From Pre-Alcohol to Fiber: Genetically Engineered Probiotics with Zack Abbott, PhD

Welcome to The Perfect Stool: Understanding and Healing the Gut Microbiome. This is your host, Lindsey Parsons, and today I'll be speaking with Dr. Zach Abbott, the CEO and co-founder of ZBiotics. Zach has a PhD in microbiology and immunology from the University of Michigan and holds a bachelor's degree from UC Berkeley where he double majored in immunology and classical art and archaeology. Zach's PhD thesis was on bacterial gene regulation, and he became an expert at understanding how bacteria turn on and off different functions in response to their environment. But before our conversation, if you haven't yet followed or subscribed to the show, be sure to do so. If you want to get transcripts of the podcast, pop over to my website, HighDesertHealthCoaching.com, and sign up for my newsletter. You'll also get my free ebooklet, Finding Your Root Cause Through Stool and Organic Acids Testing, when you sign up. And if you haven't yet done my quiz on which stool test would help you get to your root cause, you can find a link in the show notes and take that. Now onto the show.

Welcome to the podcast, Zach.

Yeah, great, great to be here. Thanks, Lindsey Parsons.

Yeah. So why don't we start with how you got into developing probiotics?

Absolutely. So I started from when I was doing my PhD, I was working with bacteria and I really, really fell in love with all the things that bacteria were capable of doing as I started studying them. On the cellular level. And my research was really on how bacteria turn things on and off. And I thought that their capabilities were really impressive. And then separate from that, being part of my program and seeing the research of other microbiologists, I saw there was a, a lot of really cool research on all of this, the good bacteria in and on your body and your microbiome. And I think many people had been introduced to as a kid that bacteria were bad, they were germs. And so my initial interest in microbiology was really around preventing disease, infectious disease specifically. Which I do think is really interesting, but I really had my eye, my mind blown wide open to see that a lot of human health is actually dictated by the function of good bacteria that we interact with all the time. And so that got me really excited about whole new worlds and levers that we can pull for human health. So then kind of marrying those things together, understanding how bacteria function and thinking about ways that we could direct their functions to things that would be useful for human health rather than purely focusing on how we could prevent infectious disease. That was kinda how I got into bacteria and probiotics and eventually into engineering probiotics to, to sort of specific functions.

Yeah, I know. I was always surprised when I realized that when you say take an antibiotic or do something else to reduce the population of bacteria, that you're not getting rid of all of it. You never get rid of all of it. There's always some little bit of it somewhere in there. Even like when people have gut reports where it says below detectable levels, you can still bring those back. Like they're hiding somewhere in there.

Absolutely. Yeah. Yes, exactly. They, you'll never get rid of all the bacteria. And a, a, that's A really generally a good thing that you can't get rid of all them and be, but it also is what creates a lot of problems with things like antibiotics that because a few selectively can persist, then they have the advantage when they grow back. And so you get this reduced diversity, which ultimately in the gut microbiome specifically is a bad thing. The more diversity, the better for, for the gut microbiome.

Right. And then of course that those diverse microbes in that there are still some of the pathogenic ones, but as long as the diverse either are commensal or at least some are, some have good things, right? And bad things about them. Neutral, let's call it.

Right, right, right.

Bacteria. As long as that's the majority of what you've got, you're usually in good shape.

Exactly. I mean, so I think a good way to illustrate this is the fact that you have about as many bacterial cells as you have human cells in your body. And, but what's interesting is that all of your human cells have the same roughly 20,000 genes that perform the same roughly 20,000 functions. But all of your bacterial cells are all different and they have different sets of genes. So you actually have 150 times more more bacterial genes than you do human genes on a pure numbers basis. Functionally speaking, you're, you're far more bacterial function than you are human function. And, and so when you decrease that diversity, you lose a massive amount of diverse functionality. And so all those functions that those bacteria are doing to help you digest your food, help educate your immune system, help you modulate and mediate like your stress and the hormones and all cholesterol, all these things, they, they do so many things for us as sort of like symbionts or, or commensals like floating around. So the more of those you get rid of and the, the fewer different bacteria you have, the fewer functions you have, you're really reducing your own functionality in a way. And so that's really, I think what's important is preserving that diversity and functionality for human health.

