Episode 117: The Hidden Microbial Drivers of Chronic Illness with Dr. Amy Proal

Adam Rinde (00:00):

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Adam Rinde (01:04):

Welcome back to The One Thing podcast. I'm your host, Dr. Adam Rinde. Today's conversation is one of those that I've been really looking forward to having. I'm joined by a repeat guest, Dr. Amy Proal She's a brilliant microbiologist and a co-founder of the Poly Bio Research Foundation. She's doing some of the most innovative and courageous work in exploring how persistent infections contribute to chronic illness. In this episode, we dive into how microbes, many of which live quietly in the body, may be influencing conditions like long covid, Alzheimer's disease, chronic fatigue, and even pots. They're doing this by impacting our mitochondria nervous system and immune function. It's a wide ranging and deeply important conversation that challenges conventional thinking. In medicine, Dr. Proal shares emerging science on how viruses and bacteria may persist in tissue and nerves, including the vagus nerve and how this persistence can drive inflammation, energy loss, and immune dysfunction. We also explore therapeutic approaches like low dose rapamycin, interferon modulation, and mitochondrial support. Whether you're a clinician, a patient navigating complex illness, or just someone who's curious about the root cause of disease, this episode will give you valuable insight into a growing body of research that's reshaping how we understand chronic conditions. Let's get started.

Adam Rinde (02:33):

Dr. Proal, welcome back to the One Thing podcast. It's great to be here with you again.

Amy Proal (02:38):

Great. Thanks so much for having me back on. I look forward to the conversation.

Adam Rinde (02:42):

Same here. The previous episodes were so well received and I go back to them all the time for referencing and share them, and it's just always a delight to get to speak with you. And it seems like every couple years we've been connecting and so much ground has been covered in those two years. It's just exciting to get into this.

Amy Proal (03:05):

I agree. It's a good thing that there's a lot of updates, which means that there's movement in this space, so it's great to come back on.

Adam Rinde (03:14):

So I thought we could start with just sort of a big picture update on the landscape of chronic infections and how they're relating to common chronic conditions and maybe not so common chronic conditions, especially I think you've mentioned a lot of work recently in the space of cognitive impairment or cognitive decline. So I'd love to hear just kind of a big picture update on things that you've seen emerge.

Amy Proal (03:44):

Yeah, it's a really important topic to talk about chronic infection across a wide range of chronic diseases, especially now in a time when I'm excited because there's more energy behind the, actually, first of all, admitting that we're living in an epidemic of chronic disease. In other words, we're really in a bad place and we've been in this place for a long time where the rates of most chronic conditions continue to increase. People often continue to get sicker with a lot of different chronic conditions at earlier ages. And so we're missing, and I think everyone knows this, a lot of the factors that are still contributing to a lot and a wide range of chronic conditions are just still being somewhat missed, at least in the most mainstream standard of care. And parts of what we hear about are like, yes, increased use of pesticides, chemicals, microplastics, all of these issues are definitely, I think absolutely probably driving rates of chronic disease and our big factors that we should be looking at.

Amy Proal (04:49):

So the exposome and all kinds of other environmental factors. But part of what I don't see as much in the discussion of chronic illness and chronic disease as I would like to see is chronic infection. And I think that part of the reason for that is just because to study the impact of chronic infection on a chronic disease, it actually takes a lot of research to be able to do it well. And so just in the last years, there's groups who have been able to really advance the methods needed to find pathogens. And by that I mean viruses, bacteria, fungi, even parasites, better in the tissues, sometimes even in the brains or central nervous system of people who have a wide range of chronic conditions. And really begin to tie not just the presence or absence of those pathogens in tissue or human body sites, but also the activity of those pathogens, the proteins they create, the activity and the ability of those pathogens, for example, to hijack our mitochondrial function, to alter the epigenetic environment, to drive even senescence or all kinds of processes that are basically issues that mix and match into a wide range of chronic diseases

Amy Proal (06:07):

And some of the most just low hanging fruit when we're talking about conditions that are increasingly tied to infection and conditions that continue to escalate and affect a number of people are basically Alzheimer's disease is just like a central one. So we've seen for a long time this basic paradigm in Alzheimer's where if you read a textbook or if you're still looking at that level of evidence, people will say that Alzheimer's disease is caused by buildup of this pathological plaque in the brain. The whole illness is basically due to that plaque accumulation, and we don't totally know why it accumulates. There are genetics that sort of predispose to more plaque accumulation, but not everyone has those genetics and there are people who don't. So genetics is part of the picture, but we're missing something else. And what I think is really key is that increasingly teams have started to link persistent pathogens, so viral pathogens, bacterial pathogens to the Alzheimer's disease process.

