The Hidden World of Microbiomes with Dr. Amy Proal

That's the strategy that's used in a number of, of conditions or where people treat microbiome imbalances is use an antibiotic to knock down the bad players, bring probiotics in at that point to bring in the better players, right? So the timing there matters.

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Our mission is to decode the neurobiology of flow and cognitive peak performance, access the minds of maverick scientists, groundbreaking innovators, and world-leading experts to understand what it takes to achieve ultimate human performance so you can feel your best, perform your best, and accomplish your boldest goals. I'm your host, Ryan Dorris, and together with bestselling author Steven Kotler, I present to you Flow Research Collective Radio. Dr. Amy Proal, welcome to Flow Research Collective Radio. Really great to have you here.

Thanks for having me.

Alrighty, so first off, I'm going to just give you an intro so that the listeners here have a sense of your background and the, and the work that you do. So you are a microbiologist who studies the molecular mechanisms by which bacterial, fungal, and viral pathogens dysregulate human gene Expression, Immunity, and Metabolism. And your work has examined how dysbiosis of the human microbiome and the human virome can contribute to chronic inflammatory disease processes. And as a member of the research team at Autoimmunity Research Foundation, you've authored papers and written book chapters for organizations like the Craig Venter Institute and the Autoimmunity Network, and you've lectured at the NIH and numerous USAID conferences internationally. And you graduated from Georgetown University in 2005 with a degree in biology, and in 2012 obtained a PhD in microbiology from Murdoch University in Australia. And your graduate thesis focused on autoimmune disease reexamined in light of metagenomic concepts. So I want to start off just by asking you what the biggest shift for you was, or the biggest learning for you was, in completing your PhD. And it may be completely unrelated to the topic you did your PhD on, maybe a lesson around, you know, the philosophy of science, or a personal lesson, or it may be related.

So my PhD focused on basically tying together early research showing that chronic infection Infection with bacterial pathogens, viral pathogens, fungal pathogens, and chronic infection with many of those organisms probably contributes to a number of diseases that we call autoimmune. Also, that the activity of those single pathogens, for example, a single viral or bacterial pathogen, also have a profound impact on the activity or balance of the collective organism ecosystems in our bodies, the human microbiome. One of the greatest takeaways I had is that when you are looking at inflammation in a condition or in a person, it is very important to start to tie that inflammation to the activity of the organisms in the human body or to some of the infectious agents and pathogens that we unfortunately become infected with. Mm.

How come that's important? Curious if you could elaborate a little bit there.

It's very important for treatment is the main reason, because if you think and you, for example, in ulcerative colitis and Crohn's disease would be a good example. These are GI diseases that are characterized by inflammation of the intestine or the gut, right? And early on, research teams were just measuring that inflammation. And with that model where you're just measuring the immune response and saying, yes, there's, there's a lot of inflammation going on here. What you do for treatment is that you basically shut down or stifle the immune response. So what became the standard of care for patients with those illnesses were immunosuppressive drugs that knocked down T-cell function or the activity of other immune cells in those patients. But a little after that, teams began to collect samples from those same patients and say, wait, we're learning that there are more and more and more organisms interacting, communities of organisms in the human gut, basically the human microbiome environment, which are trillions of interacting bacteria, viruses, and fungi that have these rich communities in the gut and intestine, and now many other parts of the human body, we know. Teams began to say, are the activity of those organisms connected to the inflammation we're measuring in Crohn's disease and ulcerative colitis? Now, That research is moving forward. What happens is that the therapeutics change because now you can target potentially the organisms that may be actually at the root of that inflammation instead of having to completely shut down the immune response itself. That leaves the person in much better shape because those immunosuppressive drugs have really bad side effects because otherwise you really don't want a depleted immune system. In other words, By going to that sort of root cause level, that may be organisms at the root of inflammation in chronic disease, you can come up with treatments that are less immunosuppressive and less harmful for the patient.

That makes total sense. So it allows you with precision to address the root cause rather than just to sort of try and shut down the whole system, and as a result of doing that, potentially help the symptoms a little bit, but also knock down everything else that's good.

Exactly, because that's one of the things, for example, if you're an ulcerative colitis patient and you get on the immunosuppressive drugs, you're basically on them for life. You need to take them and manage them. And often people require higher doses to keep that inflammation down. But there's now potential that if you address the microbiome that may be at the root of inflammation, you may actually be able to just improve that, get off the medication, get back to a life where you don't always need to be on medicine. So, yeah. Hmm.