Yeah. And producing your B vitamins, like that's a huge one.

Sure. Yeah, absolutely. So many things, right? Extracting or, and/or creating nutrients in the food you're eating. Yeah. So many things.

And so how do you actually literally turn something on or off or function on or off with the bacteria? What are you doing to it physically?

Yeah, that's a really great question. What I personally love, this is what I studied, uh, my PhD. So, you know, bacteria are these just incredible single-celled organism covered in all these receptors and sensors on the outside of their cell that allows them to really quickly and elegantly respond to whatever's going on. If there's nutrient availability or, or not, if pH changes, temperature changes, sunlight, all sorts of things. They have over the last 3 billion years evolved ways to essentially sense what's happening and then pass that signal on to their DNA and then turn different genes on or off when they would be useful. So if there's no nutrients around, you maybe want to turn the genes on so you can swim, so you can go find new nutrients, right? But if you're in a good spot, you don't want to waste your energy making, making proteins to swim. You want to, you know, you want to stay, stay put, you want to moor your boat. So bacteria, the way they do this is they have their DNA, they encode for these genes, right? So there's a string of DNA that encodes for like a protein, but then in front of that gene, is like a promoter. It's another sequence of code that says, turn this on in this situation, or turn this on a little bit or a lot. And so each promoter kind of has its own instructions about when a given gene should be turned on. And so for a microbiologist like myself who studies that, it's really just about— this has been happening naturally for billions of years, and we're just getting— we're starting to learn how they do that and understand that better. And so the better we understand that, the more we can then leverage those abilities. So we can say like, okay, well, this promoter or this sequence of code, is a sequence of code that tells the bacteria to make a lot of this protein. And so we can use that and we can put another protein behind that promoter and then get a lot of that protein to be expressed. Or this promoter says only turn it on when pH is low. And so then we can, can basically leverage the bacterial promoters that already exist in order to modulate when we want sort of a gene to be expressed.

By like exposing them to a certain substance or?

Oh, to change the promoter or combine a promoter with a new gene or something. It's really, you know, that's where genetic engineering comes in. We can PCR and we can amplify DNA from the bacteria and we can stick them together using, again, bacterial processes. These are all— the bacteria have figured all this stuff out. And so all we're doing is really using bacterial, natural bacterial processes, the same as if we were to do plant crossbreeding, right? Like the plant does all the work to cross over its DNA. We just move the pollen from one flower to another. So that's moving the DNA, right? And then, and so we, so we, we facilitate the interaction we want, but then the plant does all the work to kind of cross over its DNA. And the same is true with bacteria. If like, if we want to get a bacteria to turn on a gene, we just, we say like, hey, here's DNA that we want you to intercalate and, and deal with. And so in the case of ZBiotics, with the technology we use is, is called homologous recombination. And it's the way that bacteria already added their own DNA and So we can literally just mix the bacteria with a piece of DNA. The bacteria has already had— naturally has the ability to take up that DNA from its running environment, and then it can like scan that DNA against its, its own chromosome, its own genetic code, and then swap that piece of DNA in, in a super precise location. And all that, all those capabilities are already things that bacteria can do. And so all we're doing is now we understand that they do that and we understand how that DNA has to look for that to happen. And so we can just sort of, we literally just mix them together. Same as you do like plant crossbreeding.

And it does the job.

It just mixes it on in. Exactly. It does all the hard work.

Is this what CRISPR is?

