Why Parkinson’s May Be Treatable Through Your Gut (Not Your Brain) - Transcript

Sarkis Mazmanian
Because the microbiome sort of like tunes our body, all these different systems, it wasn't designed to reverse disease. We're trying to engineer it to do that. Don't wait till you have diabetes before you stop... Before you start taking you know, your your gut health seriously, or don't wait till you have any condition. There are things you can do today to improve your gut health, to improve your microbiome health.

And the payoff is long term is your health in the decades that are still ahead of you.

Dr. Mark Hyman
Welcome to the podcast. It's wonderful to have you, Tarkis, and I've been a follower of your work and really excited to dive into how the gut plays such a role in our overall health, particularly in our brain health, which we're gonna get into today. So thanks for being on the podcast.

Sarkis Mazmanian
Thanks for having Mark, and I as well have followed your work, and I'm happy to be here.

Dr. Mark Hyman
Well, thank you. So, you know you know, I wanna zoom out for a second and and say, you know, I've been on the front lines treating patients for forty years, and you you are an academic physician from none of the esteemed institutions like Harvard and Caltech and have really done tremendous research in pioneering our understanding of the microbiome, its role in health, and particularly in the gut brain axis and how some conditions like Parkinson's and autism may be connected in part to what's happening in our gut and our microbiome. And I, you know, I've come at this from the opposite direction, is seeing patients, you know, being in the trenches and dealing with real problems that people are facing every day. And it's just striking to me how much the gut and the microbiome play a role in our overall health. And this is being, you know, born out across medicine, whether it's cardiovascular disease or cancer or metabolic health or autoimmune diseases or allergic disorders.

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

And he was like, I don't know, but I think maybe a third to a half. I would like to get your take on that.

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

Dr. Mark Hyman
Yeah. That's an astounding concept. Like, not

Sarkis Mazmanian
only,

Dr. Mark Hyman
you know, do we have, you know, about or... And as many or more bacterial cells in us than our own cells and a 100 times as much bacterial DNA than our own DNA. But up to a third to a half of all the things floating around our blood that are molecules interacting with their biology every second come from the microbiome or are derived from metabolites from the microbiome. And and I I I saw this clinically practicing medicine treating patients with autism or people with Parkinson's or people with, you know, autoimmune diseases or whatever it was. And depression or mood disorders, behavioral disorders, ADHD, all all of the kinds of things that we would see in our practice.

And modifying the microbiome by changing diet, by changing the microbes in there through herbs or drugs, We were able to see using probiotics or other things which are still not... We're studying well enough. But we we see these clinical changes that were quite remarkable. And, you know, and and looking over your research, it's really clear that you're you're you're seeing the same kind of signals. You're seeing that there's...

Is is is not just sort of, you know, some of the work you've done, you know, showing that it's not just, that, you know, the microbes are sort of incidentally involved, but they're they're actually may be causing involved. Like, I I would love to sort of have you sort of sort of dive in a little bit of the beginning of your research. How you came to understand the microbiome played a role and kind of what got you excited about this and and what you've sort of learned about at the high level around the gut brain axis and this whole communication between the gut and the brain, including, you know, our nervous system, our immune system, the microbial metabolites, hormones, all these things that start to change as we change the microbiome.

Sarkis Mazmanian
Yeah. I think just embedded in your question is is evidence that the microbiome affects so many of our... Of the organ systems in our bodies. Right? And it's not just, you know, the most obvious ones like the immune system.

When we think about the immune system, we think about how we fight off bacteria, infectious agents, you know, viruses, fungi, have you, protozoan infections. But, really, the microbiome impacts our metabolic system, our endocrine system, our nervous system, and and this has huge effects on on many aspects of our physiology. And so we became interested in in the gut brain connection largely because of of, you know, at the time, again, close to twenty years ago, anecdotal evidence showing that classical neurological conditions, at least conditions viewed as neurological conditions, diseases, if you will, have a GI component, have a gut component. So I think it's well documented, perhaps maybe more on Parkinson's than other other cases, that, you know, the vast majority of individuals who are diagnosed with Parkinson's have constipation. They show constipation years, if not decades, before their their movement disorder, the the thing that they were diagnosed with.

Right? The the Parkinson's. And so, you know, that was pretty curious. Right? You know, like, why is this brain disorder, you know, manifest in many individuals as GI symptoms?

It's true in autism. I think the data is a little bit more fragmented, and the phenotypes aren't as clear in autism as they are in Parkinson's. But clearly, many children with autism have some form of gastrointestinal symptom, whether it's abdominal pain, alternating constipation, diarrhea, and what have you. And to a microbiologist like me, this became quite interesting. It was an interesting observation is that, you know, a, what is the role of the microbiome in in these these disorders?

We're still trying to figure that out. I don't think there's there's, you know, one answer. I don't think there will ever be one answer, but we're we're trying to get to some of the the clues that help us understand, you know, how microbes shape these outcomes. Right? And just what you alluded to is, you know, what does that communication look like?

How do microbes that live in our gut, the microbes aren't in our brain? Right? In our, you know, our colon mostly, but in our small intestine as well. How do they signal to the brain? How do they send their their cues, if you will?

Right? Both bad and good. That results in behavioral changes, mood disorders, even death of neurons. As as traumatic a phenotype in the brain as one can imagine, like nerve cells actually. Wow.

Again, that's... That was really very fascinating for me and and very understudied twenty years ago. I I would argue it's still quite understudied now. Right? And so we looked at these problems from the lens of the microbe.

Right? And tried to understand what are the organisms that are at play in these different conditions, what are the signals that they're sending, what are the the the, you know, human cells that are receiving those signals, and then how do they mediate various different outcomes? Again, changes in behavior, you know, movement disorders, cognitive impairments, what have you. I think we made some headway. I think we understand a few of those signals, but the microbiome is not one thing.

It is many many things, many hundreds, if not thousands of organisms and molecules. So we have a long way to think. But I think there's, you know, very little argument in my mind that at least in animal models that there is a causal role for the microbiome in these, you know, classical brain disorders. Right? And we know that because we can just manipulate the microbiome of animals in ways that we just simply can't do.

It's not ethical or feasible to do on people. And and then get, you know, very solid, reproducible, rigorous outcomes. And so whether or not to what degree that translates to humans, I think... Feel that... And we are still trying to figure that out because, again, we just can't do the invasive experiments in humans that we can in animal models.

I think that has to be the next step, right, is to try to understand to what degree the gut or, in our particular case, the microbiome in the gut is signaling to the brain. Because, you know, I think the upside is potentially enormous, right, is if we can help people with classical neurological outcomes, you know, brain disorders, if you will, by treating their gut. Right? And I think this is one of the sort of the the north stars of our research is Mhmm. We don't try to get drugs into the brain.

It's very hard. I mean, that's, I think, the classical approach. Right? We just try to, you know, manipulate what we can, what's accessible to us. That's that's in the gut, and then the body does the rest in terms of communicating that signal to the brain.

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

Speaker 3
That's right.

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

Sarkis Mazmanian
The nervous in the... That communicates to the nervous system of our brain through the vagus nerve, spinal nerves, neuronal connections.

