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In this episode, you will learn about the role of paraprobiotics in immune modulation.

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About My Guest

My guest for this episode is Steven Wright.  Steven Wright is a Medical Engineer, Kalish Functional Medicine Institute Graduate, and gut health specialist.  He’s spent close to $400,000 overcoming his own health challenges using everything from western medicine to shamans.  Steven is the founder of HealthyGut.com.  He lives in Boulder, CO with his wife Shay and their two dogs. 

Key Takeaways

  • What is a paraprobiotic?
  • What are the benefits of paraprobiotics?
  • How do paraprobiotics support modulation of the immune system?
  • What are the five common malfunctions of the immune system?
  • How do each of the paraprobiotics in HoloImmune support the immune system?
  • What is the role of beta glucan in supporting the immune system?
  • How well-tolerated are paraprobiotics in the MCAS community?
  • Can paraprobiotics improve tolerance to foods and to the outside world?
  • Is there an interplay between paraprobiotics and the vagus nerve?
  • Where might paraprobiotics fit in a protocol with prebiotics, probiotics, and postbiotics?
  • Do paraprobiotics play a role in SIBO?


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Interview Date

March 21, 2023


Transcript Disclaimer: Transcripts are intended to provide optimized access to information contained in the podcast.  They are not a full replacement for the discussion.  Timestamps are provided to facilitate finding portions of the conversation.  Errors and omissions may be present as the transcript is not created by someone familiar with the topics being discussed.  Please Contact Me with any corrections.  


[00:00:01] ANNOUNCER: Welcome to BetterHealthGuy Blogcasts, empowering your better health. And now, here's Scott, your BetterHealthGuy.

The content of this show is for informational purposes only and is not intended to diagnose, treat or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health related decisions with your own personal medical authority.

[00:00:35] SCOTT: Hello, everyone, and welcome to episode number 182 of the BetterHealthGuy Blogcasts series. Today's guest is Steven Wright. And the topic of the show is Paraprobiotics.

Steven Wright is a medical engineer, Kalish Functional Medicine Institute graduate, and gut health specialist. He has spent close to $400,000 overcoming his own health challenges using everything from Western medicine to shamans. Steven is the founder of healthygut.com. He lives in Boulder, Colorado with his wife, Shay, and their two dogs.

And now my interview with Steven Wright.


[00:01:12] SCOTT: It's great to have Steven Wright back on the podcast. We did a deep dive into his healthy gut products in episode 149. I urge you to check that out to learn more about how to create a healthy gut. Today we're going to talk about paraprobiotics, which is a relatively new concept on my radar, and excited to learn more about it. Thanks for being here again, Steven.

[00:01:12] STEVEN: Yeah, thanks, Scott. I'm happy to be back and excited to be back.

[00:01:37] SCOTT: First, what is a paraprobiotic? How are paraprobiotics different from what some have termed ghost probiotics? How long have we known about them? And then really, what led you to exploring paraprobiotics as deeply as you have in the past few years?

[00:01:56] STEVEN: Okay. Well, let's start from the last question and work our way back to what they are. When the pandemic was kicking off in that February, I was pretty concerned about the well-being of my wife – now wife, Shay, and my family. And I did what I think a lot of us did in this area of medicine, which was like, "Okay, high-dose everything. High-dose vitamin A, and D, and zinc." And maybe we can just like load our immune systems up and that will protect us in the advent of interaction with this virus.

And then it wasn't but a few weeks into March or start of April where we started to see these cytokine storms. And the reports were coming out that there was a number of people who were dying due to an immune system that basically went like all out. It didn't know how to turn itself off. And it ended up killing people.

And this really was kind of shocking and confusing to me and just kind of added to my anxiety at the time. And so, I started to think a little bit differently about the immune system and that maybe my approach for my health and my family's health was not complete yet.

And so, I started diving deep into, "Okay, what is influencing the immune system? How does the gut influence the immune system? And how can we prevent like this overactive response to a novel virus in this case?"

And that just basically led me down like a search pass like how do you even try to search for that? Well, I was like, "Okay, well, what's a substance that has worked for influenza in the past?" And so, I just tried to like search the entire world for all the types of things that had worked for viruses in the past. And I kept coming back to paraprobiotics, which I had never heard of until April of 2020 there.

And I started reading on it and I was like really interested. This is cool. This was like a paraprobiotic, a dead probiotic. Some people had called them ghostbiotics. I don't believe that they're different at this point. I think people are using a lot of different names for them.

And so, I thought, "Wow. Okay, so we have this paraprobiotic thing. Let me just buy them. Let me buy all of them." And I couldn't find them on the market. And that was really frustrating to me. And that sort of led us to where we are now, which is that I thought I was building this thing to protect against viral infections. And while each one of the strains in the product that I ended up building does have data against that, it kind of ended up being like this Post-It note moment, which I don't know if you're familiar with the Post-it note thing. But the chemist at 3M was trying to build the best, strongest super glue in the world. It was going to be like the spaceship glue. And the end product was it didn't – it wasn't that strong. But you could keep using it over and over again.

And so, I thought I was trying to build this sort of viral protection product. And instead, it seems to be affecting people in ways I didn't expect. People with brain issues, skin issues, food allergies. And then hay fever or environmental allergies seem to be getting the most benefit.

And so, I think the coolest part about this is that there are these classic compounds, these dead probiotics, that seem to impact our immune systems, human and mice, and there's a lot of data on it, in ways that the alive versions do not. And that is really cool. And I think part of the future of how do we re-tolerize ourselves in the world. And so, that's kind of how I'm thinking about these conversations, is like we have ever-growing mold, we have ever-growing Wi-Fi, we have ever growing toxins. It seems like we can't escape this burden we're putting on our bodies.

How can we – rather than like retreat from the world and go into a bubble, how can we figure out how to be with that ever-growing burden? And I think paraprobiotics can help us potentially re-tolerize to the world.

[00:05:58] SCOTT: And it's interesting because these are relatively new on the scene in terms of the health application or at least my understanding of the potential health application. But they've been in Japan. My understanding is that they've been researched and talked about for a few decades now, right?

[00:06:16] STEVEN: The Japanese are typically ahead of us in many regards especially when it comes to novel compounds and things like that. And yeah, they've been researching these things for three decades or more. And we're going to talk about this more in a bit.

But essentially, the most frustrating part of this conversation, I think, for a lot of people including myself is that the specific strain, but also the way it's killed. The age of it. All this stuff matters. And so, the products end up becoming trademarked. They end up becoming proprietary and patented and all these things. But these companies have literally been working with these strains and killing them at different ages and experimenting with them for many, many decades.

And so, the end product is we get these really cool novel strains. But the hard thing is that I don't know how applicable it is to the non-trademarked or the non-proprietary ingredients. And then that's really, I think, part of the confusing story here, is that we have a lot of data. But the data is very, very specific. And I don't know how we can generalize it yet.

[00:07:23] SCOTT: We think of probiotics as living or hopefully living. Unfortunately, a lot of times what we get as probiotics may not be as living as we think. But now we're learning about paraprobiotics, which are killed or dead. From a health management perspective, when might we want an alive organism versus a dead organism? And might some of the benefits, even from probiotics, might those also be more from the cell walls as opposed to the fact that it's living or dead? And then kind of building on that, talk to us about the difference between immature cells and adult cells when we're talking about paraprobiotics.

[00:08:04] STEVEN: Yeah. The entire talk here, the takeaway is not that probiotics are bad. But I think the talk is that the probiotics, and paraprobiotics, and the components of their cell walls, and what they are is a much more complex story than anybody wants to admit.

And so, I would say 98% of all the research on probiotics have been done with strains that you're correct - we don't know how alive or how dead they were. Because many of them, if they're not in a specific environment or a specific type of enteric or delayed release capsule, they die pretty rapidly. The supplement companies have to like double the dosage on the label.

And so, let's say you got that one month after manufacturing. The amount of active or alive probiotics at one month is significantly different than 12 months. But they still build it, so that at 24 months, it has that minimum number on the label.

And so, when we look at the research studies, we can basically say that 98% of these bugs were not protected. They weren't "protected from stomach acid". Stomach acid deactivated some portion of that load of probiotic.