That's really helpful. So I want to actually zoom out a little bit and touch on the microbiome. In the peak performance world, people hear things like the gut-brain axis mentioned a lot. People hear a lot about the microbiome. Probiotics are constantly recommended to everyone, but I'm not sure that a lot of people actually understand what the microbiome is or what the implications of a healthy microbiome is for key facets of performance like cognitive performance or a well-regulated autonomic nervous system. So could you give us a breakdown of just what the microbiome is in the first place and then speak a little bit to, you know, why it plays an important role on the different elements of performance?

Sure. So the microbiome, in simple terms, are the communities of organisms that live in and on us, and these are extensive ecosystems where you have many bacterial organisms, fungal organisms, and even what are called bacteriophage, which are viruses that infect bacteria and by doing so modulate their activity. You have these organisms that are basically interacting together and signaling together in different areas of the human body. When we first started to study the human microbiome, there was a transformation in being able to understand what was going on with the microbiome around the year 2000. Because before that, when scientists were trying to find an organism in the human body, they basically had to try to culture it, which is a very difficult procedure. Picture your old-school scientists with a petri dish and a white coat. They're trying to culture the organism and make it grow in that petri dish. That was the main way that we would find bacteria in the human body. But around the year 2000, The technologies that were being used to sequence the human genome, which were sequenced then, started to slowly be turned onto the organisms in the human body as well. Those are technologies that identify organisms in the human body based on their genetic sequences by using computers to identify their genetic sequences and pull together what's in a particular sample instead of the need for culture. As soon as those computer-based tools were brought into the study of microbiome, it blew up. There were just so many organisms that the culture techniques were missing, so that there was this era of exploration where first we started to turn those tools onto the gut, for example, where we knew there'd be bacteria, right? And we found there were many, many more organisms than we thought interacting in the human gut, but then also the mouth, for example. The mouth, the oral microbiome, has a huge number of interacting organisms in the mouth. But then Increasingly, we've turned our technologies, these same computer-based tools, onto other body sites even, for example, the bladder or the pancreas or even the blood now. We realize that in most people, even those body sites are not sterile. They usually do have some organism in them. For example, the lung microbiome is another big topic. There are interacting organisms in the lung. We now understand a couple of things. We now understand that these vast organisms in and on us, we now understand that these ecosystems exist beyond just the gut and the mouth, and that they're actually organism ecosystems in the lung and other body sites, and then their activity has great importance because first of all, there's just a lot of organisms so that their genomes outnumber ours. In a sense, if you're considering What is human? You think, okay, we have our human genes and you can count the number of human genes that any particular person has. Well, we have more microbial genes in us because of these organisms than we have human. We're outnumbered by the genes and genomes of our microbial inhabitants. That's where people have tried to capture that by using, for example, the term superorganism. Some people will say humans are actually superorganisms, are the output of what we really end up doing is a mix of what our human genes are doing and what the organisms in us are doing and creating. And that comes down to the fact that organisms create many different products, many different proteins as part of their metabolism. So a lot of the molecules that end up in our human signaling pathways are actually microbial in origin. So in other words, our organisms are completely, completely intertwined with our human signaling. So when something goes wrong in disease or performance, you have to immediately think that there's probably, it's probably a mix of issues with the person's human genome, how they were set up, but also there can be this influence from the organisms that they have on that signaling. And what's cool is right now we are, you know, we're playing with technologies, for example, CRISPR, that might be able to edit the human genome. That's hard. We may get there, But there are— it's actually easier, and there are more ways to switch up your microbial organism populations. And so there's a lot of therapeutic potential in the possibility that you can sort of maybe improve the composition of organisms in a particular body site that's contributing to your signaling in a way that can up your performance or improve your health.

Well, the, the point about genes within the microbiome being categorically distinct from human genes is fascinating, especially given that there's more of those genes. What is it that makes them distinct from human genes?

They're, they're just foreign, but they have, you know, their, their similarities. In other words, so a good example would be their dopamine. For example, our human genes can create and code for the expression of dopamine, a signaling molecule. But there are bacteria that are often part of these microbiome ecosystems that also create dopamine as part of their lifestyles. When someone has an imbalance of dopamine signaling, you can start to wonder if there can be a microbial component to that in addition to just what their human body is doing. In other words, some of the microbial genes are foreign genetic material, But they're— they've coexisted in humans for so long that they're just so intertwined with us that, that at the end of the day, it's hard to separate out their activity.