CRISPR is sort of similar. It's actually very similar. It's another bacterial process. Interestingly, bacteria evolved CRISPR as a way to defend against viruses infecting the bacteria. And so basically CRISPR says like it has like an ability to basically do kind of a find and replace function like you would do in a Word document. So it gets educated by being infected by a virus and say like, okay, this sequence is viral. And so then it can say, it can take that sequence and then scan its genome. And then every time it finds that sequence, it can cut there, like really precisely at that specific sequence. And so we can now leverage— with CRISPR, we've sort of co-opted or changed or leveraged the function of the bacteria to very precisely cut DNA in a specific location and then co-opted that for us to like, in terms of editing or inserting something new into a very precise location. So it's a bacterial process that we've rejiggered or utilize in a unique way. And so homologous recombination is just, it's very similar. It also, homologous stands for homology, right? Like there's like a level of identity. So if we give you a certain, if we give that piece of DNA a certain sequence, then the bacteria will match it to a very precise location where the sequence is identical and then it will recombine or cross over all on its own. So with homologous recombination is really what that process was intended for DNA editing. And CRISPR is more like a defense system that we've rejiggered for DNA editing.

And why would a bacteria choose to change its own DNA?

Yeah, that's why they're so successful. They've been around for, you know, bacteria have been around for, for 3 billion years. And the reason they're able to do that is they're able to adapt and change as conditions change. So they, and one way they do that, they, they play a numbers game, right? So bacteria divide very quickly. They have many brothers and sisters that are, they're essentially identical. And so if a bacteria is swimming around the environment and there's, there's always bits of DNA floating around everywhere when, when cells die and things, they release their DNA. And, and so it's basically its strategy is, okay, I'll grab this piece of DNA and I'll, I'll check and see if it's like, if it's relatively similar to my own DNA, then it's likely that I'll be able to understand or express this code. So I'll just throw it in and see what happens. And maybe, maybe it's bad and maybe I'll die, but whatever, it's okay. 'Cause I have many other brothers and sisters who didn't take this piece of DNA. It's so we'll go on, but. On the off chance that it's good for me, then I'll be more successful and then I'll be able to proceed on. And so it's one of the ways— it's basically a survival strategy for bacteria to constantly be editing their DNA. And they have many ways that they do this naturally and lots of systems. And so really in the last like 50 years, humans have just become better at understanding all the ways that bacteria naturally already edit their DNA and then we can leverage them or guide them to make edits that are beneficial or perform some function that would be useful for us or for humanity.

Yeah. And how quickly can they do this homologous recombination?

Bacteria do that pretty much instantly in a matter of minutes. But for a scientist to just sort of direct that process, it's, we have an idea, we have to design the DNA and order the DNA and then mix them together and then select for the ones we wanted. And so that whole process takes a few weeks or a month.

Yeah.

Okay.

So I understand that you've got a couple interesting products based on this whole concept.

Yeah.

Tell me about the first one you started with, the pre-alcohol one. 'Cause I have a couple of clients that use that and they say it works for them by preventing hangovers. So tell us how that works.

Yeah, yeah, absolutely. It's a great lead up to, to that. So took probiotic bacteria, safe edible bacteria that you already eat every day called Bacillus subtilis. And then using homologous recombination, we basically inserted a gene that encodes for a protein that can break down acetaldehyde, and acetaldehyde is this toxic byproduct of alcohol that forms largely in your gut when you drink alcohol. The alcohol, the ethanol, is converted into this very toxic byproduct called acetaldehyde. And then usually that gets absorbed into the bloodstream. It sort of like wreaks havoc throughout the body, and then it makes its way to the liver where the liver breaks down the acetaldehyde really efficiently. But at that point it's kind of too late. And so kind of already had this, this damage. And the idea was that your liver expresses this protein, has this gene that can help combat the acetaldehyde. And, and actually most life on the planet contains a homologous version or similar version of this gene, this acetaldehyde dehydrogenase gene. We picked a version of this gene from another bacteria and we gave it to this probiotic bacteria. And so then now when you eat this bacteria, it can essentially break down that acetaldehyde as it forms in the gut before it gets absorbed and wreaks havoc and ruins your next day essentially. So that's the idea with the first product.

Cool. And I know it comes in like a little bottle of liquid, right?