And so, I think the probiotic story is not as simple as is it alive? Or is it dead? Is it protected or not? It's like, in that strain, for that specific person, was it helpful? And what did it do?

And I think what we see is that these specific strains can help with specific outcomes when they are alive. And then there's not that many studies that I found. But the studies I have found where they take the exact same strain and then they kill it, the answer is they don't do the same things.

In fact, I was looking at a cool new pair of probiotic I just found like literally yesterday prepping for the show. The species is TKW10, I believe? And I might be misremembering because I've read a little bit too much research trying to prep for this show.

But essentially, I was like, "Wow. Look, I think I found an athletic paraprobiotic." Because that was like the title of the study. But when I read the tables of research, the alive version actually allowed the athletes to go longer in their bike riding and they gained more muscle than the dead version. But the dead version allowed them to recover faster and have less like soreness after exercise.

And so, I think what we're going to see is that each of these strains are modulating certain variables. And we're going to build products based on how sick someone is and what kind of outcome they want? There's a decent amount of negative literature now that alive probiotics in very sick humans. Think elderly, think very chronically diseased states, like high amounts of leaky gut, they can actually over-stimulate. The alive bugs can over stimulate the immune system and cause sepsis or sepsis-like symptoms. And if there's really bad leaky gut, there's data showing that they can translocate through the gut into other organs.

And so, probiotics are powerful. But there's like a growing list of reasons why, I think in certain states of health, we would probably want to shy away from them and maybe try to build someone's body up using like a paraprobiotic maybe first and then introduce the alive version later or some other combination of that.

[00:11:26] SCOTT: That helps with the alive versus dead. But then when we're talking about paraprobiotics specifically, are these killed at an immature cell state? Or are these adult cells? Or are there variations in terms of when different types of paraprobiotics are actually killed?

[00:11:46] STEVEN: The answer, again, is convoluted. And the answer is yes. For instance, in the HoloImmune product, there's one string, HK137, or Immuno-LP20, it is an immature cell. They actually did a study in 2012 where they showed how much potential did it have to activate IL-12? And if they killed it early, say, teenage lifespan, it actually produced a better outcome than a very young cell or an adult-size cell.

The many other paraprobiotics in the market are either unwilling to share their stage in the life cycle or are most likely adult stage. And so, when you look at the – when you look at the studies, but then when you contact the companies, what you find is that there's many ways to kill these things. You can kill them with heat. And there's temperature ranges there. You can kill them with pressure. You can kill them with UV light. And you can kill them with like acids and chemicals.

And each way that you kill, the exact same strain changes the – it basically changes how the cell looks at a microscopic level. It does change it slightly. And some of those methods burst the cell a lot more than other methods.

And so, for instance, the Immuse strain in HoloImmune, they're very proud that their heat-killing method is like a low temperature and it basically keeps the cell membrane in the cell intact. And they're very proud of that. But you can find other Lactobacillus rhamnosus lysate studies specifically out of Russia on a fermented dairy source where they're very proud that they're basically slicing the cell wall up all the time. They don't have any intact cell left. They're very proud that it's all chopped up basically.

And so, I think the story here is going to get really interesting over the next 10 years. Because what it seems to indicate is that the style of killing the bug, the age of the bug, will produce different outcomes when it comes into contact with our immune system.

[00:13:52] SCOTT: I want to talk a little bit about the role of paraprobiotics on our microbiome and then also on our immune system. Do you think of them as having a direct beneficial role on our microbiome? Or are we talking more about the immune modulation side of things? Or do they maybe have a role on both of those areas in terms of improving the microbiome of the gut but also modulating the immune system simultaneously?

[00:14:20] STEVEN: I would say it's probably 90% immune modulation. Maybe 10% biome. Or I would say maybe the ecology of the gut. And let me explain a little bit more. The studies are not as powerful. If you wanted to isolate an alive or a dead bug and say, "I need to produce a different Akkermansia or something in the gut. Or I need to produce more butyrate." There is much better data and there's much higher volume of outcome if you're using certain alive bugs to try to manipulate the microbiome or cause a difference in that type of thing. Or specifically, say, tight junction for leaky gut. Something like that.

The converse is true for paraprobiotics. If you were trying to produce, let's say, better – or less IgE formation, or better Th1, Th2 dominance. If you're focused in on the immune-specific cells or immune-specific markers, the data is really strong for paraprobiotics.

And so, I see it as, essentially, we're introducing information. These are dead cells and dead cell parts. It's information to the gut and to the body. It's being taken up by the GALT system. And then it influences the ecology around the intestines such that they then have a feedback loop back into the actual intestine area, say, introducing more defensin, more secretory IgA. Maybe they're able to shut off inflammations faster or better, things like this. That in turn impacts in a second order consequence the microbiome makeup and kind of what is allowed to live in the gut.

[00:16:10] SCOTT: Do we think there is any direct effect on the microbiome like taking a probiotic, for example? Or based on what you were just saying, it sounds like most of the effect is more indirect, where the gut immunity, the GALT? That gut-associated lymphoid or lymphatic tissue is improved? And thus, potentially, then, if we have better immunity in the gut, the immune system then is also better able to surveil or monitor our microbial milieu. What do we think the impact of these paraprobiotics might be on the gut microbiome itself?

[00:16:47] STEVEN: At a base level, they are introducing some potential food, right? For certain bugs. You could potentially make the argument that part of that cell wall, as it gets broken down, is a prebiotic potentially. It's at least sourcing or funding certain species of the microbiome, which then will interact with the rest of the species in the microbiome.

I really think of the microbiome as like a hippie commune. They all need to be doing their jobs. Somebody's got to go get the food. Somebody's got to weed the garden. Someone's got to watch the kids. And so, I would guess that there is a direct correlation to improving a certain amount of species. But again, I think that impact is very minimal if we're looking at what do these things do.

I think the majority of it is it's impacting the immune system. It's impacting the GALT, which is then a second order consequence, like you said, of what is being allowed or surveilled in the gut. And how does it interact with what's coming into the gut?

[00:17:43] SCOTT: Let's talk then a little bit more about that immune modulation piece, the immune system, and the effect of the paraprobiotic. Over the last several years, it's become super obvious to me that immune modulation is often, maybe even almost always, more important than killing or attempting to eradicate a microbe that many of the symptoms we experience from a microorganism are really tied to the overreaction or hyper-vigilance of the immune system.

And so, if we can better modulate the immune system, we also then are creating more tolerance, creating more integration. We are reducing our symptoms because we don't have that hyper-vigilant type response anymore. How does a paraprobiotic help to support a more balanced or better modulated immune system?

[00:18:37] STEVEN: The research seems to indicate that these bugs are like very specific with what they upregulate or downregulate. For instance, the L-92 inside of the formula, their studies on mice and humans really suggest it goes in there and helps block IgE formation.

And so, from that mechanistic data, they then ran studies on hay fever in humans, on eczema in kids as well as adults. And they found favorable outcomes in each of those situations.

The other bugs that I've studied – I have not seen another bug that specifically touts or suggests that it is the one that's manipulating IgE. And so, what I'm seeing or what I'm thinking is happening is that each of these, not only the cell receptors that are on the cell, but also the makeup of the cell, seem to provide some sort of information, like enough of this nutrient or enough of this compound that the other bugs, like the LP20 bug, it upregulates IL-12 and seems to improve the Th helper to Th suppressor ratio.

Now, again, I don't see any of that talk in many of the other paraprobiotic studies. And so, it seems like whatever's being consumed by like the Peyer’s patches and the GALT experience down there around the gut, it seems to modify either the innate side, or the adaptive side, or for one specific part of the adaptive side.

And so, what I think we'll see is that if you have a certain desire, whether it's like, say, it's hay fever, or food allergies, or something like that, you will be looking for bugs that specifically plug into that part of the immune system and are helping to upregulate or downregulate whatever's related to the dysfunction in that area.

[00:20:28] SCOTT: One of the things that I've observed over the years is people that have chronic infections have this idea of if I can just do something to boost my immune system, that everything will be better. And my understanding is that, oftentimes, we don't want to boost the immune system particularly if we have autoimmunity or hyper-vigilant immune responses. That we really want to more modulate the immune system. I'm wondering if you can talk a little bit about the difference between boosting and modulating the immune response?