Amy Proal (07:09):

And really some of the most compelling work on that topic started in 2018 when a group at Harvard Medical School that we know well who is still working on the topic realized that the Alzheimer's plaque, this plaque building up in the brain might have a function. In other words, maybe it isn't just accumulating in the brain for no reason, maybe it's forming for some reason, maybe it's forming in response to something. And that was a key paper that this group at Harvard Medical School published in 2018 where they said, and this continues to hold largely, that the plaque could be an antimicrobial peptide, which is this basic part of the immune response that forms in response to any viral pathogen or bacterial or fungal. It's just a very basic component of the immune response that will form to basically control infection. And so what they did is they used neuron on a dish models and also studies in mice to show that if they put a herpes virus, which is a virus, that 90% of the human population harbors at least one herpes virus, right?

Amy Proal (08:16):

So commonly, and we don't clear those viruses, they persist in us across the course of our lives if we have them, that if they put a herpes virus into those models, the Alzheimer's plaque forms right around the herpes virus and in fact almost encases it and digest it in bleach. So in other words, the plaque is forming due to the infection. And that is really one of the beginnings of these paradigm shifts in Alzheimer's disease where it's like, ohoh, maybe we have the model wrong and maybe infection is at the heart of this. And so one of the studies and teams that's followed up on this that I think is a great finding is Ben Reed head's team at Arizona State University, and he recently published a paper where he showed the cytomegalovirus, which is one of these herpes viruses in the brains of patients with Alzheimer's disease, co localized again with Alzheimer's plaque.

Amy Proal (09:06):

But really key to the study is that he was able to get tissue from patients who unfortunately passed away from Alzheimer's, but he got their tissue and analyzed it, and he got tissue from several key body sites. One was the lining of the gut, other tissue was from this vagus nerve, which is this very important nerve that basically innervates every trunk organ of the body and then connects to the brain and basically is a conduit between the body and the brain. And then he got the brain tissue from the Alzheimer's patients with where the Alzheimer's plaque was, and he was able to show that cytomegalovirus was in the tissue of the gut of certain patients who had this inflammatory sort of brain cell in Alzheimer's, also though in the vagus nerve directly. So there's incredible images of that paper of just cytomegalovirus just in the vagus nerve and then in the brain strongly suggesting that the virus might begin in someone in their lifetime in the gut, maybe just kind of hanging out, maybe not doing something that bad, but over time literally might crawl up the vagus nerve, which is really a super highway for a nerve infecting virus like a herpes virus.

Amy Proal (10:14):

And Herpes viruses are literally, we call them, they're neurotrophic, which means that they preferentially infect nerves. So many of us have also thought, why would viruses that infect nerves leave the vagus nerve alone? So one of the things we've always wondered is are viruses or other pathogens almost using the vagus nerve as a highway between the body and the brain? And this study suggests yes, probably right and then ends up right in the brain tissue of patients with Alzheimer's disease. So these are compelling findings just suggesting, yeah, these viruses that many of us harbor depending on which nerves they travel and what location they get into, they very well may be really driving this. And one of the craziest just studies out there that hangs out there in terms of just treatment or just preventative strategies that we can do to potentially just prevent this herpes virus activity associated with Alzheimer's disease is a study from Taiwan where it was a teen that looked at medical records.

Amy Proal (11:16):

And what they did is it was a large number of people's medical records, and they looked at people who'd been given very common herpes existing medications like Valtrex or Valganciclovir, which is a commonly prescribed medication for cold sores or genital herpes. And they looked at people who'd been given those drugs more routinely for things like cold sores, and they compared their rates of developing dementia to people who had not taken those antivirals. And the rate of dementia in the people given those antivirals more was almost 10 times lower than the people who had not taken them. So this is just some of the lowest hanging fruit where one of the trials that we're trying to get support for is for Ben Reidhead group to run a trial of valganciclovir, this existing widely available antiviral in people with pre dementia to prevent progression to Alzheimer's disease. So really cool opportunities there to use, like I said, even existing antivirals to potentially have an impact on a disease that otherwise has very poor treatment options.