Dr. Mark Hyman
Yeah. We we've kind of... That that whole second brain thing, we we've... Think I we've known about for a while, and I think it's such an important piece of this. So I I didn't mean to leave that out, but but it's these other pieces that are sort of new in in thinking.

Right? Okay. Well, we know that the nervous system, the gun, the nerves in the brain, we we can map them out. They're well understood in traditional medicine. But the idea that there's some strange metabolites from your microbiome that are changing your biology in ways that create demonstrable disease, it's not something the average doctor actually even thinks about.

Sarkis Mazmanian
Right. And, you know, we'll take that that data that we talked about a couple minutes ago of, you know, what percentage of the molecules in our blood are of microbial origin. I can't quote you a number, but, you know, there are a large number of molecules in our brain that come from our gut microbiomes. Right? And we certainly know this in animals because, again, we can just do do those refined experiments.

But through extrapolation, through experiments like, you know, looking at post mortem tissues or c... You know, or CSF, I think there are very strong clues that... And Stan's work is some of this, Stan Hayton, who you mentioned, you know, contribute to some of this, is that there are microbe molecules that float around our brain. But what would they do? And the vast majority of which, you know, we don't even know what they are, let alone what they're doing.

Dr. Mark Hyman
So saying for brains this may not be a a wrong statement.

Speaker 3
Yeah. I think

Dr. Mark Hyman
it's kind of hard. I I I I remember Rudy Tansey talking about this that there are discoveries in Alzheimer's brains, and he's one of the leading Alzheimer's researchers in the world at Harvard who who who has described this phenomena of microbial compounds in the brain or even microbes in the brain that potentially come from the gut. And and it's such a it's such a hard leap to think about how does that happen because, you know, we think about the gut as this tube. It's impermeable except for nutrients, and yet that's not necessarily true. I mean, your work particularly in the autism models have been fascinating around how, you know, you see increases in gut permeability.

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

Sarkis Mazmanian
Our our work is grounded in in in animal models, particularly mouse models. And so I have to say, there are caveats, obviously, to animal models. They're not they're not humans, but we try to reproduce the human condition to the best of our abilities. This work started many years ago with a collaborator, Paul Patterson, who was here at Caltech. Paul was quite interested in the role of the environment on behavior.

And I'll fast forward, you know, hopefully, I'm not doing a disservice to the decades of work that he did, but I'll just fast forward to to how he got involved, is he had looked at epidemiologic data showing that an infection during pregnancy resulted in an increased risk of that child having autism. He modeled this in mice, essentially gave pregnant mice the flu, and then the animals had not just behavioral disorders, which he had characterized and continued to characterize. But when we started working with him, we looked at the gut, and we found the permeability that that you mentioned, the inflammation in the gut that you mentioned and and other GI symptoms, and we found changes in microbiome. And we thought to ourselves, this this is probably more than just a coincidence because of that emerging literature in people that the gut was involved in in in autism. And so we started digging.

We went into, you know, looking at immune... The immune side, you know, and I think there's still a lot to be done in other people that are that are doing that in terms of profiling what are those immunologic changes. We got really interested in in, as you mentioned, metabolites, the small molecules. And that... And again, we're just explorers.

Right? So we go, we we look for things, and and when something looks interesting, we we we dive in and try to follow those leads to try to understand really mechanisms of action. Like, really, are not just what's there, but what what are what are those molecules doing? And so we did something called a metabolomic screen, which basically is a profile of molecules, right, in in these animals. And we're comparing the animals that had the behavioral conditions, behavioral deviations, if you will, similar to those that didn't.

And we found high levels of a particular class of molecules. These are small phenolic molecules that look like amino... They come from amino acids, kinda look like amino acids. Reminiscent... They're not neurotransmitters.

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

Right? That the the molecule that stands out in our animal dataset is a molecule almost identical to one that's that's elevated in people. And, again, you know, from a scientist perspective, that was enough for us to put our our our resource and effort into trying to understand what that molecule is. And I'm just using this molecule as one test case to really give us an example of how how these connections work, these gut brain connections work. And so over the years, we, you know, through...

You know, with help from lots of collaborators, found the bacteria, the bacterial genes that produce these these... You know, this molecule and this this class of molecules. And they started asking ourselves, alright. Are they just there, or are they doing something? Right?

So then we set up these experimental systems where we can, you know, you know, control the levels of production of of for ethyl sulfate and related molecules in the gut, and then we can behavior test those animals. Right? And so this is now sort of the... You know, again, it doesn't rise to level of causality, but I'd say contribution to behavioral deficits. And we showed that if we l...

Again, de novo discovered this molecule, but if we then, you know, artificially elevate the levels of the molecule in in mice, because, again, we can engineer bacteria to produce those molecules, those mice had very potent signs of of anxiety, but they also had speech issues or or or changes changes in social behavior, social changes in repetitive behavior. And those are conditions. Again, there's no... Mice don't get off.

Dr. Mark Hyman
And what language do mice speak?

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

Dr. Mark Hyman
Their speech... Their sound patterns. Yeah. I get it. I'm just teasing.

Sarkis Mazmanian
There are stereotypical vocalizations that animals make, and they do this in particular just to go go into a little bit of detail, I do think it's interesting, but... Is that, you know, in a in a courtship paradigm or in an aggression paradigm, if you put animals into those into those contexts, then they vocalize. Right? And so you can... It's such an induced vocalization and then see how different are different groups of animals in their speech patterns, if you will.

Right? And so, again, they don't... They speak mouse, as you said. But, again, we can see, you know, all their changes from baseline. Right?

And so, again, but I also wanna emphasize, you know, you know, there is no mouse model of autism. Mice don't get autism. Right? But we can model certain behavior.

Dr. Mark Hyman
They're behavioral correlates. Like, they're behavioral correlates of autism in mice, and and you see those rise when this level of four ethylphenol sulfate rises. And it it... How is that not caused? Like, you...

If you if you kind of like have an normally behaving mouse Yeah. You give it this this somehow induced its levels of production of this this molecule, and then it induces these behavioral changes, and then you dial it back and they go away. How is that not causal?

Sarkis Mazmanian
We don't know what's actually elevating those levels in people. Right? And so why why do people have high levels of four ethyl sulfate, which we then showed in the subsequent papers. So, again, once we found this in mice, then we looked in in human tissue, feces, and serum, and we found that elevation. That primary change, we don't know.

Right? And the other aspect, which I also alluded to, is, you know, in science, you know, to to get... You know, to be able to to make confident claims, you really have to make systems very simple. Right? So to go into these reductionist models.

And so, again, we're working in an area that's where we can make, you know, causal contributions or causal claims about very specific things. But then when you zoom out, like, again, this molecule is produced by this bacteria. It gets in the brain. It affects brain function. But when you zoom out into a person, there's no one molecule.

There are hundreds of molecules. Right? And then that person has infections. That person has lifestyle, you know, changes, you know, dietary patterns. Their their genetics are super important, right, in how it manifests.

So it can't... I don't think it rises to level causal in in humans because that molecule at at identical levels in two different people could have two different effects. Right? For exam... I could have a genetic vulnerability, for example, that makes me predisposed to adverse behaviors if that, you know, a certain molecule is elevated.