[00:20:59] STEVEN: Yeah. I mean, I think as clinicians, an area that has been really struggling for most people and a lot of the patients out there is like they keep wanting to kill things. Like you mentioned, everything's a killing protocol. If I get this lab test that comes back with this positive marker for – I don't know. It could be Lyme. It could be a gut pathogen. It could be SIBO. It could be a number of things. The first instinct is like go kill, kill, kill.

But I think what we've seen is that, in general, that way of trying to treat the body seems to fail for the majority of folks. And I believe part of the reason why, is that the reason that person has that bug to begin with is their current body's immune system has failed in its ability to protect the organism. And that means it's out of balance. It's missed one way or the other.

And so, if we assume that it needs more muscle, right? It needs immune steroids or whatever. It's got to crank itself up and go kill, kill, kill internally, we're making a huge assumption. Because we don't really have a lot of great testing yet. There is some super advanced Cyrex and Vibrant America test that can start to shed some light on this. But the amount of people who even know about these tests and are running them, I think it's growing. But it's pretty small at this moment.

And so, we don't necessarily have an easy way to say like, "Is your immune system over-vigilant?" like you said. Is it under-vigilant? I've talked about these sort of five mistakes that the immune system is making, which of the five is it making?

And so, I think what we saw with COVID, what we're seeing with infections, is that we want an immune system that's very smart. We don't want it to be strong. We wanted to understand what's coming in. Is this a bunch of grass pollen? Is it springtime? Okay, great. We don't want to respond to this grass pollen with a hammer. We want to respond with a feather. Is this Giardia coming in from some mountain water? Okay, great. Let's bring out the jackhammer and let's get rid of this because we do not want Giardia in the body.

And so, we want, like you said, a modulated response to whatever foreign object is entering the body. And I feel like where a lot of people who are struggling with chronic illness are stuck is they have a pattern that's sort of the way their body responds. And they respond that same way, whether it's corn, or gluten, or seed oils, or grass, or pets, or mold, or some sort of bacteria, or something like that. Instead, we want to have a much more sophisticated approach to responding to these incoming invaders. And I think that's what you see when you look at a resilient person or a resilient immune system, is they're able to be with the environment and whatever's coming at them.

[00:23:51] SCOTT: You mentioned the terms innate and adaptive in terms of the arms of the immune system, the innate immune system, being kind of the first line of defense that we can oftentimes get stuck in. When we have some of these chronic conditions, that can lead to ongoing inflammation. We then have the adaptive immune arm, which is more the building up of immunity, the B cells, the T cells. Talk to us about the role that paraprobiotics play on both sides of the innate and adaptive arms of the immune system. And then extending on that, you mentioned that there are five common malfunctions that you see with these two arms of the immune systems. Maybe you can dive a little bit deeper into what some of those malfunctions are?

[00:24:34] STEVEN: Let's start with the five malfunctions. And I think that kind of starts to describe the various types of immunity. And I just want to say, again, I am not an immunologist. I've been reading about this stuff for many years now. And I still get very confused on it. It's a very complex topic. And I feel like even the immunologists don't understand sometimes and are very much arguing amongst themselves.

The five common things that I'm seeing for sort of like immune dysregulation or dysfunction is, number one, an underactive innate immunity. This is kind of like an immune system or a person who's a little too passive. They don't respond appropriately to an incoming bug. And therefore, their adaptive immune system is going to have to work overtime in the future to try to help them recover.

The next thing is the exact opposite, which is an overactive innate immunity. I think this is what we see a lot with the folks who are trying to get well and who are reacting to all the foods, all the environmental stuff. Their innate immune system is too aggressive towards whatever's coming at them.

Then we have poor communication between the innate and the adaptive sides of the immune system. Because again, the innate system is working all the time. It's kind of on vigilant duty. It's on night watch all the time. And then if it continues to see an incoming bug, or an incoming allergen, or something like that, it will begin to talk through your cytokines and various signaling mechanisms to, like you said, the B cells, and the T cells, and the dendritic cells, saying, "Hey, this thing is happening. And we're kind of starting to lose the fight. We could use some help here."

And so, sometimes that communication between the innate and the adaptive immune system is dysregulated or not happening. This is what you see as we've especially been all exposed to it now with the elderly populations, and the fact that their reaction to the vaccines and other types of inoculations are not as good. There's like a disconnect between telling the adaptive immune system, "Hey, let's go. We got to make some of these antibodies or something like that."

On the adaptive side, we have under active adaptive immunity. This is like forgetting that a gut interacted with some sort of virus. Forgetting that it should be on guard. And then we have the overreactive, which is typically your autoimmune conditions, where it's making antibodies or it's making cytokines to everything. It's like going crazy.

And so, these sort of five patterns seem to be common. And you can kind of link them up to whatever someone's experiencing in their symptomology. Paraprobiotics can work on the innate side or on the adaptive side. And they can also work on the communication between the two.

The communication between the two I think has a lot to do with your dendritic cells and actually your mast cells. They really are spreading a lot of talk between the two sides. On your innate side, this is where you have a lot of people like to think about natural killer cells. We can modify those with a lot of paraprobiotics, but other compounds as well.

On the adaptive side, this is where we're looking at T helper cells, T suppressor cells, we're looking at B cells. We're trying to make sure that the – a lot of times – and I believe, unless it's an elderly person or a very immuno-compromised person, on the adaptive side, we're just trying to get it to work appropriately and not over-produce to its own cells, or to grass, or dogs, or something like that.

[00:28:03] SCOTT: Let's talk a little bit about the plasmacytoid dendritic cells, or pDCs. How they enter the paraprobiotic conversation? As I understand, the pDCs can secrete interferons that can be very helpful in viral immunity. But I've also read that they can be initiators of autoimmunity and initiators of other inflammatory diseases. What's the interplay between paraprobiotics and pDCs? And does the activation of pDCs through paraprobiotics have the potential to increase the risk of developing autoimmunity?

[00:28:38] STEVEN: Yeah. Plasmacytoid dendritic cells are a special class of dendritic cells that seem to have sort of leadership capacity across the innate and the adaptive immune system. In other words, they can secrete interferons to say, "Oh, my gosh. Make more natural killer cells right now." But they can also secrete interferons and say, "Hey, B cells, kick it into gear here. We need some antibodies or something like that."

And so, they have this sort of leadership role and that they're able to crosstalk across much of the innate and the adaptive immune system.

And in the research, they are very important for viral infections. And not everything that I've read suggests that it boosts it. For instance, in HoloImmune, only one paraprobiotic, the immune strain, seems to preferentially boost these pDCs. Again, I don't think that there's another paraprobiotic out there yet that is saying, "We've done the research on rodents and on humans, and this is definitely interacting with pDCs. As far as, I know it's still only Immuse. It's not to say somebody else won't come out with this later. But at this point in time these, things are very specific.

And so, the interesting thing about the Immuse strain is that they've studied it across humans and kids, and there's like 29 studies with animals as well. And they studied it from exercise to lost work days. And they find that, just in general, these humans are slightly healthier or more resilient. That's how I would classify the research if you had to sum it all up.

And so, I think that speaks to what do plasmacytoid dendritic cells do. Specifically, what that paraprobiotic is upregulating is basically the tolerance and the ability of the innate and the adaptive size to respond to stress from a final exam or stress from a really intense marathon bike ride. It's basically helping that body be more resilient.

And so, I think they're very important as we look into that crosstalk and that lack of communication for humans. And then the studies in humans are just really robust suggesting, like, "Hey, if you want to be more resilient, you want your plasmacytoid dendritic cells to be capable and able to respond."

Now to your point, there's a growing amount of data coming out that these plasmacytoid dendritic cells are out of control in certain autoimmune conditions, specifically lupus and I think a few others. But definitely in lupus. And the question that I've asked them, and I haven't gotten a direct answer on yet, is like what are we looking at here?

When we look at the research so far in the autoimmune conditions and the mice conditions with the plasmacytoid dendritic cells going crazy, would Immuse or these paraprobiotics be adaptive – Or adaptogenic? Sorry. Is the word I was looking for. Where it basically helps it regulate? If it's over-expressing, it can kind of tone it down. If it's under-expressing, it's toning it up. I don't have that answer yet. But the research suggests that's what they're doing.