Fascinating. Really interesting. I've heard probiotics being described in the past as like dropping off a group of 20 people in the middle of Manhattan and assuming that they're going to be able to clean up the entire city and all the people within it. And I think it's— and it's— that example is alluding to the vastness of the microbiome relative to taking something like a probiotic. And so I'm curious what your thoughts are on probiotics and what positive impact they can have on the microbiome and thus performance.

Mm-hmm. So I'm a PhD researcher, not an MD, so I don't have direct medical advice. But from a PhD perspective, probiotics do make a lot of sense. But I do think that probiotics need to be incorporated into a treatment plan with other elements. Because if you, for example, have a very imbalanced gut microbiome, we often use the word dysbiosis to mean that. When we're talking about a microbiome community, it's a little like the rainforest or something. You could have a part of the rainforest where animals are eating different animals and there are all these different relationships happening, but those relationships are happening in balance so that the community is basically stable and flourishing. Now, with the human microbiome, it's similar. You can have many organisms and some of them are, in a sense, attacking each other, infecting each other, but it's happening within a state of balance and all the relationships are playing out so that the overall state of balance is okay. But sometimes, Good bacteria, but bacteria that are more important for health-promoting processes become diminished and bad organisms take over a microbiome community. And that can lead to a general collective shift in the composition and activity of the organisms there. And we refer to that often as dysbiosis, which basically is like an imbalance of those ecosystems, right? So if you take a probiotic, your gut is in a state of dysbiosis, in other words, the organisms there are already out of balance, the probiotic may have a little trouble figuring out how it's going to fit in so that you just put a new influx of organisms into an already confused community. I would think that you want to think through at least a couple of steps, in my opinion, first. One is that a consideration for chronic symptoms or just health is that the barrier of the gut when it comes to the gut microbiome is important. If there's an imbalanced microbiome community in the gut, that can lead to inflammation that causes the lining of the gut to become worn down. In simple terms, that's sometimes referred to as leaky gut. What can happen then is organisms that are in the gut leak into the blood, and there they stimulate many more inflammatory processes that are detrimental for the patient. One of the things I think is important with probiotics is you want to make sure the gut isn't too leaky before you take a probiotic, because you then run the risk that you take a probiotic and it just becomes some of the organism that leaks into the blood, right? Because even a beneficial organism, you really don't want ending up in your blood, right? So there are some supplements that I know some people take to sort of strengthen the gut barrier lining to work on that. In other words, sort of working on the, the lining of the gut itself and the integrity of the gut itself makes sense to me before using probiotics. I think you want to make sure that you take care of some potential, any potential pathogens in the gut as well. So sometimes depending on the person, there may be an overgrowth of bad bacteria or a pathogen in the gut, like a virus or something like that that's detrimental. And you, it's probably makes sense to try to deal with that first, to use some kind of antibiotic or antimicrobial to knock those bad organisms down first before you then repopulate with the probiotic that's better, right? That's the strategy that's used in a number of conditions where people treat microbiome imbalances, is use an antibiotic to knock down the bad players, bring probiotics in at that point to bring in the better players, right? So the timing there matters.

That makes total sense. It's a great point as well around leaky gut and the importance of the gut lining, irrespective of whether the additional components going into the gut are positive or negative, you still don't want them to leak into the bloodstream.

Yeah, exactly.

And then to switch gears a little bit to inflammation, although obviously all of this is related, could you give us again just a foundational breakdown of what inflammation even is? It's another one of those words that everyone hears but is rarely actually clearly defined for people. So I would love just for a breakdown on inflammation, when it can be good, and obviously when it can be not good and what impact it can have, again, on cognitive function and other facets of performance.