Right. Yeah. So like a half ounce liquid shot. The idea is there's the bacteria and a little bit of flavor in the bottle. Drink this before you start drinking, then the bacteria already have the ability to pass through your stomach acid unharmed. It's one of the reasons why we picked Bacillus subtilis. It's this really amazing bacteria that has already came prepackaged with the ability to tolerate your stomach acid and become active in, in the gut.. And so then once it's in there, it starts expressing this enzyme. This enzyme helps deal with any extra acetaldehyde that might be floating around.

So when you say it's expressing the enzyme, does that mean it's putting it out there into your digestive tract?

Yeah. So in the case of the first product, PreAlcohol, what we actually did was instead of having a bacteria make and then secrete the enzyme out into the lumen of the gut, instead we decided to actually have the bacteria, cuz it was, it was easy to do, import the acetaldehyde. In fact, that already happens naturally. So actually the enzyme is still inside the bacterial cell, but then the acetaldehyde gets in there as well. And then the bacteria can convert that into acetate, which is essentially the short-chain fatty acid. It's essentially vinegar. It's innocuous. So from there, other metabolic things happen, but from the perspective of detoxification, it's the molecule's been detoxified. So all that happens inside the cell.

Yeah. So is it best to take it immediately before you start drinking?

Yeah. So this fundamentally is why I really was excited about the idea of engineered probiotics was that these bacteria will stay active, so they'll be able to make this enzyme continuously the entire time they're in your gut. And so with Bacillus subtilis, it typically passes through your gut in about a day. So you should have the ability to make this enzyme for about 18 to 24 hours after you drink ZBiotic. I typically take it immediately before I drink just because that's when I'm thinking about it, that's when I'm with my friends. But you could take it, you know, several hours before you started drinking and, and that would also be fine cuz the bacteria would already be in there and they'd be persistent for I could say about a day.

Now I'm not encouraging heavy drinking, but someone knows that when they go out, they do it up and they're having say 8 drinks. I don't know, 6 drinks. Should they re-up their dose somewhere after the first 4? I mean, how much can it handle really?

Yeah. So as you said, to be clear, I mean, product is built for as another tool in the toolbox for a responsible drinker. This isn't a get outta jail free card. It, it breaks down acetaldehyde, but that is only a part of why you might not feel great the day after drinking. The ethanol itself, a lot of that is absorbed into the bloodstream, which is kind of the point, and then it has the effects it has. And then most of that ethanol is processed by the liver. When that ethanol is processed, it goes from alcohol to acetaldehyde, and then subsequently immediately from acetaldehyde to acetate. So you don't get a lot of acetaldehyde formation in the liver like you do in the gut, but the liver is still dealing with a lot of ethanol, and that's a challenge. And the ethanol itself, It causes, causes poor sleep. It monkeys around with some of your hormones, like your hunger and satiation hormones and your ability to process sugar and, and, and insulin regulation. So there's a lot of things that are happening that this product has no effect on. So you still have to drink responsibly, but the, but especially as we get older, many of us probably anecdotally have noticed that 2 to 3 drinks when you're 45 hits a lot different than 2 to 3 drinks when you're 25. And that's in part because we get worse at dealing with that acid aldehyde. We have a bigger inflammatory response, we have less ability to tamp down inflammation. And so being able to target that acetaldehyde even after a few responsible drinks is valuable and still making sure we're pacing ourselves and getting plenty of sleep. Those are all really, really essential. But more directly to your question, is there a limit? Do you need to re-up? The answer to that in terms of gut-derived acetaldehyde is no, you don't have to re-up. There's enough bacteria in a bottle so you can handle as much acetaldehyde as you're likely to be exposed to in a night of drinking. That being said, there are many other things you're dealing with. So the more you drink, the more those other things might have impacts that start to get more and more magnified. And so we can deal with the acetaldehyde, but you're on your own for the other stuff. So still requires responsible drinking, but you definitely will feel better either way. So if it happens to be one of those nights, you're going to a bachelor, bachelorette party, you're going to a wedding, you're having a celebration and you know you're gonna drink more than you normally would, and you know that that's gonna result in you not feeling great the next day. Right. Having probiotics will help make sure that when you wake up the next day, you feel better than you would've felt otherwise. And your results in terms of what better means is gonna be variable from person to person and how sensitive they are specifically to the acetaldehyde. For some people, anecdotally, they say that they feel great, they feel nothing. And then others say, well, I definitely still feel groggy or, you know, a little sluggish or whatever, but the majority of what I'm dealing with is, is gone or, or is much better.