But I would say that we have to look at this. We have to be careful with it. And for those really sick folks, we would want to really monitor them and we want to get more data. I'm going to keep pushing the companies and see what happens. Because there's definitely clear evidence where they're knocking out plasmacytoid dendritic cells in lupus and getting better outcomes. And they're starting to investigate it in cancer and some other things.

Most of that type of research has failed, like most of those drug trials. Whenever we've been like, "Oh, it's definitely amyloid beta plaques for Alzheimer's. Let's just knock those out. And I'm sure we'll fix Alzheimer's. Oops. That didn't work." 20 years down the drain.

I think we repeating some mistakes when it comes to some of this research. But I do think we should – I'm going to keep monitoring it and I think we should keep on top of it because there's clearly an interplay here.

[00:32:29] SCOTT: When we think of immune modulation, many people talk in terms of Th1, Th2, Th17, Treg cells. Those T helper, T suppressor cells. Many people with chronic illness, if we're thinking about chronic Lyme disease, maybe even mold illness and so on, mast cell activation, there is commonly a Th2 dominance. There's often an underperformance of Th1, which leads to some of these microbes then kind of overgrowing. There can be Th17 driving autoimmunity. How do the paraprobiotics modulate the immune system in terms of these T cell responses?

[00:33:09] STEVEN: Again, I'm not sure that there's a ton of consensus on Th1 versus Th2 dominance. But my experience is that it's really hard to find someone who has autoimmune conditions who doesn't also have food allergies or environmental allergies.

And so, if we think of Th1 dominance as being like autoimmune related conditions, and we think of Th2 dominance as being like, "Oh, that's the asthmatics and the allergen related conditions," they seem very overlapping in my clinical experience.

And so, I actually think it's the immune system sort of on a teeter-totter that it's just whiplashing back and forth between producing too much Th2, producing too much Th1. It can't get itself quite into balance. The over-expression and the inability to dampen these responses seems to be very related to everybody in that category. And I would call them like the category that they're having two aggressive other response to the world.

And so, paraprobiotics, some of them can – for instance, the LP20 strain, does essentially help make more T regulatory cells and more expression of them to help dampen these responses. And so, I do believe that even our feedback, our clinical feedback, as well as our customer feedback, is that the product seems to work really well for those people who are stuck in that whiplash. They're stuck on Claritin. They're stuck with their – they're reintroducing foods after their elimination diet. But they can't really get past like a mid-level diet. They're struggling with like normally safe foods for a resilient human, such as some FODMAP foods. Like, cruciferous vegetables, or even corn, which I consider are pretty safe food as long as it's organic, things like this.

If we can help the adaptive immune system stop whiplashing back and forth and being overexpressed, I think we can sort of dampen the response from that side of the immune system. And paraprobiotics are showing benefit both in the research as well as in life experience, clinical experience, that they're affecting something there.

[00:35:23] SCOTT: Your product, HoloImmune, is your paraprobiotic product. There's three paraprobiotics. There's beta-glucan as well. Maybe walk us through each of the paraprobiotics. What they're intended to do in the formula? You have the Lactococcus lactis or Immuse, Lactobacillus plantarum or Immuno-LP20, and Lactobacillus acidophilus strain L-92. Talk to us about each of those and why you selected those specific paraprobiotics to be in your HoloImmune product?

[00:35:54] STEVEN: Again, one thing was that they needed to have robust data on humans? Not just one study. Not just two studies in humans. But multiple human clinical studies and multiple animal studies. There are some really cool paraprobiotics out there that have one or two papers on both animals and humans. But not like a lot of papers.

And so, I was looking for strains that have been put through the ringer both in animals and humans. And then I was looking for strains that did different things. Actually, one of the concerns I had when building this product and selecting the strains was could I accidentally drive someone's Th2 dominance worse? Could I drive someone's Th1 dominance worse?

As I read the research, I was like, "Wow. This is definitely going to interact with these individual's immune system." I don't want to invest a lot of money and a lot of time into a product that ends up hurting a bunch of people. And so, I was actually pretty concerned about that.

So then I started – after I went through like, "Okay, what has a lot of data? What has data on viral infections and coming out of that? How can I select maybe ones that sort of offset each other?" If one is going to boost the Th1 side, can I find one that also boosts Th2?

And so, the L-92 strain, like I said, helps block IgE formation. And much of its data is on atopic dermatitis. It's on hay fevers. And so, that's very much thought of as like a Th2. That's very much like an overreaction to the Th2 stuff. Whereas the Th1 stuff or the autoimmune conditions is much more of like a T helper cell related thing. And so, the LP20 strain has much more data on that and IL-12.

And then finding Immuse was really cool because that's the plasmacytoid dendritic cell that's sort of hopefully linking both sides. Because I was trying to find a paraprobiotic that also directly impacted the innate immunity. I didn't want to just be boosting the adaptive immune system with L-92 and LP20. I wanted to find something that could also boost innate immunity. And so, that's where the Immuno strain came in.

That was kind of the thinking, was like how do we just wade through all the – these companies are putting like 10, to 20, or 30, maybe $50 million into these strains. And so, they're going to try to put out studies that show them to have like the best outcomes. But we've all read the research sometimes. Or we've all fallen for really cool ideas only to see them not work in clinic.

And I was trying to wade through that and find out what is the most robust data? What might play together? And how could we build a product that is going to hopefully get us an outcome no matter what?

[00:38:36] SCOTT: In addition to the paraprobiotics, you also have beta-glucan in the formula. We know that many people have low secretory IgA. But some can also have an elevated secretory IgA. How does the beta-glucan support secretory IgA? Is it more modulatory? Or do those people that maybe already have an elevated or high SIgA maybe need to avoid beta-glucan? And then given that beta-glucan is derived from a fungus, do you find that those people with the history of mold illness are tolerating it?

[00:39:11] STEVEN: When I looked into what else could we do in the gut immune system area? It was very clear that secretory IgA needed to be supported because its ability to bind to incoming toxins as well as bacteria and viruses. And sort of mark them or detoxify them was really important. And also, knowing that a lot of people with chronic illness have a depressed secretory IgA, as you mentioned.

And so, as I look through the research, beta-glucans were like just the hands-down winner. That even at 100 milligrams, they were showing good outcomes for secretory IgA as well as all kinds of things from less lost work days to better athletic performance.

And so, when I looked deeper into the research, it was very clear that some people were very concerned about the fungal source and the type. There's a debate in the beta-glucan community about is it 1,3? Is it 1,6? Does it come from oat? Does it come from mushrooms? Or does it come from fungus?

And I read as many papers as I could until I got really close to crying and realized that like, at the end of the day, I think they're all splitting hairs. The majority of the research on beta-glucans for like the history of what I could find in the research was done on fungal derived 1,3/1,6 blends. It was not the super specific 1,3 blends or the 1,6 blends. Or the mushroom and the oat-derived versions are pretty new to the market and don't have as much data.

As I kind of just took a step back and said like, "What works even at 100 milligrams?" Well, we have data saying 1,3/1,6 fungal-derived works at even 100 milligrams." We put 250 milligrams in the product knowing that that also works. And it's been studied way above 500 to 1000 milligrams.

And so, I assumed there would be blowback because it come from a fungal source and people were going to say like, "Well, I think I'm going to cross react or I'm going to have struggle with this." And I still went ahead with it because the data was just so much more supportive for that type of product. And so far, the refund rate on the product and the feedback on the product is right in line with all our other products, right? Around 3% of people react to it. And the majority of these people I would consider hyper-reactors to everything. These are the mast cell activation syndrome people. The super high histamine related people.

I don't believe you could say like these are fungal people. In fact, we have a huge mold following. And many of them already have had mold battles or are undergoing one and don't seem to be reacting specifically to it because of that. I think the people who do react to the product are having doing more of a histamine or just a complete immune sort of awakening explosion. And it's not the fungal sourcing issue. It's just the product in general.

[00:42:03] SCOTT: Yeah. And unfortunately, too, there's the overlap between the limbic system in this patient population that there already is that hyper-vigilance that's happening. And so, even in some cases, I'm not saying this is always the case. But in some cases, just knowing that there is beta-glucan derived from a fungus. Sometimes that's enough to trigger that limbic response where we're then going to be more reactive just because we know that potential is there.