OK. Yeah, so inflammation really refers— it's a broad term that means that any component of the immune system, mostly the cells that comprise the immune system, are activated in a way they otherwise would not be, usually under conditions of more balance, right? So you have with the immune system, you sort of have two branches. You have the innate immune system, which is sort the very primal part of the immune system, the most basic part of the immune system. And those cells tend to recognize most foreign organisms, foreign chemicals, toxins, and they'll respond to those. So those are your— you have neutrophils, mast cells, and often macrophage cells. Those are these immune cells that will basically, if something's wrong, for example, let's say the microbiome is not in good shape, or let's say someone has a mold exposure and there's still some issues with mycotoxins or something, those cells will kind of be recruited in to be like, there's a problem here, there's a problem here, there's a problem here. And they— that signaling actually results in inflammation. They're more active than they otherwise would be right now. What happens is those cells will sometimes— will signal sometimes when it becomes enough of an issue to what's called the adaptive immune response. And those are your T cells, your B cells, your bigger players that really come in when there's enough of an issue, they're more specific. The innate immune cells, it would be a little bit of equivalent to an army back in the medieval times. You have an army and you have the foot soldiers that go first and the archers, and they're just trying to target whoever they can. But then at the back you have the specialized cavalry. Well, those are your T cells and B cells that will come in and identify very more targeted pathogen threats. For example, a specific virus or a really specific issue. If those cells come in and that inflammation is not resolved either, you're going to get perpetual signaling on the part of those cells and they will remain active as well. Inflammation could really result from any combination of those different immune cells. You might have just innate immune activation, you might have some T cells involved depending on the nature of what's going on. Over time though, that can be basically very exhausting for the immune system. You don't really want your cells to always be perpetually active, that burdens you, that's energetically demanding. That being said, you did mention though, you do want these cells to function. For example, if you get COVID, if you're infected with SARS-CoV-2, you do want a robust inflammatory response in a sense. You want immune cells to come in and recruit it. You want them to recognize the virus. You want them to target the virus. You want B cells and T cells called in. There are times when there's actually a problem that you want inflammation in a sense to occur. For example, In some infections, you'll get a fever. And there's actually some thinking that a fever within limits should not necessarily always be taken down with Motrin or with other therapeutics because the heat from the fever sort of, you know, is almost a part of the reflection of the inflammatory signaling that actually means your body's kind of heating up to go against the threat in simple terms, right? So you don't always want to stop your immune system if it's combating battling something, but there's a, there's a happy medium, right? And you certainly, people have problems when they may have an issue that's not being addressed. For example, their microbiome in the gut is just imbalanced. So you have this perpetual recruitment of inflammatory cells. That's, that's not doing anyone any, then you just have chronic inflammation, right? Long-term inflammation that goes on and on and is energetically demanding and detrimental. And depending, you know, When you talk about cognitive function, there's many routes by which that can affect cognitive function. If we're going to talk about microbiome, one of the most direct routes that that can happen is via the vagus nerve. The vagus nerve is a very important nerve that innervates from the brain, innervates every major trunk organ of the human body, so the gut, the lungs, different body sites. If it senses inflammation in those body sites, it will convey a pro-inflammatory signal to a region at the back of the brain called the dorsal brainstem. That can cause on that side of the brain inflammation of the cells there called microglia, which are brain immune cells that can become inflammatory. If those cells are active, those microglia, you get what's called neuroinflammation. It can also lead to autonomic problems, as we mentioned before, because the brainstem has important nerve bodies that control the ability of a person to move correctly from sitting to a standing position, to not get dizzy when they're moving. So if you have a sort of pro-inflammatory signal from vagus nerve affecting the brain that way, you can throw off those autonomic signaling pathways as well. And you're starting to see someone who now has central nervous system issues that can contribute to problems with function.

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Hmm.

With respect to the vagus nerve, you know, picking up on and then accelerating inflammation is one way that you could potentially measure that through heart rate variability as a metric. I'm assuming that would be, you know, an indicator.

Yes. Yes, people do measure vagus nerve activity through— and I'm not an expert in this, there are physiologists that do this more than me— but heart rate variability is one of the metrics that can be associated. So vagus nerve gets involved in, in regulating sympathetic versus parasympathetic tone. Sympathetic being sort of our flight-or-fight response. So we want, you know, and these are evolutionarily conserved responses. If you were back in the jungle as an early human, you need to be able to run if an animal attacked you. So you have this ability to, to spark what's called sympathetic nervous signaling, where you can really move quickly in response to a threat. And that can be very helpful for sports now and everything, but you don't want that to be signaling at night when you're trying to go to sleep. Then you actually want a different tone called parasympathetic, which is more, a more of a relaxing type of nervous, uh, tone. You want that happening then. So Vagus nerve gets involved in the control of those functions, and because of that, heart rate variability will change based on parasympathetic or sympathetic tone. So you can use measures of heart rate variability to try to understand where you're at with that signaling.