Adam Rinde (12:24):

I mean, this is just mind blowing to think of looking at disease through this lens because even today I was doing some research on pots and secondary to people, a lot of people with long covid will develop postal orthostatic ARDI syndrome pots. And I found out just through my research, that a lot of times what's going on is an autonomic neuropathic process where there's an autonomic neuropathy and secondary to potentially secondary virus. And so it's just really interesting to tie all these conditions where the viral pathogen is disrupting the nervous system. I mean, even MS has been linked to Epstein-Barr virus

Amy Proal (13:16):

Very directly with some really even good mechanism by which the Epstein Barr virus can do it. But just to go back to where you mentioned COVID and SARS-CoV-2 and Long, we absolutely do see a lot of, just like you autonomic dysfunction in patients. And obviously the vagus nerve does play a role in controlling autonomic function. So it actually gets into innervates the back of the brain at the brainstem. And there's nerve bodies right there where the vagus nerve enters that are key in controlling autonomic function. So technically, if the vagus nerve, if signaling from vagus nerve is thrown off, but can be a big driver of autonomic dysfunction, and even with SARS-CoV-2 and Covid, we've asked, could the vagus nerve be directly infected and at least some long covid patients? And the truth is, maybe it could be because there's a really fascinating autopsy study that collected vagus nerve tissue from people who passed away from acute covid.

Amy Proal (14:14):

So this is acute covid, but they identified the RNA, the backbone of the SARS-CoV-2 virus in every single vagus nerve sample that they analyzed in the study. So obviously the virus can get into the vagus nerve, so can it persist in the vagus nerve? Probably right, because that's one of the bigger trends we see in long covid, different reasons why people develop symptoms after covid. But one of the biggest ones that we've been studying is really just the straightforward fact that some people don't fully clear the SARS CO two virus over time, and instead a small amount of virus persist in what we call a reservoir. So basically a little bit of virus remains in the tissue of a gut or in a nerve or possibly in the lymph nodes. And obviously the vagus nerve could be potentially a reservoir site too. And if it was, you'd expect there to be profound autonomic dysfunction. So sometimes one of the most simple possibilities for autonomic dysfunction could relate to infection of the vagus nerve. It's something that we consider.

Adam Rinde (15:16):

Yeah, I mean there's so many different types of microbes that probably fall under this lens that you're looking at. Can you just comment on the spectrum of microbes that you're looking at in connection to chronic illness? I mean, does it go beyond these viruses that we've mentioned?

Amy Proal (15:37):

Yeah, the herpes viruses are the most studied viruses for persistence in the human body, often in what's called the virome. So basically all humans often starting in the womb meeting, right, acquire viruses, they can be passed to people from their mothers. And the herpes viruses are documented as some of those, but really they also include the papilloma viruses, Anello-viruses, other parvo viruses in Entero viruses are increasingly studied as viruses that are also capable of persistence in human body sites. So there's just a growing scope of viruses that we find in people's tissue in different studies, and some of those viruses are RNA viruses. And for a long time those viruses were not really thought of as persistent viruses. In other words, it was thought that if you got an RNA virus, which for example SARS-CoV-2 was an RNA virus, it was thought that RNA viruses clear they don't persist like the herpes viruses.

Amy Proal (16:34):

But the truth is, the more that we study some of the RNA viruses, the more that we find that some of them are capable of persistence and they have their own mechanisms. It's not quite the same as the herpes viruses, but they're also able to remain sometimes in inert forms where it's similar to the dormancy where herpes viruses will sometimes persist where they won't be active. They'll kind of be in a latent form or a dormant form, but a form that if the immune system, if the function of the immune system goes down for some other reason, stress or some other issue or God knows mold exposure, any of these things they can kind of reactivate and cause more problems. We also start to see that now with RNA viruses. So that's adding a scope of other viruses into people that can also be disease drivers. And then with bacteria, there's a lot of them, mycobacterium, tuberculosis, chlamydia pneumonia, PJ Vallis, which is an oral pathogen that's also been found in the Alzheimer's brain in one study.

Amy Proal (17:31):

There's the parasite pathogens, for example, which are dramatically understudied, but could be huge players in chronic disease with basically toxoplasma being one of the more just obvious ones. Toxoplasma is a parasite that infects often the central nervous system where it remains apparently in a latent form or this dormant form, but obviously could act up in ways that can drive a number of symptoms. And I think the current estimate is that 11% of the US population harbors latent toxoplasma in essential nervous system and in certain parts of the world, up to 50% of people do. And that parasite drives often neuropsychiatric symptoms or neurocognitive symptoms. So when we're looking at diseases, even schizophrenia or just whatever it is, conditions where we start to see changes in neuropsych symptoms, we can't rule out these parasites either that are big possible drivers of those kinds of symptoms. So there really is a huge diversity of pathogens that can accumulate in people and really become implicated in these chronic diseases.