[00:42:29] STEVEN: Yeah. Yeah. I mean, that's a whole other show if you haven't done it yet, just about the placebo and nocebo effects. And that's 100% happening in some cases.

[00:42:39] SCOTT: With this HoloImmune product, can there be an initial immune activation response or a die-off type response where someone might initially feel worse when they start taking a paraprobiotic? They start getting their immune system more modulated? Do we have that potential? That when we start to modulate the immune system, what are some of the things that someone might notice? And could any of those indicators be potentially uncomfortable for the person taking the product and yet still be a good sign?

[00:43:11] STEVEN: Yeah, great question. And so, let's divide people between the super crazy sensitive and then just the super sensitive. And so, the super crazy sensitive, I'm going to classify them as people who have to start with a sprinkle. Who are actively doing limbic reset training or other parasympathetic training because they really have to almost live in a bubble, right? Their world has to be very hyper-controlled, both the air, the water, the food the products. Otherwise, they have a reaction.

Those folks need to be more aware just like they are with everything else from curcumin to HoloImmune. And they should start slow with a sprinkle. And they're the most likely to have a reaction.

Even the sensitive folks though, they should be on guard. The majority of them do not report at one pill or a half pill a day like some sort of die-off experience. They don't necessarily report like an immune stimulation. If you're going to go to a immunotherapy program where they're injecting you with the toxin or something, like they do in some of the exposure therapies, you're not seeing like a uptick of rashes or an uptick of nasal congestion or something. Whatever your pattern might be there.

In general, it is typically going to happen like right away in the first like 24 to 48 hours. If that's the case, they should half the dose. And if they can't tolerate that then, then it just might not be the right time for them.

The majority of people just kind of get going on it and then start to notice things usually in seven to 14 days. And the things that they would be wanting to pay attention to are the things that they struggle with. Let's say it's someone with unexplained rashes, dermatitis, dry skin, things like this. The bugs have been studied for that. So, you could pay attention to your skin quality.

If you're someone who reacts to foods, I'm not saying you can take this and just eat whatever you want. But I am saying that, as you get cross-contaminated or as you try to expand your diet, it should be easier.

The big thing that a lot of people are reporting, and it's not everybody, but maybe 30% to 40% of users is a neurological benefit that happens pretty quickly. And so, if you play some sort of memory-based game, if you play like the Wordle games, the crossword games, pay attention to how quickly you solve the puzzles. Pay attention to your scores and things like that. Because there seems to be a neurological soothing for the people with some sort of interaction between the gut and the brain.

[00:45:51] SCOTT: Starting low and slow in more sensitive people. And then what's the target dose of HoloImmune?

[00:45:58] STEVEN: We're still trying to get a full grasp on exactly the benefit for each population. But I would say one capsule per day works extremely well for the majority of folks. I would say 60% 70% of people feel it. They have less hay fever. They have less rash. They have less everything.

A lot of people, that 30% or so, can have like double the benefit at two per day. And then we've had some rare occasions. We've had a number of concussion patients who are struggling. They're doing hyperbaric oxygen. They're doing keto. They're doing all kinds of concussion protocols and still struggling with dizziness and sensitivities, like light sensitivities, things like this. And they've been taking like four a day spaced out throughout the day and are able to have some resolution of those symptoms. Do it for a loading phase of like eight weeks or so, eight to twelve weeks, and then come down to one per day and not have a recurrence of those issues.

I do think that there could be a loading phase for people as we're sort of retraining or retolarizing the immune system. Again, if we go back to the mechanisms of how we hope it's working? What the studies suggest it's doing to the body? If we load the body up, almost like you're going to the gym to get a better body. You're going to try to push the weight. You're going to try to get the body you want. Maybe you have to lose some fat, gain some muscle. But at some point, you may decide that like, "Hey, I've achieved 80% of what I want to achieve. I don't need to go to the gym four days a week. I only need to go two days a week or one day a week." And so, I think a very similar analogy applies with these products and this product specifically.

[00:47:41] SCOTT: You mentioned earlier, Cyrex is one of the labs. They have their Lymphocyte Map, which I personally did not long ago. And fortunately, things looked really good. But I'm interested in whether or not you've done any before and after testing? Or had anybody send those to you such that they've done maybe a Lymphocyte Map, they start HoloImmune, they've done another one to see what some of those documented shifts might be in Th1, Th2, NK cells? All of that? And any testing yet that we're aware of in this paraprobiotic realm?

[00:48:14] STEVEN: My wife, Shay, was – part of how we started to find the Post-It note moments and started to find out some of the stuff is she had completed her breast cancer sort of like intense treatment. And we were searching for how do we know when we're just doing functional and integrative medicine in longevity? And when are we doing cancer therapy?

And the answer – I still don't know of anybody out there really that has an answer to that. When do you give up your cancer therapies? And when you go back to just working on longevity?

And so, we found a doctor, Dr. Tom Incledon, at Causenta Wellness in Scottsdale, who specializes in stage four cancer and very complex issues. And he said, "I have a way. It's going to cost you a lot of money." We did about $25,000 for the testing. More testing than I ever knew was available on the market.

And I had gotten her on HoloImmune. Because she's my partner, she resists all the stuff I create because she doesn't identify with having gut issues. She doesn't identify with having these things. But I got her to take HoloImmune because of the viral protecting properties. And so, she's a bit depressed because her mom had passed away. She's playing the crossword games every day. Taking HoloImmune. She's got to stop for seven days to do this $25,000 for testing. And so, she stops, and her tests just drop off. On her crossword games, they just drop off the map. She's confused. She's drinking way more coffee.

We get the neural panels back from Vibrant America. We didn't do the Cyrex. We did every test Vibrant offers. Plus, a lot of other tests from a lot of other companies. And what was interesting is that when we reviewed her immune panel, their lymphocyte panel at Vibrant, as well as her neural panel, she had really low B cells. And then she had high Tau plaque and high amyloid beta 1-42, on the neural test from Vibrant America.

And so, she goes back on the two per day. She likes two per day. And she's like, "I got 20-year-old brain back." That's what she says. But if I had asked her, and if I asked her now, "Do you consider yourself to have brain fog? Do you consider yourself to have neurological issues?" She would argue to the end of the Earth that she had those issues.

But the test showed that inflammation. And being on and off of HoloImmune showed that there's some sort of direct inner play between her immune system, and her brain, and her gut. And so, I hope that if people are listening to this, they try the product, they run a lot of these Cyrex Lymphocyte Maps, or Neural Zoomers, or other Vibrant tests that we can do some before and afters. Because I think we're going to find some really cool stuff here.

[00:50:52] SCOTT: We know that a lot of the community listening is very sensitive. We talked a bit about that. Don't tolerate very many supplements. Don't tolerate many foods. Don't tolerate a lot of environmental exposures. Have mast cell activation syndrome. Have immune hyperactivation. Let's talk a little bit about in that population and maybe specifically kind of the mast cell activation syndrome, which is a very large portion of the population that we're talking about here. How well tolerated has HoloImmune been in that more sensitive population?

[00:51:30] STEVEN: It's been really well tolerated if you're not introducing it when someone is in the hyper-reactive stage. And so, again, if we're thinking about how MCIS presents and how these people are presenting, if they're reacting to perfumes and smells, if they're mostly having to live kind of, again, more in a bubble in order to get through life, the HoloImmune product could over-stimulate them.

And so, I think it's better to introduce whatever limbic training you need to introduce some mast cell stabilizing compounds, like quercetin, maybe tributyrin, things like this. And then once they're a little bit more stable and they're trying to re-engage with the world – and I think that's the key. If we go back to the very beginning of this chat, which is what is your tolerance with the greater world around you?

When they're ready to engage with the world and expand the diet, expand their environment, that's when HoloImmune seems to really help them have a breakthrough. Because you're bridging from how do we just sort of crutch the system? How do we crutch the mast cells to – how do we get the mast cells and the immune system at large to deal with regular life? And so, it's very well-tolerated when it's in that sort of second phase for these individuals. It's not as well tolerated in the beginning.

[00:52:50] SCOTT: Let's talk a little bit about responses people have had to HoloImmune where maybe they observed that they could tolerate more foods? Or could tolerate more or different external environments and not be so reactive? In those people where their world has become really, really smaller and smaller due to hyper-reactivity, are we seeing HoloImmune potentially allowing them to have more tolerance with foods and the external environment?