Yeah. I've actually never had a hangover in my life.

Like I, well, you are, I don't know, one of the chosen ones, I guess. Yeah.

I don't know why, but I think part of it is always because my own body will not let me drink too fast. I'll just get to a point where I'm just, I need some water. Like I have to, I have to keep flushing this out.

Right.

I cannot force myself to take another sip until I've, until I've diluted it a little bit and it'll help my body process it.

Totally. That's a big thing that you're hitting on there, which is that one of the biggest determinants of kind of how you feel the next day is the rate of alcohol consumption, how much alcohol per unit time. And so pacing yourself is like one of the best things you can do to set yourself for a good next day. Yeah.

And that's, and drinking, drinking a lot of water with it. Yeah.

Yeah, so water is good because it increases your blood volume and it basically allows more flow through of your liver and your kidneys, which are the organs that are dealing with these toxins, alcohol and acetaldehyde. So the more flow through you have there, the better your body's gonna be able to handle this exposure time you're gonna have to these toxins. So definitely drinking water, it is also really good for pacing yourself. So yeah.

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So some clients pointed out, and I, I know that when you have an overgrowth of Candida in your gut, it produces acetaldehyde as well. So I'm curious whether this might be a good treatment for people who really have an invasive candidiasis and, uh, and have all the concurrent symptoms like brain fog and mm-hmm.

Yeah, I think it's a really interesting and reasonable hypothesis. We, we didn't test for that specifically, so I couldn't say for certain, but the bacteria are intended to deal with gut-derived acid aldehyde. So I think that the most common reason that we experience gut-derived acid aldehyde is from consuming alcohol. But of course, theoretically, another source of gut-derived acid aldehyde would potentially be a target as well. But I, I couldn't say for certain because the dynamics are different. So I'm not, I'm not certain, but it's certainly a reasonable hypothesis.

Yeah. Okay. So then your other product is called Sugar to Fiber, which comes as a prebiotic drink mix. So tell me about that one.

Yeah. So I'm really excited about this. We just launched this one a month ago, so we launched PreAlcohol back in 2019 and it's been that long.

Okay.

Yeah. Yeah. And it's been really fun these last, I, I guess like 5+ years of us learning what it's like to try and tell people about the product and get people interested and all those sorts of things that I had to kind of like learn on the fly, but Yeah, with the second product, I've just been so excited about the fact that we're able to tell a bigger story. Having one product was great and it's a really fun product and people really understand the use case and the problem. But I hated the fact that all our conversations were always around alcohol. There's so much more we could do. And so I'm really excited that we have another product now to tell the broader story of all the cool things we can— there's many more things we can do. But our second product, as you said, is called Sugar to Fiber. And so we've engineered this bacteria, same, same bacteria, Bacillus subtilis. So we've engineered it now to express an enzyme instead of breaking down acetaldehyde. This enzyme can convert sugar into fiber again in your gut. So fiber is just a long string of sugar stuck together. This enzyme is basically able to take table sugar or sucrose. And so sucrose is just a glucose and a fructose stuck together. So it can break that apart and then take the fructose and stack a bunch of fructoses together, make a long chain a fructose fiber, and that, that fiber is called levan. So levan is a fermentable fiber that helps feed your microbiome. And so that's, that's the idea behind the second product.

Okay. And when it feeds your microbiome, does it produce butyrate or is it, what kind of, what kind of fiber is it?