Adam Rinde (18:40):

So how is these findings and this direction informing what PolyBio Institute's going to be focusing on in the years ahead?

Amy Proal (18:51):

Yeah, I mean, first what we've been doing a lot is a lot of work on long covid because when the pandemic started, as much as it was a terrible thing that so many people got covid at the same time, it allows us as researchers who are studying the chronic impacts of infection to actually study people infected with covid over time in a way that's been really hard with other pathogens. So we have a lot of groups at different universities that we're working with that are tracking people who get infected with SARS-CoV-2 and using very cool tools to be able to understand what the virus is doing to drive dysfunction. So in that space, some of the key things that we're looking at and I think are the basic persistence of the virus, but then again, one of the areas that we're most interested in continuing to work on is the ability of SARS CO two and other viruses and bacterial and fungal and parasite pathogens to directly hijack our mitochondrial function. And I think that some of the studies that we're seeking to move forward the most are really on that intersection of what pathogens do to directly alter the energy output and mitochondrial output of our human cells. And part of that is based on a truth that I think more people need to understand, which is that especially for viruses, viruses are actually called obligate intracellular parasites.

Amy Proal (20:11):

And what that means is that they do not have the machinery to make a copy of themselves on their own. They simply cannot replicate on their own. They must by definition hijack the mitochondria of the host cell. They infect and pull the substrates like the nucleic acids or the things they use to create new versions of themselves out of our own human mitochondria in order to replicate, they must do that. Every virus does that. So every single time that you have a viral infection, including those that might not clear the metabolic output of the infected cells, inevitably changes. And almost all viruses and other pathogens will basically push people's mitochondria when they hijack them to what's often called a Warburg metabolism. It's a metabolism where there's a lot less efficient production of a ATP, which is the main energy molecule that mitochondria make. Basically there's less a ATP produced and more lactate as an output, and it pushes into this state where your energy production is worse and your byproducts of mitochondrial function like lactate are increased, and that is not a great state to be in. So understanding is the relationship between mitochondrial dysfunction in a lot of conditions and these infections is a huge intersection to be able to say, yeah, and your mitochondrial function isn't great, but could that again be tied to some of the pathogens in you and their activity? It's a key area research.

Adam Rinde (21:42):

Wow. Yeah. So microbes have known how to become involved with mitochondria since the beginning of time. I mean, that's the origin of mitochondria,

Amy Proal (21:52):

Right? You're exactly right. Mitochondria themselves are derived from bacteria where back in the course of human evolution, certain kind of bacteria infected humans, and they were good energy producers. So our human genome basically co-opted those bacteria and basically increasingly kind of made them function as part of what our human genome does, which is really crazy, and that is how mitochondria are derived. So literally when you're talking about this interplay between mitochondria and other pathogens, it sure makes a lot of sense because we understand that every organism in the human body has complex relationships with others. So even bacteria are infected by viruses which are called bacteria phage or there are all kinds of things. So the idea that mitochondria wouldn't either be hijacked or have defenses against other pathogens is impossible. And in fact, mitochondria are increasingly actually studied as organelles of the immune system because when they release, for example, reactive oxygen species, so for example, when mitochondria are not in good shape, they'll release these basically pro-inflammatory signaling molecules called reactive oxygen species.

Amy Proal (23:08):

But when they do that, that's often their response to the fact that they're being hijacked by an infectious agent. It's what they do to combat the infection to push back against it. So a lot of these mitochondrial byproducts that can be detrimental are actually produced as part of mitochondrial defense. So in other words, if we kind of mitigate the infectious, I would hijacking a mitochondria, we have opportunities to mitigate some of those defense associated compounds like reactiviated oxygen species that they produce. So again, it's another opportunity to basically decrease inflammaging or other factors associated with aging or chronic disease.

Adam Rinde (23:51):

We had a geneticist on the podcast named Richard Bolles who does a lot of work with autism and cyclic vomiting syndromes. And his whole focus is as a geneticist, is on mitochondria apathy, this whole collection of conditions that are tied to mitochondrial dysfunctions. And that's exactly what he is talking about, the oxidative stress. And if you keep peeling back, what is the root cause? And that's kind of like all of our dreams, right?

Amy Proal (24:25):

Yeah.