[00:53:19] STEVEN: Yeah. We are seeing people drop off their antihistamines, like Claritin. I was able to get Shay, my wife, off of like a 30-year usage of Claritin. And we've seen some other team members and some other clinics be able to transfer people off of stronger antihistamines onto HoloImmune and then continue to interact with the world and reintroduce things like, for instance, strawberries. There's a well-known person who couldn't interact with strawberries. She has MCAS, and HoloImmune allowed her to basically eat strawberries again.

And so, if we look at the data in these paraprobiotics, all three of them, usually they tested them for 8 to 12 weeks. And over those 8 to 12 weeks in humans, whatever the outcome they were chasing or looking for, it got stronger or better each week as it went.

And so, if we think about someone who's in a hyper-reactive state whose world is kind of shrunken in and they're trying to re-engage with the world, I think the appropriate thing is go slow, go low. And also realize that is – literally, you're ingesting something that's saying it's okay to be in relation to the rest of the world.

Give it some time. It's not a pharmaceutical drug. It's not a miracle pill in that regard. You do have to basically let your immune system sort of warm up. Just like the training analogy, you don't go into the gym and just pick up 300 pounds and squat it. It takes you a while to get there. And in the same regard, HoloImmune is like a trainer to your immune system to relax into the world.

[00:54:56] SCOTT: We're both in Colorado. Allergy season has started in the last week or so. I wonder if you can talk a little bit about paraprobiotics in terms of respiratory health? In terms of how they might support people dealing with seasonal allergies? And is there a role for paraprobiotics potentially in people with asthma?

[00:55:17] STEVEN: Yeah, the answer is yes. Because when we look at the etiology of a lot of these conditions, again, we often see a high-drive of IgE formation. And the L-92 strain specifically helps to inhibit that. We also need more T helper cells to just kind of modulate everything and bring Th1 and Th2 out of some sort of like whiplash into a just less – the volatility. Less volatility between the two sides basically.

And so, there are studies, especially on the L-92, strain for hay fever. And basically, the studies showed that, over the 12-week period – the sampling at four weeks eight weeks and 12 weeks. And each of those time frames, the people's like itchy eyes got less. Their complaints around their symptomology was getting less over time.

And so, there's not data on what happened after the study. I can't say that if you just took it, that would like "fix your allergies". I'm not saying that at all. It seems to be mark more of a supportive agent during allergy season.

And then if we think about asthma, if we think about how butyric acid and – in general, I mean, I guess I don't know if you agree with this, Scott. But one way I've thought about the immune system after I've looked into this is that it's kind of like WhatsApp for the body. It's a communication protocol in some ways between the gut and whatever your genetic weak link is.

It's got some food coming in. It's got environmental toxins. It's got water, air coming into the gut. The gut then sends the signals through the body, through the cytokines, through the histamine pathways. And then wherever you accumulate your genetic weak links. For some people it's asthma. For some people it's rashes. Some people, it's brains. Some people, it's heart. The immune system is like the communication protocol to that end point.

And so, to say that the immune system is "wrong, broken" I think is kind of the wrong way to look at it. We should look at where the end point is. Like asthma, it's in the lungs. And then we should say, "Okay, do we need to update the code or the incoming information?" And a lot of times the answer is yes. The protocol, the communication protocol, isn't necessarily broken. It's just transmitting the wrong data to the endpoint.

And so, I think in a lot of cases we can do this through, like I said, quercetin. We can do this through zinc. We can also do this through paraprobiotics. Where we can change the signal that's propagating through the system, in this case, asthma to the lungs. And we can slow down that communication. We can slow down those cytokines potentially and help alleviate those symptoms. I don't think we're going to fix it with something like just paraprobiotics. Because we're talking about the whole gut in and of itself and all the signals that it's sending out to the rest of the body. But I think it's one tool to help modulate that sort of communication protocol.

[00:58:24] SCOTT: You mentioned some of the research that had been done on skin conditions. You've mentioned rashes. Do we know or have any feedback on HoloImmune or paraprobiotics in people dealing with psoriasis or eczema?

[00:58:38] STEVEN: Yeah. So far, we've had really good feedback. That would be like one of the top things I would use this product for would be somebody with psoriasis, eczema, unexplained rashes that they can't get a diagnosis on. And then for some folks, it really does help with dry skin as well.

And again, I think of the skin as kind of like the outside version of the gut. And the gut is sort of communicating all the way through to the skin. And so, you can look at our customer reviews on the site. And I would say maybe 25% to 30% of them are very happy about some outcome related to their skin. The LP20 Strain has data on less wrinkles and more like less dryness. The L-92 strain is the one that has the dermatitis and eczema data.

[00:59:25] SCOTT: I wonder what would happen if you made a topical paraprobiotic? How that would modulate the local immune system for people that have conditions like that? That's an interesting idea.

[00:59:37] STEVEN: It's happening. Yeah, there's a few studies.

[00:59:39] SCOTT: All right. Cool. Very cool. If we think about paraprobiotics as immune modulators, they then, in turn, would potentially be modulating the inflammatory response. Do we think of paraprobiotics as having a role in reducing systemic inflammation? And do they have any antioxidant properties potentially?

[01:00:02] STEVEN: I don't know about antioxidant properties. I can't say that I've seen or read anything regarding that specifically. But if we look at, again, systemic inflammation, again, I think the immune system and people probably will be really mad at the whole communication protocol analogy of the immune system. Everybody can nitpick about immunology right now. And everyone's an immunologist. I am not one. But I have been reading about it intensely for a few years now.

And a part of systemic inflammation to me is the inability to turn off the inflammatory response. In other words, the innate immune system gets going in one direction and nothing's telling it, "Hey, slow down." Or the adaptive immune system gets going in a certain direction like making Hashimoto's antibodies or something. And nothing's telling it to cool it.

And so, that's just one aspect of systemic inflammation. There's lots of things that can cause it. There's lots of things that can impact it. But I think where paraprobiotics would play a role in systemic inflammation is helping the body to produce more plasmacytoid dendritic cells, helping it to produce more T helper, T suppressor cells that will help turn off runaway inflammatory pathways on the innate side or the adaptive side.

[01:01:16] SCOTT: Are there any direct anti-microbial properties of paraprobiotics? I may be misremembering. I seem to remember that maybe there were some anti-fungal properties of some of the paraprobiotics. Are there any direct antimicrobial properties? Or is it all through immune modulation?

[01:01:34] STEVEN: I would say probably 98%, 99% of it is through indirect immune modulation. Because again, these are dead cells. And sometimes the cells are – the cell wall is intact. It's still whatever it looks like in the attacked state. Sometimes it's broken apart.

And so, if the broken apart cell wall contains some sort of chemical compound that might be indirectly anti-microbial, I think that might be happening. But in general, I believe they'll be up regulating something secretory IgA. They'll be up regulating maybe some alpha or beta defensins. They'll be just priming the plasmacytoid dendritic cells better to kind of deal with whatever pathogenic microbiome that's happening.

[01:02:17] SCOTT: In one of the earlier interviews that you had done on paraprobiotics, there was some discussion about paraprobiotic's ability to raise butyrate. And I'm wondering, is that a significant increase in butyrate where there might actually be some clinical benefit? Or is that more research-based and really looking at smaller shifts in butyrate with paraprobiotics?

[01:02:40] STEVEN: Yeah, I would say, at this point, it's again second-third order consequence. It's much more – like if you're a gun to my head, you're like you have to raise butyrate in this individual. I would not choose a paraprobiotic to do that. I would be choosing a prebiotic, probably a resistant starch. I might choose some Lactobacillus rhamnosus GG alive and some Bifidobacterium to kind of cross-pollinate and work on that person. Or just directly replace it with like a Tributyrin.

The data suggests that, indirectly, the paraprobiotics are creating a better environment down there. And through that better environment there was a 12-month study on the LP20 strain where they gave it to these people for 12 months and they're like, "Hey, we got to figure out if this is going to over-activate the immune system long term. And could we harm people?"

Luckily, they found they did not over-activate the immune system and they didn't harm anybody. And what they did find was like these subtle shifts in the microbiome over the 12-month period that you might characterize as closer to a healthy person or a control person in a study.