You have a genetic landscape that doesn't make you vulnerable. You could have high levels of that molecule, but you don't manifest behaviors. Right? And so, again, think it's important to be rigorous and and and also know the context in which you're working. Right?

So, again, the data show that that molecule is important. This class of molecules are important. In whom are they important? And, you know, what else is going on? Those are the blind spots that we still have.

Dr. Mark Hyman
I mean, that's such an important point, Sarkis, is that it it... You know, they're such heterogeneity in the population, and the genes load the gun, but the environment pulls the trigger. So the same insult might not cause a problem in one person where it might cause a problem in another person. And we see this all the time in medicine, and we try to label people with these categories of illnesses like autism, but these are... There's no such thing.

There are autisms, and there are Alzheimer's or Parkinson's is whatever the plural is of that. And and I think, you know, we're we're so used to these sort of very narrowed disease classification systems that we missed the reality that that these conditions are quite heterogeneous even though they may manifest the same way symptomatically. They causally might have very different patterns and they might be variable factors that are including genes and environmental factors. And that that there are no two cases that are exactly the same. And I see this as a doctor practicing medicine in the trenches that, you know, I'm humbled by the fact that, you know, how little we know.

And then actually, know, by listening to the patient, you will learn a lot. I I think William Moulter said, listen to the patient who has the disease rather than the... Think about the name of the... Whatever the disease that the patient has. And I think that's that's really important.

And I think I think with with autism, I've seen clinically so many cases where we've looked at the gut microbiome. We've seen abnormalities in there. And I remember one of my professors was a pediatrician named Sydney Baker, and he he was an incredible pioneer in this field and treated thousands of kids with autism. And he used to talk about, you know, if you've seen one kid with autism, you've seen one kid with autism. And when we looked at these kids gut, whether it was symptomatically or just looking at their stool or even things like organic acid testing, looks in some ways that the microbial metabolites that come from the gut that are in that metabolized by the body and excreted in the urine, we can measure those things.

And we don't completely understand how they all interact or what they do, but their signals are there. When you see these things, it it correlates with with these symptoms. And when you treat them, these kids often will get better. And I've seen many kids in my practice who... When you when you optimize their gut health and you get rid of the bad bugs, you put in good bugs, you you deal with the leaky gut phenomenon.

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

So that's why your work is so important because it's kind of teasing apart, like, how this all sort of interacts.

Sarkis Mazmanian
Yeah. I mean, especially for something... For a condition like autism, right, where there isn't a a a, you know, a blood test or a brain scan, right, we're using behavioral assessments, which are... Which can be quite subjective. Many of the behavioral assessments require parent reporting.

Right? Parents tend to be, you know, not the most accurate in terms of being able to to recall what happened a week ago, a month ago, a year ago, right, in their environment or or to their child. And, obviously, there's the the very strong emotional psychological component to this as well. Right? And so I think that makes the problem even more difficult to solve.

Right? It's because the definition of autism is not one thing. Right? And and, again, it's it's subject to to a lot of noise based on... I mean, just like data noise based on the observer and and and and the reporting.

And so now we're trying to take what is likely a biological... A heterogeneous biological group and superimpose on them the ability to assess their biological state with a heterogeneous set of tools. Right? So that really compounds our ability to know really what's going on. Right?

And I think that's something that that the autism field would really benefit from is, again, like like a biomarker. Right? Like, one, if there is ever such a thing. And there may not be. Right?

I mean, I think autism could be quite quite, you know, different in the fact that multiple etiologies, which are like this trigger, if you will, all converge on behaviors that we call autism, but the origins are all different. Right? They just manifest in in the same way. But if we had something reliable where you can track it, you know, with a, let's say, a blood test and that tracks with behavior, right, then I think we can start asking those questions of, okay, you know, as you've talked about in your practice, when I treat the gut, what do I see objectively? What can I see confidently change in that individual?

Right? And so I think, you know, obviously, other conditions, we have better... A little bit better understanding. And, you know, again, these objective biomarkers, you know, like, something you can measure that is independent of, let's say, placebo or independent of opinion or or recall. Right?

And that makes... That allows us to make headway faster when you have those those sets of endpoints or or those reliable outcomes.

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

Sarkis Mazmanian
But what defines talking? Right? So number of words in a given amount of time, you know, the the complexity of the language, the the Yeah. Size of lexicon. Right?

And so... But I I would

Dr. Mark Hyman
I mean, going from not talking to being fluent, I would say is a pretty good biomarker. And I've seen that happen. I've seen that happen and it's like something is going on and it's often when you treat the gut or when you get rid of things like gluten or when you do, you know, kind of these weird sort of manipulations of the the the body and and it's sort of ecosystem. Sometimes things will just click into place. And so I think I think we were chatting a little earlier how, you know, a lot of the autism field feels like this is a durable problem.

Like, it's it's genetic. It's it's non modifiable. It's fixed and it can't be changed. And I think, know, your work shows that that clearly can when you take the the the germ free mice, in other words, having a microbiome and you put in the poop of an autistic person or mouse. I don't know how you exactly did it.

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

Sarkis Mazmanian
I can. But again, you know, the caveats are that it it... It's an animal study. I want... Before I talk about our our work and what we've in terms of of showing the contribution of of the microbiome to autistic, you know, traits in mice, Just going back to to your point about about language.

You know, the the... What you described to me is something I've heard many dozens, if not hundreds of times. Right? People who have treated the gut. Because, again, I I just hear these these stories.

Right? The gut... And and, you know, to to the people who are observing them, like, parents, you know, other caregivers, what have you, to them, it's black and white. Right? It's that this child, you know, was a certain way for years, and we improved their their gut function, and they're no longer the person we've known for years.

Right? And so it it's hard to argue that point. Right? But I would say, Mark, in... And you tell me as a clinician, right, translating those observations into clinical results is challenging without those quantitative metrics, without being able to actually put numbers around what you're seeing.

Right? It's not... Again, And it's not that people, you know... I don't disbelieve. It's not that that it's an issue of belief.

It's an issue of, like, yeah, I don't know, the the language scientists and and and physicians speak in terms of saying, okay. Now I believe what I just heard. Let me, based on that information, make a set of decisions. Right? So that's why I think, again, you know, trust me.

I I I like to push the envelope. Don't get me wrong. Right? But at the same time, you know, there... It has to be...

Whatever claims we make, we have to be able to validate it and substantiate it in ways that are objective. Right? And so, again, so I think there is value in being able to find those those metrics. And maybe it is something like just recording. Right?

And and especially these days. Right? Because you could sort of really deconstruct language in ways that are that that are, you know, quite sophisticated. Right? And put numbers around that...

Those those parameters. I think then scientists will say, okay. I believe now there's a change from before and after, right, that that gut intervention, and let me now dig in to see what the what the biology is. Yeah.