Adam Rinde (24:25):

So this seems like it's just kind of really looking straight in the eye of the root of disease. So it's very exciting and I think I have to thank you for the last five years of rolling out your research and all the things that you've been kind of like a flashlight on where to look and where to think through on cases, especially with hypercoagulation, that was a big finding in these postviral syndromes, and it's really helped so many people to know that and to look for it. And now I think connecting with you recently it came at an opportune time because I think there's this sort of notion of we have these conditions and we have these microbes that are drivers, but why isn't the immune system doing its job? It's like, why is there a persistent, why is the system not working? And so from a standpoint of clearing the virus and helping restore homeostasis, just as reached out to you to talk a little bit about what's happening with the immune system. And we got into talking about mTOR. I was just wondering if you could sort of unpack that a little bit for us.

Amy Proal (25:46):

Yeah, exactly. A lot of factors probably end up impacting who would clear a virus Sarco two and who wouldn't. But one of them is that if you see, first of all, the SARS-CoV-2 virus when it infects, has multiple proteins that knock down interferon signaling. And interferons are just these key signaling molecules that are part of the immune system that play a central role in keeping almost all pathogens in check. So basically, let's say there's a herpes virus and it's trying to act up interference come in and are like, no, no, no, no, no, you don't. And they kind of shut down that activity. So good control of interferons is really necessary for good control of infection. And SARS-CoV-2 just totally disrupts interferon signaling. So one of the things that's happening there is that's a problem. So it becomes almost like the holy grail of dealing with long covid patients or people who have issues with any infection ongoing issues is like, what could we do to improve interferon signal?

Amy Proal (26:48):

Is there something out there that could do that? And one of the studies that caught my eye was a study of low dose rapamycin, actually, where teams have been trialing in some, basically at this point, some of the main trials have actually been in healthy older adults in attempts to promote actually longer lifespan or healthspan at least, where people are taking a low once week dose of rapamycin, which is very different than the conventional dose of rapamycin in its common indication or most used indication. Rapamycin is actually used in a very high dose every day for organ transplant rejection. And in that dose, it's immunosuppressive, and it's not something we would give to people with a lot of these infection issues, but in a low once weekly dose, it seems to have almost opposite effects where it actually seems to stimulate parts of the immune system, or at least there's early data suggesting that it might.

Amy Proal (27:41):

And so two studies basically really caught my attention, and one of them is on a Rapalog, so it's a compound similar to rapamycin, but I think you can extrapolate enough. And what the group showed is that in older adults taking rapamycin, a couple things happened. First, at the end of the trial, they gave them the influenza vaccine and the people who had been taking rapamycin in this low dose had a more robust, a more energized response to the influenza vaccine than the people who didn't, which just suggests that the immune system was in better shape. At the end, it was like, okay, that's interesting.

Amy Proal (28:14):

And then one group measured after people had taken this low dose, the signaling of those interferons that I mentioned before, and they actually found that the people who had been on the rapamycin or the rapalogs had upregulated interferon gene expression. So it was like, wait a second, that is huge. If there's any chance that low-dose rapamycin could be upregulating interferon signaling, we should follow up on that. And then one group also looked at T cells, which can basically become exhausted over time. And especially if T cells continue to have to, let's say you don't clear an infection, T-cell come in and say like, Hey, it's still there. Hey, what do we do? But if they can't actually fully clear it, what they do is literally become exhausted and they start to express markers that show they're exhausted, and one of them is called PD-1.

Amy Proal (29:05):

So if we're in a lab and we find a T cell and it's expressing this PD-1 marker, we're like, oh, that's an exhausted T. So at the end of one of these RAP AOG trials, the participants had less signs of T-cell exhaustion, like the T-cell exhaustion had improved versus the people who hadn't taken it. So we look at rapamycin and we're like, wow, if there's a 1% chance that taken in a low dose, it could be improving interferon signaling, improving T-cell exhaustion, or just sort of improving immune function generally. That's huge. So we just started, which I'm really excited about, a low dose rapamycin clinical trial, long covid at Mount Sinai where I serve as the scientific director of a long covid clinic there. And we're measuring, which is good in the participants, we're measuring that interferon signaling, we're measuring the T-cell exhaustion and other measures.

