think it's called like 101 or something, is it a natural product? And so the dogma has been that if something occurs in nature, then no one can own it. There've been some end arounds, legal end arounds on that as well. And so, but the vast majority of cases, you have a microbe, I need that microbe. A drug company cannot patent the microbe that they're giving to me.

1:57:43So the approaches that they're taking are essentially formulations, methods of use, right? And in some cases, genetically modified organisms that have a property that they can protect. As soon as you start to genetically modify it though, it feels less like a natural intervention and more like a drug. It does. Or more like a Monsanto seed or something like that. It does, it does. And then you open up the regulatory problems, right? Is because regulators are bullish on the microbiome because it's natural, once you start making it not natural, then you're gonna have to satisfy. And again, there are paths for that as well.

1:58:19And so I think that's one strategy. But again, for a drug company to do what you just suggested, and there are some really interesting candidates, right? So there's some disorders where you can just take a microbe and just have it make more of what it was making and that would be therapeutic, right? You know, for drug companies to do that, I mean, the investment is so heavy, the upfront investment is so heavy before they see the return that, again, they're just not doing that, at least not at scale, like not a large scale at this point. And there have been a number of pharmaceutical companies, you know, smaller biotech companies as well that have taken, not pharmaceutical, small biotech companies that have taken this approach.

1:58:54By and large, they just haven't done well, meaning having genetically modified microbes as therapeutics. It's a case-by-case basis. in some cases, they probably made bad decisions. But overall, my view of that entire area is that it's probably too ahead of its time, right? There wasn't enough of sort of a receptive audience from pharma, if you will, for those drugs to find a home ultimately. So again, I think people will just keep knocking on those doors and hopefully, you know, we'll learn along the way of like, what are the organisms? What do we need to do to those organisms to get the IP protection?

1:59:31Because that's gonna be important. Again, if you think from a business standpoint is any company, whatever the product is, right? If they can't own it, then they can't monetize it in a way that they'd like to. There's no economic incentive, yeah. So it all goes together. Right, so with the two companies that you have, you have Axial and then Symbiotica, what's the other one called? The other one's called Nuanced Health. Nuanced Health, I don't know why I thought, anyway. I used to have a company called Symbiotics many years ago. Oh, that's what I was thinking of. Okay, so what are those ventures looking at?

2:00:03What are they focused on? Sure. So Axial is a clinical stage company, meaning that they've already taken drugs into clinical trials. And they're essentially a gut brain company. And so their programs are in autism and in Parkinson's. And their approach is actually quite interesting. And again, a lot of this is technology that originally came from our laboratory. so academic research that then the company translated into medicines. And the approach they've taken is to essentially not try to develop drugs that come from the microbiome, but identify pathways in the microbiome that if you can drug with a small molecule, you'll get benefits, right?

2:00:46And we've already talked about two of the examples, right? So one is 4-EPS. So 4-EPS is being made by a dysregulated microbiome. It's making more 4-EPS than it should. So both Everyone has four EPS in their bloodstream and the microbiome makes it, right? But some people are just making orders of magnitude more. And we feel like that's tipping the balance towards disease. And so what Axio has developed is a drug that essentially sequesters or binds four EPS as it's traveling through the gastrointestinal tract. Bacteria make the molecule, the drug binds it, sequesters it. And then, sorry to your audience, we just poop it out, right?

2:01:20Yeah, it just becomes neutered. That's right, yeah. And just lowers the concentration and gets it back to a more sort of homeostatic or healthy level, right? And shows efficacy in early human studies, but also, you know, a lot of mouse work as well. And so again, the approach is to use drugs to drug the microbiome, but not use bacteria or fecal transplants or microbiome molecules. And the other is in the Parkinson's space. Again, I alluded to this earlier, is that again, in some percentage of Parkinson's, maybe somewhere around 20%, there's this microbial bacteria that makes a microbial molecule, which leads to alpha-synokin aggregation.

2:01:59They develop a drug to inhibit this process. And again, the drug is only found, it's only retained in the gut. It does not enter the circulation. It certainly doesn't go to the brain. So we know its mechanism of action is in the gut. And so the company took this route of developing these types of therapeutics for two reasons. The first is if a drug doesn't enter the circulation, it's much less likely to have side effects, right? And so the safety profiles on the drugs they've developed are exquisite. But the other is thinking about pharma is pharma is more likely to invest in small molecule drugs, the types of drugs that Axial is making than they are in fecal transplants or live biologics, as we just talked about.

2:02:44And so we feel like those drugs are just more transactable. Those assets are just more transactable but because now you're speaking pharma's language, right? Small molecules that could be manufactured, quality control, batch to batch variation, and you own the actual molecule, you own the actual drug, right? And so that's Axial's approach is essentially try to understand how microbes are talking from the brain to the gut and then intervene in that process as therapies. How far along are you, particularly with the Parkinson's intervention? Like I'm imagining somebody listening to this who's in the early stages or perhaps is at risk.