Dr. Mark Hyman
It's a great it's a great point. And I I think, you know, when I... When I'm thinking about these kids, and and I've seen literally hundreds of these kids along the whole spectrum of neurodevelopmental disorders. And there are common themes. Like, kids have all have a lot of oxidative stress, and you can measure that with, you know, lipid peroxides

Speaker 3
or

Dr. Mark Hyman
eight hydroxy to deoxyguanosine, which is a DNA addict, like a damaged DNA byproduct. They have low glutathione. They have impaired methylation. They often will have problems with the the microbiome which you can measure and and there may be things that aren't like well accepted, but they're things like urinary metabolites of a daratumatol, which is a fungal metabolite or other other metabolites from microbes that we can measure and that they change when the behavior changes. So the docs says stress comes down, methylation patterns improve, glutathione comes up.

We see, you know, the the the microbial metabolites change. These things we can observe and I... Or we see, you know, intestinal inflammation improve. So there there are subtle markers like I had one kid who was autism. We had high calprotectin, eosinophil protein x, which are biomarkers of gut inflammation.

Well, didn't fully have colitis or also colitis, but he had something cooking in his gut. And so we we normalize his microbiome by you know giving on a remember we gave him I think we had a good rifaximin and and and any fungal fluconazole to kind of reset the bugs and probiotics. Those are sort of nonabsorbed antibiotics and in any fungal and and and probiotics. He he got better and and those numbers came down. So there there weren't like an autism biomarker, but they were things we use in medicine to measure function in the body that are that are a little bit more tangential, but seem to be kind of moving in tandem with these kids when they when they're bad they're worse and when they're better they're better.

Sarkis Mazmanian
And

Dr. Mark Hyman
so I mean that's that's what I've seen clinically and I know it's not it's not it's what we call anecdotes. And I think you know the the the plural of anecdotes or anecdote or something. And and I think that the whole phenomenon of n of one studies I think is really interesting because that's I think where we're gonna start to learn more. If we can start to be more rigorous about these n of one studies where we we... The person is essentially their own control before and after.

Speaker 3
And it it is it

Dr. Mark Hyman
it is a messy problem

Speaker 3
because these are,

Dr. Mark Hyman
you know, the the... This whole... Our whole movement of medicine from being reductionist and specialty driven to being a more understanding the body's a system or network and the microbiome is the most important example of that in human biology. You know, the the labels and ways we describe things don't match the the observations anymore. And so we have to change our theories when when our theory doesn't explain our observations.

And that's that's kind of where we are in medicine, but the clinical practice hasn't quite caught up with where you are in your research, unfortunately.

Sarkis Mazmanian
And I think it will. Right? Because, you know, at the end of the day, the clinicians who are, you know, who are on the front lines, obviously, they wanna do the right thing for their for their patients, and and they'll try, you know, they'll they'll use the tools that are available to Right? But, again, there... There's a certain, you know, threshold of evidence that they need before they say, alright.

I'm gonna start implementing this. Right? Again, some people are just gonna be, you know, more, you know, pioneering, if you will, right, and and, you know, take calculated risks. Right? But, you know, I think mainstream medicine tends to be very, very concerned.

Again, you... And you would know you would know better than I I would. Going back to to the the studies that we did. So we did a a number of different We had been... One of the places we started is we had been previously working on an organism, a gut microbe that had very potent anti inflammatory effects.

Something I worked on early in my career. And this in and of itself, I think, was was quite a sort of a sea change, if you will, in in how we view microbes is that we had discovered an organism that actually dampened the immune response. It actually balanced the immune system. Oh. Right?

Because, again, you know, we all think of the immune system as something that becomes activated. Once there's an infection, the goal is to then clear the infectious agent and our immune system evolve to do that. Right? And in most cases, it does it quite well, and it actually does it without us knowing in in in many cases... In most cases.

So what we discovered was an organism that actually did the opposite. It actually helped the immune system fight off infections. It actually helped the immune system not become over activated. So, again, you alluded to autoimmunity. What is autoimmunity?

It's when your own immune system is attacking your body. Right? It thinks there's an infection or it becomes activated for some, you know, usually unknown reason, and then there's... Over time, the chronic immune activation leads to tissue damage. If it's in the brain, it's multiple sclerosis.

If it's in the gut's Crohn's disease, if it's in the the joints, it's rheumatoid arthritis, so on and so forth. Right? And so the organism that we had discovered actually was protective against these autoimmune or allergic conditions because it dampened the immune system. And so now fast forwarding to the animal results that I described a few minutes ago, we found elevated levels of inflammation that got in these mice. And so our our hypothesis was, well, let's put in this bacteria that dampens the immune system and see if we then get behavioral improvements.

And we actually did. Right? And so once we added this organ... The name of the organ is called bacteroid fragilis. It's in about thirty to fifty percent of the healthy human population.

Generally, it can be in pretty high numbers in in most people. It's a healthy organism. A healthy gut bacteria. Right? Or gut bacteria that is about healthy people.

And it it... You know, when we treated mice with this with this, you know, let's say, I call it next generation probiotic, the mice improved in their autism like, quote unquote, symptoms. So then we said, okay. Well, it must be the immune system there. Right?

Because that's how we've been studying this organism. It wasn't. Because we knew the molecule made by the bacteria that dampened the immune response. And when we put in a bacteria that was missing that molecule, the organism was still able to improve behavioral outcomes. And we didn't see much change in the in the inflammatory patterns in the animals.

So, again, a good, you know, maybe story. Like, your initial hypothesis could be wrong, but that's, you know, a long way. So find something because the organism, regardless of its ability to modulate the mucin, was still providing behavioral improvement. So we wondered, well, then why is that?

Dr. Mark Hyman
What was it? Yeah. What was it?

Sarkis Mazmanian
And so our best guess, we don't know for sure to this day, but our best guess is that in addition to dampening the mucin, we found that the organism actually helps repair that leaky gut phenotype that we talked about. Right? So, you know, what does that do? Right? The...

You know, just very basic. The gut lets nutrients in and keeps toxins out, right, or excretes, you know, waste from the body as well. Right? Again, overly simplified. When that discrimination of knowing what to let in and what to keep out is broken down, then harmful things get in and we consider 40 PS and other molecules to be in that category that are elevated because of the leaky gut.

And so we shorten animals, and we shorten in cell cultures at this organ that someone's able to reseal that barrier. So think of this as like a zipper, right, that is then, you know, zipped up or or or sealed by this bacteria in ways that we still don't understand. But once that happens, once the gut is repaired, less of these toxic molecules get out of the gut and into the circulation. So they're... Effectively, their concentration drops, and they're no longer inducing these behavioral deviations.

Dr. Mark Hyman
That's amazing.

Sarkis Mazmanian
No. But, I mean, again, it just it just tells you... And I think this is to your point, but in in a way, in an experimental system where, again, we know exactly what those variables were. That person didn't go out and eat a cheeseburger, you know, while

Dr. Mark Hyman
we're

Sarkis Mazmanian
eating them or take an antibiotic while we treat them or have you because we can, again, you know, very carefully control the environment. And we know it's because of of this of this microbe. But, you know, again, maybe this is an example of what you were talking about that you you know, we know we're treating the gut in this particular case. The organism does not travel to the brain. Right?

But it then short circuits that flow of these of these neuractive... These neurotoxic molecules, and the consequences is improvement.