Yes. The kind of fiber levan is, as I say, a soluble fermentable fiber. And so it's a prebiotic fiber. Its primary goal of this product is about increasing the amount and diversity of fiber that's hitting your microbiome. And, and, and that's exactly right though. There's good studies already on Levan and other oligofructans that their ability to support short-chain fatty acid producing bacteria, short-chain fatty acids like butyrate. We already know that having this fiber is, is gonna be good for short-chain fatty acid production and diversity. First and foremost, just like the first product, it's not a get outta jail free card. Can't just go out and eat a bunch of cotton candy and, and, and then have a healthy gut. We're talking about 5 to 10 grams of sugar being converted into 5 to 10 grams of fiber a day. So 5 to 10 grams of sugar is not, it's not really about sugar reduction so much, but 5 to 10 grams of fiber is a meaningful amount of fiber. What is cool about this product specifically is that by building that fiber directly in the gut, there's a lot of advantages relative to maybe taking a fiber supplement. One of them is that we can build really long chains. So the longer the chain of fiber, the, the more beneficial it is. So when you eat fiber supplement, that's usually a processed fiber. And so the chain length is already relatively short. And then when it passes your stomach acid, it gets chewed down even further. And so by the time it hits your colon, it's, still beneficial, but like the benefit has been reduced. And so we can build a longer chain fiber. And then another cool thing is that when you eat a fiber supplement, for instance, a scoop of fiber and it's like 10 grams of fiber, you're getting that all as one bolus all at once, like 10 grams that goes through and hits your gut all at once. It's sort of like feeding frenzy, but your bacteria don't necessarily get the full benefit as it passes through. This is distinct from our product where we're making a slow drip of fiber all day, like pulling small amounts of sugar out of each meal. Converting that into small amounts of fiber. So it's like slow drip of fiber that kind of hits the gut and, and maximizes utilization. So there's some really cool advantages here, but ultimately the goal for anybody who's investing in their gut health, and I'm sure your audience knows this, is, is really about, as we talked about at the beginning, diversity. Diversity of microbes means give them, giving them diverse food. For bacteria, that food is fiber. So a diversity of all different kinds of fiber. And so the best way to do this is lots of different kinds of fibers from the foods you're already eating. That's the best way. So it's not just about the absolute grams of fiber because fiber's not all one thing. You have a, a wide diversity. And so one of the things when I designed this product was that we wanted to make a fiber that you likely weren't going to be already getting from other parts of your diet. So we picked a rare fiber. Levan is a fiber you're really unlikely to get from your food. It's really uncommon. Pretty much the only food source of levan is a fermented soybean food called natto. So that's the only way you really are really likely to get any meaningful amount of levan from your diet. So this way by taking this product, we're not only giving you more fiber, which on an absolute value is good, it also is giving you a, a fiber that you're unlikely to be getting elsewhere. So it's kind of increasing the diversity of your fiber as well.

That's interesting cuz I just got a nattokinase supplement for my husband because of the, oh, interesting fibrinolytic activity of nattokinase and breaking down fibrin in the blood vessels to try and prevent clots and, and yes, calcification of the arteries, et cetera. Yeah, exactly.

So that nattokinase is, is a an enzyme that's made by Bacillus subtilis. And of course it's called nattokinase cuz it was discovered in natto, which is the— bacillus is the fermentative agent of natto. The fiber, or levan, is like the string of sugars. And then the nattokinase is a protein made by the bacteria. So different mechanism, different functions, different mechanisms. But nattokinase is a really, really interesting enzyme in that, yeah, they can break down fibrotic tissue. And so they've all kinds of really interesting studies on heart health, like you mentioned, atherosclerosis, things like that. But lots of really cool things about bacterial biofilms and all kinds of interesting stuff that nattokinase could potentially have an impact on. So we're really excited about, so it's already a protein that Bacillus subtilis makes. So for us it would just be about engineering the bacillus to be able to make that more reliably. I think we're really excited about potential of nattokinase in, in its own right.

Yeah. So how, when you're creating genetically modified bacteria, can we be sure they're not gonna take over our microbiome and do something they weren't intended to do, or even worse mutate and do something else? Like how long were they studied and don't bacteria mutate pretty easily?