And then you mentioned neuroinflammation as well, um, related to glial cells. To what degree— and again, I know you're a researcher rather than a clinician, but just based on your awareness of the research, to what degree do people generally suffer from neuroinflammation? Do most people have some level of neuroinflammation that is potentially having a negative impact on their ability to focus? And as a result of that, maybe their ability to access a state like a flow state?

Yeah. I mean, I'm not sure. A lot of the neuro— to really measure neuroinflammation correctly, you need to do that right now in a research setting in what's called a PET scanner. So you can go to— we do— our research team have some studies running on neuroinflammation right now. So you get in a scanner, and they will inject you with a radioligand that will tag a protein that recognizes activated microglia in the brain. and that circulates through you while they image you in a scanner, a specialized PET scanner that can pick that up in the brain. And those PET scanners though are only available now at sort of a limited number of research centers. So in other words, you can't really go as a patient to your doctor and say, give me that neuroinflammation PET scan, right? So for that reason, I would say we don't necessarily have the best, just sort of gold standard measurements of neuroinflammation in the average person, because we tend to only invest and do that research when it's a condition, MS or Alzheimer's or something like that. That being said, there are just many elements, like I said, that would suggest that people would have low-level neuroinflammation if any of what I had just described was happening in them. As I mentioned, you can literally see a route via which the gut microbiome is imbalanced and now you have perpetual immune cells that are saying, hey, this isn't great here. There's imbalance here. There's too many bad organisms here, and that inflammation will be sensed by the vagus nerve and conveyed to the brain. At the very least, it would logically result in some neuroinflammation. Again, you may not have a serious neuroinflammatory disease, but you may have elements of that. That's entirely feasible to me just from a basis of logic.

What are some ways that people can keep the negative forms of inflammation that are more chronic low so that they are at less risk of having impaired function as a result of inflammation that may be not severe to the point of needing to go to the doctor, but lingering in there and inhibiting performance.

Yeah. I mean, again, I'm not a doctor, but from a research perspective, you would obviously want to try to keep especially the gut microbiome in good shape. There are a range of diets and different therapies out there that people use to try to do that. I think that exploring those possibilities makes sense. A lot of times people eat more paleo or keto often because sugars and carbohydrates will feed— they generally feed bacteria. Bacteria in your gut, sugar and carbohydrates, they metabolize quickly. They can just burn through that and that's the fuel that they need. Sugar is an easy fuel for us, but it's also an easy fuel for our bacterial and fungal organisms. If your gut microbiome is in a good place and the organisms are in a harmonious place, I would go ahead and eat some sugar. That's not going to be the worst thing. You almost want to maintain that community. The problem is if there starts to be overgrowth of bad bacteria, or for example, Candida or different forms of fungi that can be problematic, You don't want to feed that. So you, in some of those cases, patients will actually limit carbohydrates and sugar in their diet, pull those out, and go through a period where they, in a sense, in simple terms, starve those bad organisms so that they can't have access to the easy carbs and sugars, and then bring in some of the probiotics or other things like that to try to improve the gut, and then slowly work back to a point where they're eating more sugars and, and and other, you know, carbs. So in a sense, it— you kind of need to know where you're at in that. But you can see our diet can have a pretty big impact depending on, on, on where your gut health stands, right? So just alone, uh, food choices are one obvious area. But, you know, other things that I just think make sense from a straightforward perspective are, for example, I'm interested in hyperbaric oxygen therapy or just therapies that oxygenate the human body, I don't see any downsides in those because one thing we know is organisms that are like pathogen especially, which, and by the way, you know, pathogens, single pathogens, for example, the herpes viruses or bacterial pathogens, they can get caught up in these ecosystems. They can become players in certain people's health issues. They're big drivers of inflammation when they're actively signaling. None of those pathogens and bad organisms survive well in a highly oxygenated environment. It's a known thing that pathogens actually will induce sometimes what's called a hypoxic state. They'll actually, when they are causing disease, create genetic or signaling changes that make the area of the body they've infected have lower oxygen called hypoxia. So if you can push back against that and oxygenate the body, oxygenate tissues, you are making the environment less hospitable to negative organisms in a simple sense. So some straightforward oxygenation probably wouldn't hurt anyone either.