Dr. Mark Hyman
You know, you brought up the concept of a leaky gut, and this is something that I used to be laughed at when I mentioned in academic circles a few decades ago. And now here you are talking about this as a sort of established fact. And I think we we do now understand that the gut is a semi permeable membrane that allows hopefully just nutrients and things that we want in and keeps bacteria and toxins and food fragments out. But when that is interrupted, it it can disregulate things in multiple ways from allowing microbial metabolites or the signal molecules to get through or actually just activating the immune system or irritating the nervous system in the gut that the brain nervous system. So there's so many mechanisms by which it can cause neurologic disruption and and systemic disruption.

But you know, you you you you kind of highlighted this particular story of your science which is that you added a bacteria that that had an effect, which is to help seal up this leaky gut that had been consequences in terms of the behavior of that animal. You've also done the opposite, which is you've taken poop from an autistic kind of model of mice, and you put it in a germ free mice, and you've induced abnormal behaviors. So it kinda works both ways. Right?

Sarkis Mazmanian
Again, our microbiomes, your mind and vast majority of people, we have somewhere between two and five hundred different species of bacteria. Depends on how how they're sort of computationally accounted. And, you know, it's really the balance between those organisms that mediates, you know, the balance between health and disease. Right? And so, again, all bacteria are not bad.

All bacteria are not good. Some are... Some could be good in certain contexts and bad in other... It's it's it's, you know, it's pretty complex. Right?

But, you know, again, we think of infectious agents as something that comes into the body and causes the disease. What... The microbiome's impact on our physiology isn't something from the outs... Usually, it's not something from the outside coming in. Right?

It's that the ratios of the organisms that were there are altered. Right? And so when you do these wholesale depletions, antibiotic treatment or one other thing we do is we grow these mice in the... In these bubbles, these sterile chambers. Right?

But there's no microbes in there. So you know about, like, people with, like, skid mutations or impaired immune systems. They... Like, they pour in a bubble. Right?

They... And then as well, we can grow mice now. So there's... You know, the genetics are identical. Food environment is identical.

They just have no microbes in them. Right? So really clean systems. Artificial because there's no germ free humans. Right?

But we know exactly what's in or not in those animals. Right? So we do... When we do these manipulations, we're getting rid of everything, the good and the bad ones. Right?

Dr. Mark Hyman
Yeah.

Sarkis Mazmanian
So, you know, the next level, which we and and many other people are now moving towards, is how do we think about recreating natural situations where we're not just removing all the microbes, the good and the bad ones, or we're just putting in the good ones or we're just putting in the bad ones. Right? But we're, you know, reproducing this imbalance, if you will. Right? And so one of the ways to do that, and there's probably a number of ways.

Right? But one of the ways to do that is then take fecal material from humans with a particular condition and then put them into the animal models. Right? And there are caveats to this. Right?

You're putting human microbes into into mice, and you're looking at, obviously, all the mouse readouts that we talked about. But this is much more natural in terms of of reproducing the human condition than anything we do when you just start off with mice. Right? For a number of different reasons. Eight, mouse and and human microbes are vastly different.

Right? Number one. Number two, the mice that we work with in in academia, in pharma industry, what have you, they have very depleted microbiome. And this is sort of a tangent, so I wanna label it. Because they're they're eating that

Dr. Mark Hyman
crappy industrial mouse food instead of, like, wild mouse food. Right?

Speaker 3
That's fine. It's like humans.

Sarkis Mazmanian
But it... It's really a commercial thing. So the animal vendors have depleted the the microbiomes just so they can have a reproducible standardized microbiome. Right? And so...

But, again, what has that done? It's divorced the function of that microbiome from the things that we're looking at in mice. Again, this is endemic. It's pervasive in biomedical. It's a huge shortcoming.

Right? It's something that we're working to to try and, you know, improve, but it's we're not gonna change, right, the way the way experiments are done. So that being said, right, is, you know, how can you make... Or how can I make mouse models more reflective of human biology? Right?

Again, we have a couple of levers to pull. And when you make these germ free animals, they give you results, the animals that we test, but they're also a tool. They're a tool because now you have no mouse microbes. Again, a completely sterile mouse gut. So you can transplant the human microbiome into those animals without competition from the mouse organism.

So what does that allow us to do? Again, in addition to studying microbes, is to say, alright. If I take poop, a source of mycobacter from a person listed with Parkinson's, and, you know, a household control, a spouse, or a population control. Right? And I put these organ...

These entire groups of organisms into mice. Now I can say, what's the outcome in that animal? Do they have symptoms of Parkinson's? Or is the mouse that received the Parkinson's microbiome, does it have worse motor symptoms or worse movement disorder, neuroinflammation, symptoms, than a mouse that got a human microbiome from a person that didn't have Parkinson's? Right?

To me, that's a much fairer comparison, number one. Right? It's closer to humans, which I think is very important. Right? But it also allows you to, again, as I said, recapitulate or reproduce that natural state, right, of an imbalance in, you know, you know, the the organisms that were there.

Right? I think this is, you know... I personally believe this is a very, very powerful tool. Right? And the reason why...

It's not just us. There's like 50, 60 papers in the literature from labs all around the world that show that you can transplant some human phenotypes into mice just by moving the microbiome from humans to mice. Right? You're not changing the genetics of the animal. You're not giving them chemical exposures.

Not even putting them on, like, processed, you know, ultra processed foods or anything else. Right? You're not giving them infections. You're just moving the microbiome. Right?

And in doing that, you can see, again, increased movement disorders. And if the mouse is, you know, common sense with the Parkinson's microbiome, increased behavioral deficits, if it's common sense with a microbiome from person with autism. We've done this in multiple sclerosis, but it's been done in depression. It's been done in rheumatoid arthritis. Right?

So it's been done in a number of. Right? And so then I think there's there's two things. A, it... You know, I think it advances the concept that microbiome change is meaningful.

Right? We're not just measuring the change in in humans. We're actually putting that microbiome to the test, albeit in an animal. Right? But now gives you an experimental system that you can take apart in ways that we can't in humans and really get to underlying biology.

Right? Learn things that the that the typical mouse that the world, you know, scientists use, that that information, you just can't get because it doesn't have that human microbiome with that original change in the ratios of organisms that were there the entire time.

Dr. Mark Hyman
Well, don't if you intended this or not by your work, but I I know there are people out there in the frontiers of medicine who are taking healthy microbiomes from healthy donors, if there is such a thing, and and using it in patients with Parkinson's or with autism. And they're actually seeing changes. And I've I've heard enough case reports where I'm like, oh, this is fascinating. Because when I when I hear, you know, one story of okay. When I hear two or three or four of the same story, I go, oh, and there's maybe something paying attention worth paying attention to here.

And and and, you know, I'm not suggesting in any way that anybody go out and start doing poop transplants from healthy kids to kids with autism or people with non Parkinson's presentations with people with Parkinson's. I'm not saying that. We're not ready for that yet, But it's an interesting phenomena that that we're seeing out there that people are are desperate with these conditions and they're trying to do something and and sometimes it's working. And it might have to do with what you're talking about. But but, you know, we've had other scientists on the podcast neurologists talking about Parkinson's from a different perspective and environmental toxins, is a whole different thing.