Yeah, well, and that's what we were talking about at the beginning, that bacteria do mutate all the time. That really isn't a problem 'cause that's happening no matter what, right? So if you eat a native bacteria, it's gonna be mutating and changing all the time in response to its environment the same. So take our first product as an example. What we've done here is we, we've basically taken a bacteria you already eat every day, and then the only difference is that now we've inserted a gene that encodes for an enzyme that breaks down acetaldehyde. Acetaldehyde is a molecule that doesn't really provide a competitive advantage for the bacteria. It doesn't— there's no advantage for the bacteria to be able to break that down. It's not a very common molecule. You're only really being exposed to it while you're drinking. And, and even then, the ability of the bacteria to break it down doesn't provide any advantage to the bacteria. So there's no real benefit. And not to mention that in addition, 70% of all life on the planet, including many of the bacteria already in your gut, express an enzyme to break down acetaldehyde, including many of the cells in your body. So all we've given you is by giving you this bacteria, we're, we're just making sure that you have enough of that enzyme at the right time. We're not actually introducing anything new. If it were to mutate, it, you know, the only things it could really do would be to mutate to make less of that enzyme, and in which case you're basically just reverting back to what it was before, or to make maybe more of that enzyme. But again, that's not really gonna provide it with any advantage. It's unlikely to mutate in that direction, but even if it did, it wouldn't really be a problem cuz that enzyme just breaks down acetaldehyde, which is a molecule you should have none of. It's a very toxic molecule. It's, it's not like in trace amounts this is valuable in some way. We're not really introducing anything new, so therefore there's not really any unknowns. And I think that's one of the biggest risks, right? When you're genetically engineering something, you're making something new. And something new doesn't inherently mean that it's unsafe, but it means that there are unknowns.

Yeah.

At ZBiotics, when we think about how we do our genetic engineering, we put very strict guardrails on what we will and won't build. What we will build are things where we're not introducing anything new to the ecosystem of your gut. Or the ecosystem of the environment, the toilet after it passes out of your gut. All these things are really common. So this acid idea, hydrogenase gene came from another. So Bacillus subtilis is a soil microbe. That's why you eat it every day. It's on the fruit, uh, surface of fresh fruits and vegetables. And we took this gene from another soil microbe. So it's, this gene is already in these ecosystems, it's already in your body. And so that's how we think about it. And then with the second product for sugar to fiber, this enzyme that converts sugar into fiber, this, uh, levansucrase is the name of the enzyme. This is already a native enzyme of Bacillus subtilis. All we've done is increased its ability to express this enzyme so that it will reliably express it when you eat it and when it's in your gut. But other than that, we haven't really introduced anything new. So there's not really any reasonable expectation that this will provide any challenges or problems for it.

So if there was already a bacteria that converted acetaldehyde to, uh-huh, is it acetate?

Yes. Yeah.

Why not just make a probiotic with that bacteria?

Well, because if we just give you the, and, and this is sort of the state of the probiotics industry as it is, we scour nature and then we say, here, we, we wanna deliver to you is the function, right? The ability or the ability to, to break down acetaldehyde, right? And so we say like, oh, here, here's a bacteria that can do that. You should eat this. And we have no way to be sure that even if you were to eat it, that it's going to, first of all, survive your stomach acid at a reliable amount. And the bacteria that's already in your gut is probably very likely an anaerobe. So manufacturing it would be very difficult. And then once it, once it gets into your gut, it doesn't necessarily turn that gene on, uh, in, in a reliable situation. So even though it has the ability to do that, and occasionally it will turn that gene on, it's really doing it for the purpose of, for whatever reasons the bacteria determine that they need that gene, not for the reasons that you need that gene. So what we're doing here is just giving you a bacteria where we know reliably it's making this gene at the time that you need it, as opposed to the time that, that it might need it. So that's where engineering is valuable is when we genetically modify something in, in the context of ZBiotics, What we're doing is just, just delivering reliability of that function essentially, but like the function that already exists.