That's— yeah, that makes total sense. There's a group called the Amen Clinics, founded by a psychiatrist called Daniel Amen, with The basic philosophy behind it being that psychiatry is the one medical discipline within which the brain is not actually properly scanned or measured before treatment is made. And I know that one of the biggest interventions they recommend is HBOT or hyperbaric oxygen therapy, and they recommend that specifically as well to people with concussion. I've heard them recommending it to people up to daily, sometimes for months, to really rejuvenate deep parts of the brain that are starved of oxygen. To your point, to make an environment less hospitable to the bad things we don't want. That's a great recommendation. Then one of the final questions here, Amy, I know a lot of your recent research has been around long COVID. We've had lots of clients who know people struggling with long COVID or have been directly. And this is a question that most researchers are going to hate, and I know you're not a doctor, so everyone's aware of that, but I'll ask you the question anyway. So let's just say hypothetically you woke up with long COVID tomorrow morning. At this stage, based on what we currently know about the research that's been emerging since 2020 on long COVID, what would be your approach? What would be the, the way that you would go about tackling it?

Okay, so some of the major topics that we're studying in long COVID. The first one that is actually— it's disconcerting, but is unfortunately— there is growing evidence for this topic is that in at least some patients with long COVID, they're not fully clearing the SARS-CoV-2 virus. So the virus seems to be remaining in a low-level amount, and we call that a viral reservoir. In tissue. So for example, it clears from the blood, it clears from your nose where you get that nasal swab test done, so it's no longer in these obvious areas of the body. But a little bit of virus might remain in lung tissue, might remain in the tissue of the intestine, might remain in other body sites. And so that actually is pretty much one of the central areas of research right now. And for example, there was a team at Harvard that just showed— and the study still has to be reviewed— but they showed spike protein still in the blood of patients with long COVID months after initial illness. There's another team at Harvard that still showed SARS-CoV-2 in stool sample from patients with long COVID up to 4-7 months. Not everyone, but some of the patients were still shedding the virus. There's a growing body of research suggesting that patients may not be fully clearing the virus. If that's the case, The first thing you would want to do is, is just any kind of antiviral that makes sense. And I know that people— look, I don't know enough to actually be able to recommend that very specifically because, for example, there's a big push and we want to do this. We want to know, for example, what about Paxlovid in long COVID, Pfizer's drug, for example, that people are using to target SARS-CoV-2 in acute COVID. But there are a couple variables there which are we're not exactly sure how well Paxlovid Paxlovid works in acute COVID right now. We're not sure a 5-day course is even enough for acute COVID. But give or take, there's some capacity for antivirals to be something that you would try to keep in mind, maybe, although we need to do clinical trials for this in long COVID. There was one Stanford case history where a team— where a patient had long COVID. And then they were given Paxlovid because they got reinfected with SARS-CoV-2. And then their long COVID symptoms resolved. That's one case and there needs to be a lot more research, but it's a proof of concept that it benefited one patient. The other thing that I would say that makes sense to me to do is one of the sites of what we're calling SARS-CoV-2 reservoir. In other words, if the virus doesn't clear, that seems to be the most possible is the intestinal tissue. In other words, the virus gets into the gut of a good number of people, and some of it may be hiding out in the intestinal tissue of some patients. Now, if that's the case, you want to try to make the gut microbiome that we talked about before as balanced as possible. Because when the gut microbiome itself is well-balanced, those organisms sometimes create compounds that can make the environment less hospitable to pathogens. In other words, the healthy community creates certain molecules and the healthy community by itself is less inflammatory generally. You at the very least give the immune system a break. The immune system doesn't have to figure out the mess of microbiome in the gut, frees it up a little bit to maybe go after a little bit of that residual SARS-CoV-2 virus in the gut. Also, the leaky gut issue that we mentioned before, There's a condition called multisystem inflammatory syndrome that's very similar to long COVID in children, where certain children just get very ill about 4 weeks after acute COVID, and they just get a very huge hyperinflammatory response and sometimes have to be hospitalized. Well, there's a team at Harvard that did a study on those children, and they found that many of them, even at 4 weeks, still harbored the SARS-CoV-2 virus in the gut, and they still had spike protein leaking into the blood, as we mentioned before, but they measured a metric of intestinal permeability, or in other words, leakiness called zonulin. And they showed that was upregulated. And in other words, the intestinal wall was allowing the SARS-CoV-2 spike protein to sort of leak from the gut into the blood, and that was catalyzing the most inflammation. So potentially then, again, whatever you can do to sort of improve leaky gut, keep microbiome in better shape, antiviral, stuff like that, right? You know, anything along those lines. And the other last thing is that we know another trend in patients with long COVID and even acute COVID is that T-cell activity and natural killer cell activity is, is being depleted. So to the extent that you can do anything to just improve, and this is generally speaking, the immune response— and what I mean is actually immunosuppression not great. Trying to actually invigorate the immune system, trying to keep the immune system active, to keep T cell activity, natural killer cell activity in as best shape as possible, that might be helpful as well.