So like I said earlier, these are heterogeneous conditions. They mean they... They're not one cause for every case of Parkinson's. There are many causes and many triggers that can cause the same downstream symptoms including toxins, changes in the microbiome. So I think it's just this whole area is so fascinating.

You you kind of dove a little bit into the Parkinson's area. I I think, you know, you know, we do see this and as well understood in traditional medicine that people with Parkinson's tend to have gut issues. They tend to be constipated. You mentioned often years or often even a decade or more before they get any symptoms of Parkinson's. And you're suggesting this isn't necessarily just a correlation, but there there may be some causative factor here in the microbiome that's changing things over time causing inflammatory or toxic damage in the brain that's leading to a Parkinsonian presentation.

Is is that is that kind of what you're... Where you're pointing at?

Sarkis Mazmanian
We think so. Right? So so then the the idea that Parkinson's patients, the majority of Parkinson's patients have GI symptoms is is not new. In fact, it goes back at least two hundred years. I I often quote the essay on shaking palsy written by James Parkinson himself in 1817 where he talked about GI issues in individuals that that he was studying.

And neurologists know about this because many of their patients will come in and, in addition to their movement disorders, talk about their their GI symptoms. And, again, I think there's lot... There's very large epidemiologic studies now that show that this is the case. But, again, I think there's still a chicken and the egg question, Mark, is, you know, which comes first and which one is affecting which? Meaning, is it...

Is the disease starting in the brain and affecting the gut? Is the disease starting in the gut affecting the brain? Obviously, it's different people. It could be different paths. Right?

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

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

Speaker 3
Yeah.

Sarkis Mazmanian
Others, it could be in the gut. Right? So this has evolved into into something that's now called the brain first versus body first hypothesis in Parkinson's, where, again, I think the data are just much more solid than other conditions about this GI GI comorbidity in a brain disorder. What's really fascinating is that people who have... If you look at someone who was diagnosed with Parkinson's, you look back at their medical history, oftentimes, you'll see that they either were treated or reported GI symptoms years, if not decades, before their their move...

Their or, you know, what made them, you know, go to see a movement disorder specialist in the first place. Right?

Dr. Mark Hyman
And so

Sarkis Mazmanian
Yeah. Again, it's a temporal argument. It's not it's not, you know, causal, but it suggests that maybe something started in the gut first, and and, you know, that's where it initially began, and then over time, you know, migrated to the brain. And what I mean by that is this, and this is part of that gut first hypothesis or body first hypothesis, is that there's the trigger for Parkinson's, which could be an environmental toxin, which could be a bacterium, which could be an industrial chemical, a heavy metal, a number of different things, right, or a combination of of these. Right?

It's interesting because a lot of the environmental toxins that are implicated in Parkinson's actually affect your microbiome. And so I think

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

Sarkis Mazmanian
Yeah. Is is it is it that the toxin affects the microbiome, which affects the body, or is the toxin affecting the body directly by... That's micro... Again, we don't have the... Those answers.

Right? But that being said, so if if you, you know, again, look at... You know, again, let's just call them just trigger... All those triggers. Maybe the trigger's in the gut.

Right? Because, yeah, we ingest a lot of things. Right? I mean, our skin is relatively inert. Obviously, we inhale molecules, but the vast majority of the molecules that contact our body, that go into our body, come in through our gut.

Right? And so that's where the trigger is. And so this hypothesis is that that initial pathology... And by pathology in Parkinson's, it's aggregation of a neuronal protein called alpha synuclein. Right?

So for the... For those of you that don't know, alpha synuclein is a neuronal protein. It's found, again, expressed by our neurons, our nerve cells. It has a function in those nerve cells. But what's interesting about this protein is that it it tends to clump, and when it clumps, it builds up into cells.

And if the cells can't get rid the clump, eventually the cells die. That's the neurodegeneration part. Right? The nerve death part of of Parkinson's. Similar...

Different protein, but similar concept in in Alzheimer's disease. And so the hypothesis goes that there's a

Dr. Mark Hyman
trigger

Sarkis Mazmanian
where the nerve cells are dying first in the gut because of alpha synuclein aggregation. And that's why you're seeing the constipation first because, again, you

Speaker 3
know, neurons help

Sarkis Mazmanian
us think and and sense and and all the other... Remember.

Dr. Mark Hyman
Motility of your gut is dependent on the nerve. Right.

Sarkis Mazmanian
That's right. Right. And so, you know, our our intestines, as you just said, you know, push contents through because our nerves are telling our gut muscles to contract. It's called peristalsis. Right?

So if those nerve cells die, then the muscle, you know, contents sit. Takes longer. That's constipation. Right? And so, again, this is the hypothesis.

And what is... You know, again, the extrapolation of that is that that's why the constipation comes first because the nerve cells may be dying in the gut first in some people before they start dying in the brain. So the question then is, how we start the conversation, is how does that signal get from the gut to the brain? It could be a number of different paths. I think inflammation is is is one of the most likely, but the nervous system itself is another one.

Because what's very interesting about alpha synuclein, this neuronal protein that aggregates at clumps, is we know that that protein can move from neuron to neuron to neuron. Right? And so it can actually... Like, there's like a highway of nerve bundles. I mean, we know there's a highway of nerve bundles connecting our gut, our brain.

Maybe, you know, absolute kidney is just using that highway. It started... You know, it was triggered in the gut, but it's using that highway to get into our brain. And that's why... And that process takes years, and that's why the movement disorder comes years later because that process then migrate to the brain and then kill enough neurons in the brain for the movement disorder.

Right? So, again, this is a hypothesis. I think there's a lot of evidence in people.

Speaker 3
It's interesting.

Sarkis Mazmanian
It's it's almost irrefutable that this can happen in mice because, again, we can trigger these events in the gut and see pathology in the brain. So it can happen, And that's where the frontier of Parkinson's research, at least in terms of gut brain connection is, is to try and understand, you know, is there a gut first origin in some cases of Parkinson's? And if it is, Mark, I think this... You know, again, know, I mean, it does very important knowledge, but I think this is really an opportunity. Right?

As as I mentioned earlier, it's much easier to intervene at the level of the gut than it is to intervene at the level of the gut. Yeah. Right? So if we can identify other people, identify them early enough in their disease, I think there's a good chance in the next five, ten years, we'll have interventions. So, hopefully, this is an aspiration.

Hopefully, stop Parkinson's in its tracks in the gut.

Dr. Mark Hyman
Yeah. It's so it's so important what you're saying, and I think that that the the whole sort of understanding of how, you know, these neurologic conditions are not just brain disorders. They're systemic disorders that affect the brain. Martha Herbert, who's a pediatric neurologist, wrote a paper about this to call it autism. Is it a systemic disorder that affects the brain or a brain disorder?

It's... And and her hypothesis is it's a systemic disorder. And I and I clinically observed that too and whether it's with Parkinson's or autism or any host of a number of conditions. You know, you you can't leave the gut out of the equation. It's almost like, you know, functional medicine which is what I practice is sort of the clinical application of this approach of systems or network medicine.