Now I don't believe microbiome research is anywhere near the place where we can like specifically say that person's microbiome is unhealthy in this way. And we can prescribe this one probiotic to fix it. I think that's a pipe dream at the moment. But if we look at generalized population data, after 12 months of the supplementation, they had a more healthy presentation. But they were already healthy people to begin with. I mean, I think we might be splitting hairs there.

[01:04:23] SCOTT: Do we know if there's any effect of these paraprobiotics on the autonomic nervous system? On the vagus nerve? Might there be some aspect of paraprobiotics that really can kind of help to calm down the system in support of the overall healing process?

[01:04:38] STEVEN: Yeah. There is a little bit of data. Mostly in the rats. We don't really have a ton in humans yet. That would suggest that this is happening. But the mechanism and exactly what is happening is still completely unknown. If we think about the fact that 30% to 40% of people taking this product between one to two capsules a day are reporting some sort of nootropic benefit or cognitive benefit, there has to be something that is happening likely via the vagus nerve. And it's likely related to a signaling molecule.

Maybe it's reducing IL-6. Maybe it's – I don't know. Upregulating something else that's helping parasympathetic tone? I don't know that if we know if it's – is it in parasympathetic tone? Or is it a reduction in a cytokine that is inflammatory to the brain? I don't know that we know that yet. And there are clinical studies ongoing right now on paraprobiotics for dementia and Alzheimer's. And I think we'll know in the next two to three years what they find from those studies.

[01:05:37] SCOTT: Have there been any studies looking at these paraprobiotics in people with anxiety, or depression, or any known effect on neurotransmitters?

[01:05:48] STEVEN: Not that I've seen yet. It doesn't mean that it doesn't exist. Again, this isn't what I spend every day of my week on. But I look for them because these are conditions that are near and dear to my heart that I've struggled with. And so, I have designs to try to build products for these folks in the future. And so, I always monitor the research.

If we think about neurotransmitters, again, I think being that they're dead bugs, it would be really hard to directly affect neurotransmitters. If it was affecting anxiety or depression, I would think it would be through, again, that reduction in the inflammatory state of that condition. Not necessarily a direct impact on the neurotransmitters for that condition.

[01:06:29] SCOTT: There's been some research around paraprobiotics and oral health, and specifically gum health. I'm wondering if you can talk to us about that? What have you seen? Have people commented with HoloImmune yet that they've noticed any improvement in their oral health? And does the paraprobiotic need to then come into contact with those tissues directly? Or are these the result of systemic balancing or modulating of the immune system?

[01:06:56] STEVEN: Yes. I think this is the one study that I think when people – people's eyes gloss over a lot when I try to tell them about this topic. But this is the one study where they kind of perk up because they're like, "How would that happen?" You're taking something in a capsule that is not interacting with my mouth at all. It's entering my gut. It's opening down there. And you're saying that they have clinical data that periodontal disease pockets were lessened. And that's true.

The LP20 Strain, they did a pocket study where they – if you're not familiar, they do these – basically they rate the depth of the pocket from one to four usually. And so, what they saw in the study was that the four pockets, some of them lessened to threes.

And so, the worst pockets basically got slightly better. And it was only a 12-week study. No one really knows like what happens if you take it for a year? Might it continue to get better? We don't have those answers yet. But if we think again about inflammatory disorders, genetic weak links, where do we express high inflammation states? And where do we express a lot of immune activity?

The mouth has a ton of immune activity actually going on. And I don't think a lot of people – I didn't appreciate it anyways for a long time. And so, periodontal disease seems to be – just like there's links between heart disease and the mouth, it seems to be directly related to the microbiome of the mouth and the ability to interact with that microbiome and modulate it.

And so, the LP20 strain does appear to do something there where it's correcting these pockets which are indicative of a worse disease state. And it's not touching the mouth at all. Now what happens if you put these in toothpaste? I don't know. I hope someone does it someday because that'd be pretty cool.

[01:08:38] SCOTT: As we get older, there's a concept of immune senescence, where the immune system kind of tires, or wears out, or deteriorates over time and we have greater potential for acquiring infections. Do we think that paraprobiotics can assist in mitigating immune senescence and keeping the immune system smart and alert as we get older?

[01:09:01] STEVEN: Yeah. Actually, 100%. The Immuse strain has a study on elderly individuals and their ability to acquire antibodies in that study. And so, part of the immune system, after 60 usually is when it starts getting pretty bad. After 70 and 80 is when it's really going downhill fast. Yeah, your inability.

Again, we saw this. If you go look at – whether you're for vaccines or not. If you go look at the vaccine data, the folks over 65 had a really hard time acquiring immunity using the vaccine method. And one of that is just related to their adaptive immune system's ability to acquire the antibody capacity, the B cell capacity, all these types of capacities.

And so, I do believe paraprobiotics could play a role and should play a role, at least for myself, they will, and I'm trying to get my parents on board, in essentially long-term stimulation and training of the immune system just to age well and keep it as healthy as possible.

[01:10:02] SCOTT: I read that some paraprobiotics may have a role in controlling malignant cells. I know that's not something that you're claiming that HoloImmune can do. But any thoughts on how paraprobiotics might interplay with various cancers?

[01:10:18] STEVEN: Yeah. Cancer is near and dear to my family. As I mentioned, Shae, my wife, and her breast cancer journey over the last four years. And she's doing great now. She's many years of no disease. Or no evidence of disease. And we have these $25,000 worth of tests just showing us that we have a little a few things to deal with. But her mom passed away from stage four breast cancer. And so, we've been in a cancer sort of rabbit hole or household for like five or six years now.

And cancer is very complex. And so, with complexity, people, at least I and I think most people, want simplicity because it's just hard to wrap your brain around all the possibilities when it comes to cancer. And you could apply that to mast cell activation, any number of these really complex issues.

One thing that is true about cancer and is a hallmark of cancer is immune dysregulation. Basically, the immune system cannot or is unable to find the cancer tumor cells, the daughter cells, and eliminate them as fast as needed. And in some cases, it can't find the cancer stem cells and eliminate them. Or it seems unable to detect them.

If we're looking at just one small aspect of how does cancer happen and what is ongoing with cancer and this inability to find and eliminate cells that have gone rogue or gone zombie? I do believe modulating the immune system, having the strongest, most resilient, most tolerant immune system is the way to go.

Again, the feather, the hammer, the jackhammer. We want the immune system ready to deal with whatever's coming in. If it's just grass pollen or tree pollen, we just wanted to interact with that. But should it detect some sort of rogue tumor, we want it to also react to that.

And so, having a flexible and smart immune system I do believe is the best way to have a healthy human body. And it seems like immune dysregulation is a homework of cancer. And it seems like paraprobiotics help with immune dysregulation. I believe they could play a very small part in the battle for making a healthy human who has cancer.

[01:12:31] SCOTT: When people are taking HoloImmune, you mentioned some people notice some effect within a couple of days, within one to two weeks. How long does the average person need to take it to feel like, "Oh, something's actually happening?"

You mentioned that a common dose target is maybe one capsule a day. Maybe one twice a day. And some people starting with less if they're more sensitive. Talk to us a little bit about when you might notice a shift? And then, how long might you stay at that target dose before you either would reduce or pulse? Or would you stop and then kind of maintain those immunomodulatory benefits over time? What happens once we get to that place where we've gotten the benefits? How do you then continue to use paraprobiotics?

[01:13:17] STEVEN: I guess I haven't mentioned this in our entire talk. But it's worth mentioning that this is the first time this has ever been done that I'm aware of in the world. While there's been single strains of paraprobiotics that have been on the market for 20 years in Japan, while there's been beta-glucans on the market for like 30, 40 years all around the world, I am unaware of a time in which someone has combined multiple paraprobiotics into one capsule along with beta glucans.

If it was just beta glucans in one pair of probiotic, it'd be even easier to sort of understand and make conclusions from. But it's not. It's three paraprobiotics that all have their own lineage of research with the beta-glucans. And so, these are three clinically powerful products all in a capsule. We don't know, honestly, really what happens over a year or two years’ worth of usage. We don't really know if there's an upper bound or an upper limit.