2:03:25Are there experimental trials? Is that on the horizon? On the horizon, but the first trials will be small and they'll probably be first in human studies, meaning that we're, you know, and this is still undetermined because we need to discuss what the trial looks like with the FDA, but they may likely go into just healthy volunteers, which is pretty standard for drug development. you oftentimes don't want to go into a disease population in the first trial because they're just more vulnerable and you're more likely to see adverse events. But in some cases, the FDA allows the first trial to be in a patient population because of combination they feel it's safe and that there's a medical need.

2:04:06Like for example, in cancer, you can take a lot of experimental drugs into cancer these days, especially in people who failed all the standard of care drugs. And so to answer your question, I can't give a definitive date, but based on historical timelines of drug development, if all goes well, we're probably looking at approvals more than five years from now, probably closer to eight to 10 years from now, where there's an actual drug that some population, some percentage of Parkinson's patients can actually take and be prescribed and may help their symptoms. And the other aspect is that though our goal with the Parkinson's program is to improve motor symptoms, which is classic Parkinson's.

2:04:52As I mentioned, the gastrointestinal symptoms, like the constipation can be quite debilitating and really affect quality of life. And so if we just see improvements in the constipation, then I think we're helping people just on that scale as well, right? Because again, laxatives and any current medicines just don't work for the GI symptoms associated with Parkinson's. And so a lower bar, I think, but hopefully one that will help people. But again, our goal and with the model of Reaching for the Stars is to really improve, maybe not reverse, but slow down, maybe halt the progression of motor symptoms, the classical symptoms of Parkinson's.

2:05:32Right, right. And we had a guy here yesterday called Phil Stutz, who's a, he's a psychiatrist and he's had, he's in his seventies now, but he's had Parkinson's since he was, I think he was diagnosed when he was 21. His palsy is pretty pronounced. He's lived with it for a very long time. So we, you know, we did a, he's, you know, it's, you know, it's such a debilitating disorder. You know, it's just interesting that you came in literally the day after he was here. So Parkinson's is very much on the mind and it's a, And it's a really beautiful, worthy investment of your brilliance. So thank you for that.

2:06:12I think it's a really good time for a young person to go into microbiology too. Like this just seems like a world that's gonna continue to develop and grow. And it's really at the cutting edge of some of the most fascinating stuff that's happening right now in science. Yeah, I think there's been a renaissance in microbiology over the last decade or so. And in my opinion, driven largely by microbiome research and not all the other microbiologists going on because though again, really a worthwhile cause to think about infections, infectious disease, which is still a huge problem. Nothing that I wouldn't say we've solved anything, right?

2:06:48You know, I can hear that that's misrepresenting. We've, you know, antibiotics have been revolutionary, right? Extended lifespan and a lot of, you know, children, especially, you know, childhood mortality has really, really been, you know, improved in many societies, not all societies, certainly. So we have made breakthroughs, but I think the microbiome offers just a unique opportunity to touch on a lot of other aspects of health that go beyond just infection, which is all the chronic disorders that we've just talked about. If someone listening to this is inspired by what you've just shared and is interested in learning more about this world, do you have resources, books, like where can that person turn to kind of edify themselves?

2:07:33A number of books have been written on the topic. They come to, I won't name anyone just out of my colleagues in trouble, right? But obviously searchable and easy to find. But yeah, no, we live in a world where accessing information is quite straightforward. In the absence of giving particular resources, what I would say to your audience is to really be mindful of the source and the type of information that you're being exposed to. There still is a lot of hype out there, right? And so I think, you know, trying to figure out ways of identifying the most rigorous research, the ones that just makes sense, the ones that really don't feel like they're overblown, you know, are probably the best way to start, you know, and to get that framework, that foundation of knowledge in the microbiome.

2:08:28and I may get in trouble for this one, but I'd be skeptical of anyone selling a product at the stage, right? A microbiome-based product. So just to be specific is, we can tell you what treatment or what drug or what diet or probiotic to take if we sequence your microbiome. I would be very skeptical of those sources, not resources. But from an educational standpoint, again, I think there's a wealth of information out there people just should filter in their own ways what they believe and what they don't believe. I appreciate you coming to talk to me today. That was truly fascinating. I learned a lot and I'm just more excited about this world than I was a couple hours earlier.

2:09:13So thank you. Thanks for having me, Richard. Yeah, when you make a big breakthrough, come back and share it with me. I will, I will. All right, appreciate you. Thanks, peace, Lance.

2:09:29That's it for today. Thank you for listening. I truly hope you enjoyed the conversation. To learn more about today's guest, including links and resources related to everything discussed today, visit the episode page at richroll.com, where you can find the entire podcast archive, as well as podcast merch, my books, Finding Ultra, Voicing Change, and The Plant Power Way, as well as the Plant Power Meal Planner at meals.richroll.com. If you'd like to support the podcast, the easiest and most impactful thing you can do is to subscribe to the show on Apple Podcasts, on Spotify, and on YouTube, and leave a review and or comment.

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2:11:24Thank you.