We always start with the gut. It's like whatever you're doing, like if there's a problem, generally start there and see if you if you help normalize the microbiome as best you can, is hard to do, but you can. What happens? And and often people will have pretty significant results. And even without any digestive symptoms, which is kind of the other thing that people don't understand is you don't have to have digestive symptoms to have dysbiosis or imbalance in the microbiome that causes systemic effects.

And I just... I recently had a kid who... With with Asperger's slash sort of on the spectrum of autism, and he had pretty bad behavior and and very hyper and and troubled with, you know, language and in in school kind of reading, writing, and stuff. And and he turned out he had very high levels of folate receptor antibodies which are triggered by a cross reaction to casein dairy. And and this is sort of well described in literature.

And, you know, the treatment was a form of folate called leucovorin to bypass this step and to activate this brain folate receptor. The kid also had fungal overgrowth in his gut. He also had gluten sensitivity. He also had leaky gut by objective measures that we tracked. And so we just kinda treated all these things and the mother sent me a text.

Well, my kid's normal and he was amazing. You know, like, and I... You know, we don't see that every day, but it's, you know, it's not and it's not that every kid with autism or ADD or Asperger's has this particular pattern. It's just that that there's a way in to just understand these things on an individual basis that takes into account that the gut plays a big role, that these things play are all interacting. And so I think that your work really highlights that, that these are...

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

Sarkis Mazmanian
Can I ask, so how long in your practice for those cases where you have seen improvements? How long

Speaker 3
does it usually take?

Dr. Mark Hyman
It can be it can can be days. It can be days. It it can be quick. Like, it's not long. Like, it depends on what's going on.

Sometimes there's more durable problems, sometimes kids have other issues, sometimes there's heavy metals, or sometimes there's there's things that are harder to treat. But when it's the gut and that's the problem and you reset it, it's quite, you know, it's quite amazing. And and there's often some trigger. Right? Like you said, maybe there's toxins that cause changes in the microbiome or maybe there's gluten which causes a leaky gut.

We know from Fasano's work at Harvard that that you know increases zionulin that causes increased permeability in the gut. So there's enough there there in the literature to kind of put the dots together. And you know, the art of medicine is really what I do. Science of medicine is is is great to kind of inquire and to dig in and to tease apart these things. But at the end of the day, are suffering out there.

And and this doorway through the gut, you know, is is is kind of interesting. And I I'd kind of like to spend some time hearing your thoughts about you know, what's happening out there in the space of of quote treating the microbiome, testing the microbiome, probiotics, you know, personalized probiotics, symbiotics, prebiotics, you know, polyphenols. I think that's a whole another category. So I I think, know, we're we're sort of... I feel like at the beginning of this dawn of the microbiome era, even though I've been doing this for thirty years with the training that got it.

It's still like it's still kind of like a very, you know, it's a very complex area. And I think we're just being to understand it. So I'd love to hear your thoughts about, you know, people listening. Well, what do you do? Like, how do you how do you create a healthy gut?

And how do you deal with maybe finding out if your health issues are caused by your microbiome? And then what do you do about them if you find them?

Sarkis Mazmanian
I'll I'll start with with sort of the commercial approaches. Right? So you go online, you can find a number of different companies that will, you know, for some amount of money, test your feces, you know, test your... You you send a fecal sample, they'll test your microbiome, and then they'll recommend a set of probiotics because they'll say, okay. You deviate it from what is quote unquote healthy profile...

Microbiome profile, and we can get you back back on track. I don't believe any of that, to to be perfectly frank. And I'll say that just simply because I know literature. I know the state of the art in the field, and there is no one way. There's no way to look at a microbiome and say, you're healthy or you're not healthy.

Right? Absent, like, some, like, obvious pathogen or some obvious toxin, which is not what we're talking about here. Right? And so so, you know, I'm I'm more than skeptical. I I think I just I just don't believe that that's possible because I I don't...

The science doesn't pack that. Right? So what are the things that that we can do? I think the things we can do are largely what your grandmother would have told you anyway, right, is eat a healthy diet, make sure you get a lot of sleep, good quality sleep, right, exercise. There's a lot of literature I'm sure you're familiar with on on exercise and the and the microbiome.

Right? Elite athletes have, you know, very interesting microbiome configurations. And then the other one that I don't think enough people talk about, but there's a fair amount of literature as well, is managing stress. So stress, this is the brain to gut connection, right, changes your your gut profile. Right?

So if you can do all those easier said than done, then that's, you know, I I think, you know, the baseline. And those are foundational and durable ways to keep your microbiome healthy. Right? So, again, if you're eating plant based diets, diverse plant based, you know, diet, lots of lots of fiber. You're feeding...

You're giving your mic... Gut microbes the things that they love to eat that are gonna flourish. Right? And again, you know, sleep, exercise, and stress. In terms of of actual, like, supplements or or let's just call them interventions.

Right? I think using using human milk oligosaccharides, It's another way to feed your bacteria things that they they like. You mentioned polyphenols. Bacteria love to feed off polyphenols. Right?

You know, like in, you know, green tea or coffee. Right? But other, you know, certainly other other sources as well. What I'm, I guess, maybe more on the fence about are probiotics. Right?

I mean, this might be the frontline. This might be, like, the most obvious. Right? But but the vast majority, almost all probiotics that are commercially available to us were developed decades ago. They cut their lactic aspect.

They come from milk and dairy products. Right? They don't come from the human gut. They they haven't, you know, evolved to be able to network with our bodies in ways that are indigenous, our our, you know, native gut microbes do. Right?

There are a couple of products now on the market that are human gut microbes that are commercially available. Right? And so I think those are more likely to be able to, you know, have an effect size, have have an impact on our biology. But I think this is the future, and and and I know more and more of these, you know, let's call them again next generation probiotics. These human derived organisms, not dairy product organisms, are gonna come online.

And I think that those are going to have a better chance of improving gut health and then, obviously beyond the gut immune metabolic neurological improvements as well.

Dr. Mark Hyman
I mean, are now prescription poop pills for C. Diff. Right? So you can you can actually take a quote a human poop pill. Right?

Sarkis Mazmanian
There are FDA products for for C. Diff. Right? But I see... I...

So what we're talking about in terms of C. Diff are clostridium difficile infections. Right? And so these are, like, these blooms of organisms that really cause lots of of gut damage. And they often are resistant to antibiotics, or they can become resistant to antibiotics.

And so what... I I think the the medical literature is very solid on it. There's like 50,000 or more fecal transplants for for C. Diff. Cholesterol deficiency infections is that when you replace the microbiome of a person that has this infection with a healthy microbiome, the fecal transplant therapy is better than any f...

Any other FDA approved therapy, any antibiotic.

Dr. Mark Hyman
Dramatically. Dramatically.

Sarkis Mazmanian
Yep. Over ninety percent success rate, which most FDA approved drugs don't work in ninety percent of the people that take them. Right?

Speaker 3
Not even close.

Sarkis Mazmanian
Yeah. It... It's more like forty, fifty percent. Right? And so I think that's a success story.

It's clearly a success story. Right? But that that environment of, you know, like this bloom of a of a weed, if you will. Right? You know, that's that's killing all the flowers around it.

That... That's a unique situation. Right? Again, seed infections are a handful of other bacterial infections that were essentially putting out the fire with a fecal transplant. You know, I think it's it's a miracle.