Amy Proal (29:54):

And what I look forward to is when we get the data on people in the trial, we're actually going to be able to say, yeah, did that happen? And I think that's going to be huge. So that is part of it. But going to the biggest picture of why an mTOR inhibitor like rapamycin would have potentially beneficial effects on immune function could come down to the fact that if someone still has infectious issues and their mitochondria is being hijacked, mTOR is sort of at the height of that mitochondrial signaling that can become hijacked by pathogens. So some of the main pathogens that disrupt our mitochondria do so directly by dysregulating mTOR signaling,

Amy Proal (30:36):

And often they upregulate mTOR signaling. So rapamycin, which is an mTOR inhibitor, might actually be getting in the way of the ability of some of those pathogens to mess with mTOR signaling, which could have beneficial downstream effects on the immune system because then the infection is more contained, allowing the immune system naturally to come up and better express interferon or better have less T-cell exhaustion. So really it could actually be that low-dose rapamycin is at least in some senses, preventing pathogen hijacking of mitochondria, which would be really fascinating. And all of this still needs further research. But what that means though overall is that drugs that impact mitochondrial metabolism like rapamycin or metformin, can potentially have antiviral or antibacterial properties. And that's a cool intersection now that's beginning to be better understood. So for example, in long covid, one interesting trial is that there's a trial which showed that people who took metformin during acute covid were less likely to develop long covid over time. And again, that suggests that metformin could have itself some kind of antiviral properties that actually prevent people from having issues with covid. Again, maybe because it has some effect on mitochondrial signaling that might impact the ability of SARS-CoV-2 or other viruses to mess with those mitochondria. So it's a cool intersection.

Adam Rinde (32:02):

Yeah, I mean, I heard commentary by Dr. Peter Atia about comparing metformin versus rapamycin, and one of his comments was that metformin's more like a poly pill. It affects a lot of different pathways besides just mTOR. And whereas rapamycin is very targeted, and so we have a little bit more control using low dose rapamycin of various side effects and other effects like blood sugar.

Amy Proal (32:32):

That makes sense to me. Exactly. We know that rapamycin is an mTOR inhibitor versus not totally understanding all of the metformin mechanisms and it makes sense. And rapamycin actually has a pretty fascinating history where itself was isolated out of the soil. So basically it was found when people, a group of scientists went on an expedition to Easter Island. So on Easter Island, they were going to build, I forget, some buildings or facility, and the scientists were like, why don't we just check the soil first? And the reason they did that was because the native people who were living on Easter Island, they realized that they could walk around barefoot and they wouldn't get any kind of, I don't know, tetanus type or other kind of issues. They were very able to walk on soil very resiliently, and they're like, maybe there's something in the soil. So they found rapamycin as this soil-based compound in the first properties that it was characterized for were antimicrobial or antiviral effects. In other words, that was the first understanding of what rapamycin could do. So I feel we're kind of coming back to its original discovery indication, which is impact on infection, which is exciting.

Adam Rinde (33:40):

That's really interesting. And can certain physiologic states like ketosis or caloric restriction work on this pathway as well?

Amy Proal (33:49):

Yes. So there are definitely patients with chronic disease that benefit from either a low carb diet or feel depending on the person, a lot better in keto, there are even cases of people with, there's a researcher who has patients with schizophrenia and puts them on a very strict ketogenic diet and will actually see remission of their schizophrenia while they're on a keto diet. In fact, there's even, and this was some of my early undergrad biology work, is we worked with children who had really terrible epileptic seizures, just sometimes like hundreds of seizures a day. And if we could put those kids sometimes again on a strict ketogenic diet, their seizures would stop. So there can be profound effects from a ketogenic diet. And if you think about it, there could be a lot of reasons for that, but obviously a ketogenic diet prevents this rapid uptake of glucose.

Amy Proal (34:45):

So if cells are sort of pushed by pathogens into that Warburg dysregulated metabolism, what happens is there's a bunch of glucose that's uptaken as part of that shift, and then the output has increased lactate and worse energy production, but there has to be a lot of glucose around for the pathogen in the cell to be able to move in that direction. So if you eat keto and you really dramatically restrict glucose, it's possible, at least to me, that it could just mean that the pathogens or whatever other hijacking happens with mitochondria just can't happen because there isn't enough glucose to uptake to really push the mitochondria in that detrimental direction. So there is ways then if you modulate glucose that you can obviously modulate mitochondrial signaling. So I think that experimenting with a ketogenic diet or other diets and for those reasons make sense to me.

Adam Rinde (35:38):

So from a clinical standpoint, I think a lot of people might be wondering, well, if you have this hijack going on of your mitochondria and have these persistent infections, why aren't these people ending up in the hospital? And a higher mortality rate? And the way I always look at this is the body shifts into this sort of new state of homeostasis where energy production is obviously lower and all these patients, and there's just kind of a downshift in metabolism, a downshift in overall function, and this new normal is a new normal that includes this ongoing infectious process. Is that fair to look at it that way?