That's a super breakdown. I mean, thanks. Just one follow-up question on that. I've seen a new movement of people curing their long COVID through extended fasting and claiming that autophagy is clearing viral viral debris or the viral reservoir potentially that is lingering in the gut. So I'm curious if theoretically— I know there's not necessarily any clinical trials on that, but if theoretically that is a plausible mechanism of action.

I'm open to it. I don't know enough about the details of the— it's basically just very serious fasting.

Yeah, 48 to— I think the protocol is something like fasting for between 48 and 72 hours once a week for 12 weeks.

You know, it does seem possible that, that fasting at least would keep other problematic organisms down in the gut microbiome. Like we mentioned, there'd be less fuel for them, right? You have less sugar. You're also just keeping, I guess, without your body having to process so much food and you're just kind of allowing it to be in more of a detox state. That seems reasonable to me to sort of, like I said, One of the things you can try to do is to lift the burden off your immune system so that it can do some of the work and go after the virus or repair something else. It does seem to me that I could understand a mechanism by which eating less food and eating in a way that would not give easy sugar or stuff to organisms, that makes sense to me that it might be a better atmosphere for promoting that recovery. No, it seems to make sense.

Super. Final question, Amy, which is a question about a question that we ask all our guests who are researchers. We call it the research genie question. So if you were able to click your fingers and immediately have all of the gold standard research be conducted to answer any question that you, you know, often ponder, what would that question be?

How can we tell if there is a pathogen in human brain tissue in a living person.

Can you say a little bit more about that? That's intriguing.

Yeah. A topic I didn't really get into is that in addition to microbiome imbalances being tied to chronic disease, another huge topic is just the impact of single viruses on chronic disease. For example, in Alzheimer's, I'm not sure if you've seen, there's a Harvard team that's basically made a breakthrough discovery. Which they've shown in these really cool neuron-in-a-dish models that the amyloid plaque in the brain may not be a plaque with no function. It may actually function as part of the immune response that targets pathogens in brain tissue. In other words, you could have a virus in brain tissue and then the plaque forms around it, digests that virus, and that's why you get that amyloid plaque formation. There's a huge amount of research now in which people are actually trying to understand if pathogens are getting into the tissue of the brain more than we previously thought in MS, in Alzheimer's. If that's the case, it can be hugely important to potentially paradigm shift a lot of these diseases that we're talking about tied to cognitive function. But the hardest part is that in order to study brain tissue, you basically have to do autopsy studies. You have to wait until someone passes away and get their brain tissue. And then try to understand it and look through it. But there are many changes that happen after death. So what our constant focus is, is can we use other forms of neuroimaging, other technologies to be able to understand if a pathogen, for example, a herpes virus or even SARS-CoV-2, might be in a person's brain in someone who's alive.

Super interesting. Thanks for the elaboration on that. I'm glad I asked. And thanks so much for the time, Dr. Amy. Really appreciate it. This was just phenomenal and full of incredibly dense but also actionable and useful information. So thank you so much for taking the time.

Of course. Yes. All right. Thank you.

Hey, it's Joshua with the production team. It feels good to pummel your to-do list and free up more space in your life. On the subject of punching things, meet Krista Stryker. She's an amateur boxer, journalist, entrepreneur, and world-renowned fitness expert. Here's what she had to say about training with us at the Flow Research Collective. Quote: Before learning about flow, I felt like life was just kind of happening to me. I felt there was no real control over it, why sometimes I have good days and sometimes I have bad days. After completing Zero to Dangerous, my life is a lot more intentional now. Being in flow has helped me to complete my second book as a writer and prepare for my next fight as an amateur boxer, and I can't thank the Flow Research Collective enough for it. That's epic to hear, Krista. We're super stoked that you shared that with us. And if you're listening in and you want to take back control of your time, your work, and your mind, go to getmoreflow.com. We'd love to work with you to achieve your boldest goals in less time and with more ease. Again, just go to getmoreflow.com to get started. All the best.

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