I think it's a success story, right, for for the microbiome research. I'm not sure how much that translates into autism or Parkinson's or or Crohn's disease. Right? Because those studies are being... You alluded to them.

Right? And we still haven't, like, cracked that code. Right? We still don't know what the... You know, what is the optimal donor?

How much do we have to dose? How often do we have to dose? Do we need durable colonization? Like, you need to really change things back to mind, or can you just put it out and everything goes back to normal? All that's still being still being figured out.

Right? But the basic biology, the basic system of an infection versus a chronic condition are also very different. Actually, when you're trying to reverse an outcome. Right? So, again, let's just go back to Parkinson's.

I'm gonna contrast this with some these that previously in autism. That's why I asked about the time component. It was for this reason. Right? In Parkinson's, again, there's death of neurons in particular brain regions like the substantia nigra pars compact.

Right? There's there's... Once the neurons are are dead, there's just no going back unless you're gonna put stem cells into the brain or something. Right? Nothing in the gut is gonna make those those those nerve cells.

So there's there's actual damage, right, to the brain. Like, something is, you know, for lack of a term, broken in the brain. Right? So you gotta fix that. Nothing you do in the gut is gonna is gonna change that.

In autism, I think condition's a little bit different. There there is no obvious damage in the autistic brain. Right? To me, that's more of a chemistry issue than than a a pathological issue.

Dr. Mark Hyman
Oh, there's neuroinflammation on these kids' brains. Right?

Sarkis Mazmanian
Well, can see an inflamed... But again, inflammation is toggled back and forth. Right? You can turn on

Dr. Mark Hyman
Right. It's modifiable. Right.

Sarkis Mazmanian
Death of neurons is is is a one way... Is a cul de sac. Right? And so so anything that's modifiable, I think, now puts it into the context where a gut or, let's say, other interventions, we'll come with a gut, you know, has a chance of of improving or reversing symptoms. Right?

And so, again, you know, the stories I've heard very similar to to the ones you're you're recounting here are that, you know, gut interventions tend to have within days or weeks really dramatic improvements in acute behaviors. You mentioned aggression. I think that's a very obvious one. Right? Is that you can see this, you know, aggression or irritability phenotype change pretty rapidly.

What I'd like to see are longer term studies on some of those same individuals in a, you know, clinical setting where we can measure as much of those objective, you know, endpoints as possible. What I'd like to see are longer term studies because, you know, if a child is irritable, they're not learning in class. Right? They're not developing relationships. Right?

Same with... I would put anxiety in the exact same category. Right? If a person is anxious, which is prevalent in in autism. Right?

Or they have attention issues prevalent in autism. Right? They're not learning. They're not building social bonds or or relationships. And if we remove...

And this is a question. Right? If we remove those constraints, right, if I'm not so concerned about my GI issues or I'm not held back by my anxiety or I can focus better, right, over time, do I now improve on some of those other core autism traits? You know, do... Again, my relationships, are are they getting better?

Is my cognitive ability improving as well? Right? So I think you kinda need to remove that veil, if you will, first, and... But then it takes time to learn. It takes time to develop, you know, those social skills.

Right? And so so, again, I think that's still a gap in the... In in in at least the medical literature is what are the long term benefits? Right? Not just the acute benefits like aggression.

What are the long term benefits in terms of of social engagement, cognitive improvements? Again, just learning in school, so on and so on.

Dr. Mark Hyman
Yeah. Well, this whole field is so fascinating to me. And I think, you know, your work is really looking at how the future is really about, you know, personalized approaches. It's it's targeted. It's it's not just shotgun approaches.

Take this probiotic, everything's fine. So it's... I think that that that's kinda what we're gonna learn more and more about is how do we create personalized medicine in general, and how do we create personalized microbiome treatments, and personalized treatments for different conditions, and deal with the multifactorial nature of things. It's not just one thing sometimes. So it's it's kind of it's kind of an amazing moment to be in medicine, I'd say.

And and I think, you know, for people listening, the basics go. Right? Stay away from drugs that hurt your gut. Like, don't overdo antibiotics and acid blockers. You know, try to breastfeed if you can.

You know, try not to have a seizure section. We can avoid it, you know, for a baby. You know, do do eat a wide variety of plants like this. Somebody says 30 plants a week to actually get a diverse level of microbiome support from fiber and polyphenols. That all works.

And I think, you know, there are there are doctors out there like me who are kind of on the edge and doing things experimentally, but we try not to do things that are harmful and try to be supportive. And and and we do see remarkable changes across a spectrum of diseases by by treating the gut. And your work has really been a lot of the leading light in helping us see that there's a there there, that there's something actually going on and and kind of proving unequivocally that, you know, this is not in people's head, that this is probably in their gut.

Sarkis Mazmanian
So Yeah. Again, you know, microbiome is like an organ, if you will. Right? You know? And they're just...

It is foreign. It is a foreign organ, but it has the metabolic capacity. The microbiome has the metabolic capacity of the liver. It has the same mass as the as the adult brain. Right?

I mean, this is an organ in our body. It just comes from from the environment. Right? And, you know, one of the things that I that I I... You know, when people ask for it, what can you do about your microbiome?

Again, I think that is, you know, as we just talked about, I think there's a number of things you can do. But I always try and tell people, get ahead of the problem. Right? The microbiome is not a pharmaceutical. It's not a drug.

It may be someday, but it isn't today. Right? So we still... There's a lot that we still need to learn about the microbiome to turn the microbiome into drugs or to drug the microbiome directly, which is something we didn't talk about. I think it's also quite interesting.

Right? But because the microbiome sort of tunes our body, all these different systems, it wasn't designed to reverse disease. We're trying to engineer it to do that, but it wasn't designed to do that. Right? So by getting ahead the problem, what I mean is don't wait till you have diabetes before you stop...

Before you start taking, you know, your your gut health seriously, or don't wait till you have, you know, any condition before... Or cancer or any condition. Right? Is, you know, there are things you can do today to improve your gut health, to improve your microbiome health. And the payoff is long term is, you know, is your health in in, you know, the decades that are still ahead of you.

Right? And so I think prevent... That's not something we don't do well enough in this country, but the microbiome is is an avenue or is a test case where I think we can prevent a lot of adverse health outcomes in later years by taking care of our microbiomes now.

Dr. Mark Hyman
Well, that's that's a beautiful place to stop. Thank you so much, Sarkis for your work. Everybody who's listening wanna learn more about his work, can go to Sarkis, sarkis.caltech.edu and learn all about his research. I hope you get lots of funding and get lots of support because what you're doing is so important and I think the faster we can learn about this, the better we can do a job of helping people recover from some of these really tractable chronic illnesses that often start in the gut.

Sarkis Mazmanian
Thank you, Mark.

Speaker 3
Hey, everybody. It's doctor Mark here. I'm so excited to share that my new book is officially available for preorder today. After more than thirty years of practicing medicine and caring for tens of thousands of patients, I've written the book that brings everything together that I've learned about helping people get healthy and stay healthy as they age. It's called a 100, what to do today to live a 100 healthy years.

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Dr. Mark Hyman
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