Amy Proal (36:25):

Yeah, I think so. Because part of it too is that when we look at reservoirs of pathogens, in other words, small amounts of pathogen, it's that it's like often the pathogen that's persisting in someone, it's not everywhere in an acute infection. Let's say when you get covid, just the virus can spread throughout all of your tissues and there's a lot of virus in you. But often when the viruses persist, there's just a little bit, it'll be in some tissue or in some nerve or whatever. So part of it is that you have a sort of smaller smoldering infection that isn't affecting maybe every system, but at the same time, yes, the virus isn't bacteria and parasites, if you will, I don't know. They don't necessarily want to kill their host. They in a way need a home. So they have a lot of mechanisms by which they can still drive inflammation and distort mitochondria and cause all kinds of problems, but in a somewhat more subtle way where they're able to do it while your system continues on.

Amy Proal (37:30):

And so that is a large part of what they have kind of evolved to do is to be able to persist enough to cause problems but not enough to really kill you. And so yeah, your body will attempt to, of course, kind of form a new homeostasis. It'll try to adapt to this, but the truth is that each pathogen that you don't clear kind of downregulates the immune response. So now that you have a problem with one of them, you probably have reduced interferon signaling, like I mentioned, more of your T-cells are exhausted or kind of caught up with that pathogen. The problem is then the next infection you get or even the next exposure that you have, you kind of handle worse as well. So a lot of what we look at too sometimes is almost what sometimes I call successive infection, where once someone has a problem with one infectious issue, it's almost like they're more susceptible to the next, and then that one might not clear too. And then depending on the locations and those infections, people kind of go on to develop different kinds of chronic disease, right? So it's part of the picture of just kind of different infections, sort of simmering and sometimes even sustaining others.

Adam Rinde (38:35):

So it seems like now the understanding is we have these two different levers to address this smoldering infection or precision infection. You've got the lever of the classic antiviral approaches, and then you have the lever of aiding the immune system and better functioning clearing. So more of the two main branches of infectious disease going, you got the terrain model and then exactly the past model. So I'm curious how much more you'd be willing to share about your observations with your trial. I know a lot of my patients are going on Reddit and hearing rumblings of lots of really great things coming out of the use of low dose rapamycin. Is there anything else you could share with us about observations that are ready for the public?

Amy Proal (39:31):

Yeah, we actually just started the formal trial, so we don't have enough data from that. We actually just have, our first participant was last week, so there's not enough data to share, but patients have basically started some doctors, and in fact our clinics sometimes we've just prescribing low dose rapamycin. And in those cases where we have an anecdotal report from a patient, we do hear common trends reported already, which is in this, again, it's in everyone, but certain people with long covid or sometimes even chronic tick-borne vector born illness will say that they take their dose and that day they may actually feel worse. In other words, they kind of flare where their symptoms get worse the day they take the pill and sometimes even the next day. So they feel actually worse at first. There's almost like a Herxheimer element to this in some people where I don't know if sometimes if you kill bacteria when you're dealing with something like chronic Lyme disease or whatever, the person feels worse as they take the antibiotics because as the bacteria die off, there's, I don't know, issues like toxin release.

Amy Proal (40:34):

It almost seems like that to certain people, I feel worse. And then by day three or four, whatever of the week in which they took the dose, they turn a corner and they start to feel better those later days. And some of, again, the anecdotally reported symptoms that people say improve are one is their post exertional malaise sometimes gets better. And what I mean by that is a very common symptom for people with long covid or chronic fatigue syndrome, me CFS, is that they exert themselves even a little bit. They just walk a bit or do some activity and they can do it in the moment, but then they crash after 24 hours later, they're just paying for that exertion. And so people actually have to learn to pace themselves and be really careful with what they're doing so that they don't crash. And again, some early reports of people taking this once a week, rapamycin, people have said that that seems to be better for them. They can push themselves to do something more and they don't get as much payback is kind of huge for

Adam Rinde (41:34):

Them.

Amy Proal (41:34):

And again, almost like a better feeling of resilience. Like, okay, I can kind of use my body more, move a little bit more, do something more. And before the rapamycin, I would've gotten sore or achy, but now I'm not as much. Again, look, these are early reports and I think it's really important that we get the data from our trial, but they're still encouraging.