We do know that one of the products, the Immuse, has been studied at five times the dosage. That's in one capsule. We do know that using the LP20 amount for you know 12 months, a full year, doesn't cause any issues. And the mice studies suggest that the upper limit of one pair of probiotic would be around 50 to 100 times what's in the capsule. Usually around like a thousand milligrams of some of the smaller dosed ones. Not the Immuse one.

And so, I believe the safety data is robust on these things. But in general, I think people need to realize that we are really at the forefront of immunology. We're at the forefront of these paraprobiotics as well as probiotics. And you need to be an adult. You need to pay attention to your own symptoms. You need to be taking a look at it. And you should do pill stops.

If you're someone who's adventurous, you're a biohacker, you've been stuck, you're motivated by this talk, you want to break through, great. Start and go up. Like I said, people have taken four or five a day and done that for a loading phase of around two months and then come back down and have had really great anecdotal reporting.

I would suggest that you do sort of pulse like that and also give it a pill stop. See what happens. This is not a product that I know that people should be on forever. I don't see anything that suggests they shouldn't. But I do think that we have to learn and grow together. And I would love all the feedback that I can get on this.

Because until we're much bigger company, we can't fund our own research on this. And so, I hope to do that someday. But until then, we're going to have to rely on the clinics who are feeding back data, who are using it clinically as well as the customers.

[01:15:51] SCOTT: Are there any reported side effects of paraprobiotics? Any contraindications? You mentioned people with lupus, for example, and the potential considerations around the pDC cells. Would we use this product in someone who had a diagnosed autoimmune condition at this point? What are your thoughts?

[01:16:12] STEVEN: Actually, yes. I would say the majority of our customers have diagnosed autoimmune conditions and they're using it with great benefit so far. And they're really liking it. I do believe it has a bit of an adaptogenic profile and that we're, again, not pushing just one pathway of immune modulation. We're pushing multiple and competing pathways at the same time, which was sort of a safety engineering factor that I've tried to build into the product.

I do believe, frankly, that it's safer than live probiotics for a extremely immunocompromised individual or extremely elderly individual. If we're putting it on a spectrum, I would say the research so far suggests for elderly or extreme immunocompromisation. You'd want to pair paraprobiotic over a probiotic to begin with.

But as I've mentioned, the people who have the adverse reactions so far and ask for a refund are the people who are very sensitive. Who already know that they're supposed to be starting with a sprinkle or two sprinkles. Or who have very restrictive lifestyle. They have to control many, many factors in order to get through their day. I think this comes in secondary to whatever they need to do to get out of that current restrictive state.

[01:17:26] SCOTT: Are there other paraprobiotic products on the market today that you know of?

[01:17:31] STEVEN: You can find the Immuse strains by itself. You can you can find the LP20 strain by itself. I don't know of anybody else who's done a combo product yet. There's a lot of research. They're starting to see a lot more strains come out. Companies are realizing that they could kill it. They own the strain already. They realized they can kill it and cause a different reaction. The market's still pretty narrow, and HoloImmune seems to be kind of in its class by itself. But I don't think it'll last.

[01:18:01] SCOTT: If we take prebiotics, probiotics, post-biotics, and now we have this paraprobiotic, where do paraprobiotics fit in in the context of those others? Is there an optimal order in terms of how they might be introduced in a protocol? And do we potentially need all four of them to shift our immune system and our microbiome in the direction of health? How would you layer those into a protocol?

[01:18:25] STEVEN: If I had to layer all those in, I would layer in – I would probably layer in post-biotics first or butyrates first. Then I would layer in paraprobiotics, then prebiotics, and then probiotics. I think of probiotics sort of as the last tool to pull out. And it's a very, very important tool. Like I said, there was that one strain early on that like if you want more lean muscle mass and better exercise performance, you want the live strain. You don't want the dead strain. And there are live strains that do really, really cool stuff. Whether you're looking for – we talked earlier about anxiety and depression. There's certain strains that work. There's a new one called PS128 that's in a live stream that's got some really cool research on depression.

I think they're very helpful. But I think we got to rebuild the ecological system to really benefit from them and not have reactions. And so, you can also overlay that onto – are we talking about just a generalized person going throughout their day? An athlete? Or someone who's dealing with known chronic immune dysfunction?

If you have known chronic immune dysfunction, if you have food allergies, if you have hay fever, if you have rashes, atopic dermatitis, things like this. If you have neurological brain fog, you consider those things to be part of your daily life, then we know you have an immune dysregulation. And the tools for those issues are not found in probiotics, or prebiotics, or even butyrate right now. A little bit in butyrate. But they're mostly found in paraprobatics.

But if you're talking about something else like leaky gut, you're going to be wanting to talk about your butyrates and your Tributyrins, your postbiotics, and maybe your prebiotics. Because in the long run, I think we will have something we're working on. Let's say we want to lose fat or gain muscle. Or let's say we want to stop having to take Claritin for hay fever, we should be choosing products that are matched with that based on our level of health.

And so, I guess it's a yes and. And I don't mean to make this more confusing than it already is other than focus in on products that are studied specifically for the outcomes you want and then layer them in based on their level of reactivity. And I think live probiotics have the most reactivity. Prebiotics have the – just underneath of that. A lot of prebiotics are not well-tolerated. And inulin and FOS can actually be counterproductive especially in IBD states and IBS states. They can cause weird microbiome shifts that are not good.

And so, let's prep the gut first. Let's prep the immune system first with postbiotics and butyrates and paraprobiotics. And then let's bring in the sources of the right microbiome, which is typically the prebiotics, and the vegetables, and the fruits things like that. And then let's modulate everything and kind of connect it all together with our with bugs.

[01:21:13] SCOTT: I like that. That's awesome. In our last conversation we talked about SIBO in more detail. A lot of the other products that you have that can be fantastic for people dealing with gut related issues. Do you see a role for HoloImmune in people that are dealing with SIBO?

[01:21:31] STEVEN: Yeah, I do. Again, we just tend to attract a lot of people with recurrent SIBO and recurrent gut infections because it's kind of what the company is about. It's helping the tough cases. And part I think of SIBO is, again, a mismatch in the state of the world around the body and the body's ability to be with it. And so, in other words, there's incoming food, there's incoming data that suggests that there should be an overgrowth of bacteria in the small intestine.

There's a lot of competing thoughts about live probiotics with SIBO. Some people are for certain strains. Many people are against all strains. Paraprobiotics are dead. And so, they're not introducing sort of like competing growth. Or there is no possibility of contribution to overgrowth. But there is possible contribution to up-regulating the immune system's ability to clear the small intestine and keep it clear.

And so, if we think about how we might use a paraprobiotic in a case of a small intestinal issue, is I would say you start to layer that in during your killing phase. But then you got to hold it through another eight weeks past the killing phase. And the goal is let's get that immune system at tip top shape by the time we pull out the antibacterial, the anti-fungal, or whatever it is. And so, that hopefully the body can carry itself without too much extra ongoing support.

[01:22:57] SCOTT: My last question is the same for every guest, and that is what are some of the key things that you do on a daily basis in support of your own health?

[01:23:04] STEVEN: I'm doing some breath work and some meditation again right now. And that's a huge part of my ongoing health. I do take HoloImmune. I take every one of our products every day. I don't build stuff just for fun. I also build it for my own health and getting through my day.

I think beyond that, I just try to play with our dogs, and try to get outside, and try to remember that – and I'm terrible at it. But I'm getting better. That like while the world might be seemingly melting down according to Twitter and the internet, everything's just fine. It's still one of the best times to be alive. We can do conversations like this. And we have access to these extremely cool compounds we can put in little pills and they can help us.

[01:23:50] SCOTT: Awesome. Such a great conversation. I love that you have the research that you're doing. Trying to come up with new solutions for people that are dealing with these complex chronic conditions. I'm always excited when Healthy Gut comes out with a new product. I'm looking forward to some new innovations coming our way from your work and your research.

Stephen, thank you so much for everything that you do and for helping all of us in this community. Appreciate it very much.

[01:24:16] SCOTT: Thanks, Scott.


[01:24:17] SCOTT: To learn more about today's guest, visit BetterHealthGuy.link/HoloImmune. That's BetterHealthGuy.link/HoloImmune. BetterHealthGuy.link/HoloImmune.

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