Adam Rinde (41:57):

Yeah, absolutely. I mean, the spoon model where people are using subjective ways of describing their level of function is really valuable. I mean, we don't have a lot to go by then subjective reports with a lot of these conditions, but it's great that you have some biomarkers that you're looking forward to see changes in immune function. That's going to be really exciting. I look forward to that. So far, we've traveled in a very short time. We've gone from a big picture look at the role of infection in chronic illness and specifically also neurologic disorders. And then we talked about the role of infection with vagus nerve and dysautonomia and putting a lot of pieces together here with this conversation and mitochondria, and then all the way to the role of the immune system and how to work with mTOR to help the immune system clear and help autophagy and those processes. So this has been really great update. Anything that you'd like to close with inspiring words for people and just how people can support the PolyBio Institute and anything we can do to help your cause?

Amy Proal (43:13):

Oh, well, thanks so much. I mean, I feel optimistic, honestly. I really think that, I know it's been extremely hard for long covid patients in the last years. There are no approach treatments yet. There is a really difficult landscape and there's still people who are skeptical or whatever, but overall, there really are some good groups working on this, and we have good leads on what's wrong with people. So I think now we're getting closer to running these trials and doing things that are really tangible. I think one last trial that I want to mention that excites me is that Immunity Bio is a company that actually makes immunotherapy, some targeted for cancer, but they have a drug that activates natural killer cells, and they're working to bring that into long covid, a trial that's like we're working to get off the ground. And I just love that idea because to me, it's like you said before, there's basically two approaches to dealing with ongoing infectious issues.

Amy Proal (44:06):

You target the pathogen itself, and usually that requires sort of combinations of antivirals or antimicrobials depending, and they can be herbals sometimes or antibodies. There's a lot of things there. But the truth is that even if you kill off the pathogen, but the immune system is still not in great shape, it kind of just comes back. So the key thing is to target the pathogen, but to also bring the immune system back up. So the fact that a natural killer cell activating therapy is bringing bought into Long Covid to me is huge, because normally in the past we have people who want to bring in immunosuppressive drugs to these. They'll say like, Hey, there's inflammation. Let's shut down the immune system, which we'll see every now and then someone's like, should we give people steroids? And it's like, no. And so what I think is really good is we're actually doing some paradigm shifting here where we're like, look, let's try supporting the immune system in these patients and see where that goes. And it's really exciting that some of these companies that have immunotherapies are willing to engage. So all of that paints a picture where I think at least there's a lot of groups going in the right direction for treatment of this. And hopefully that leads to some productivity over time.

Adam Rinde (45:17):

The conversations are getting so much more precise. And there was a lot of, even 10 years ago, there's just so much handwaving in this space, what are we treating? What do we do? And we're getting much further along. And the great thing is that this translates to so many different conditions that have been puzzling.

Amy Proal (45:37):

Exactly. There's a lot, we see a lot of our long covid work as proof of concept, like, okay, you can do this with one virus. We can probably repurpose a lot of what we're doing for the next. So that's the exciting part is a lot of the work we're doing can grow, and a lot of the technology we're using we can use on kind of the next chronic illness. So that's a big part of our model of PolyBio is we do a lot on the infrastructure of our research so we can keep pivoting into different conditions and different patient populations, which is exciting. So yeah, we're motivated. And yeah, if you want to support Poly bi, we have a donate button on our website, but really just tell people about us, share our work, whatever, just any of those things.

Adam Rinde (46:15):

Excellent. Well, thank you so much for being here again, and really enjoyed this. And I'm going to have to listen to this probably 10 times to grasp all of it, which is what I love. And I know my listeners really love this stuff, so thank you.

Amy Proal (46:30):

Great, Adam. Yeah, we'll talk to you again soon.

Adam Rinde (46:34):

That's it for today's episode of the One Thing Podcast, a huge thank you to Dr. Amy Pearl for not only her time, but her tireless work in helping us rethink chronic illness through the lens of infection, immunity, and mitochondrial health. It's not easy to shift paradigms, but her clarity and commitment are truly inspiring. If this conversation sparks something from you, whether it's a new clinical insight or a fresh sense of hope, I encourage you to explore more of the work being done at PolyBio. You can learn @polybio.org. And please, if you're moved, consider supporting the research or simply sharing this episode with someone who needs to hear it. As always, if you're enjoying the podcast, a quick review or share, it goes a long way in helping others discover these conversations. I'd also love to hear from you on Instagram by sharing a few comments of what you learned in today's episode. So please visit me at Instagram at One Thing podcast. Thank you so much, and I look forward to sharing future episodes.