So how do you know that while it's sitting in the bottle getting delivered, it's not already turning off that gene?

So we engineer it so that it makes that gene all the time constitutively. And so when it's in the bottle, another reason why Bacillus subtilis is such a really great probiotic and a really great bacteria that I love is that it forms a spore, which is like a dormant form of a bacteria. So So basically, when it's in nutrient-limiting conditions, it can hunker down in this hibernation state where it's totally inactive. And it's also incredibly resilient. It can pass through your stomach acid. It can deal with extremely high or extremely low temperatures. We've pulled bacillus spores— we meaning the science community, not me personally— pulled bacillus spores from ice cores in the Antarctic that are literally hundreds of thousands of years old. And those bacillus spores are still alive. So they're in that spore form. And then we can put 'em in media with a bunch of nutrients and they just wake up and nothing happened. It's the same thing here. So when the bacillus is in the bottle, it's in the spore form. It's very resilient and happy to be in there chilling for however long it, how long it's in there. As long as I don't put any nutrients in that bottle. So the bottle's just got water in it, it's fine. And then you drink it, it passes your stomach acid. And so that low pH keeps it in the spore form because it, it senses that that's a hostile environment. And then once it passes through your stomach and gets into your intestines, it senses there's a bunch of nutrients around now and the pH is more friendly and it wakes up or germinates out of that spore. And, and Bacillus already naturally does this. It came with this prepackaged, that's, that's part of its normal life cycle, right? It's on the surface of some vegetable and it's in a spore. You eat it, it passes your stomach acid, it wakes up in your gut, it floats down the river for about a day, it enjoys the nutrients, and then it passes out the other side back outta the environment. And so we just took advantage of that life cycle that already existed and then engineered it to while it's passing through that river, it expresses thousands of enzymes. And so we've just engineered to express one additional enzyme, additional, all the other things it's doing. And we know that that enzyme and that function is beneficial to you, but the rest is all the same for the bacteria.

Hey, this is Lindsey here, just letting you know that if you're tired of dealing with digestive issues like bloating, indigestion, soft stool, diarrhea, constipation, reflux, IBS, IBD, or the numerous health conditions that come about when your gut is off, like brain fog, weight gain, UTIs, fatigue, mental health issues, or complex conditions like fibromyalgia and ME/CFS, that's my specialty. With my 3 or 5 session gut health coaching packages, we'll discuss different stool and functional medicine tests to find out the root cause of your symptoms. I'll interpret the results and provide clear explanations, empowering you to make informed choices for your gut and overall health. And together we'll develop a customized action plan based on your test results so so you can find relief and regain your health and vitality. I come from a functional medicine perspective, trying to incorporate the latest peer-reviewed research and educating you on protocols used by functional medicine practitioners, but devoting lots of time and support to my clients the way a doctor simply can't. If you're interested in a 3 or 5 session coaching package, you can sign up for complimentary 30-minute breakthrough session, or if you can only afford one appointment at a time, you can book an initial 60-minute consultation. Links for those are in the show notes. Now back to the show.

So for the pre-alcohol, we've got long intestines. What is it? Something, is this be the, the length of a tennis court or the, covers an entire tennis court? I can't remember what the, yeah, what the analogy is, but right. What's to say that if you take it at 6, that what's coming into your intestines isn't gonna be absorbed into your bloodstream and already cause damage before it gets to the spores?

Yeah, great question. So this is an important part too, is that I think In terms of alcohol metabolism, the vast majority of the alcohol you drink, the ethanol is, is gonna be absorbed very quickly. Like you say, it's gonna be absorbed in your mouth, in your stomach, and the small intestine. And then that ethanol is then absorbed into the bloodstream and it circulates throughout the body and it has the effects that it has. And then it makes its way to the liver where it's broken down in two stages from alcohol to acetaldehyde and then acetaldehyde to acetate. And so, and both those steps are really efficient in the liver. A small amount of alcohol that is not absorbed very quickly like you described is gonna make its way to the colon. And in the colon, that's where most of the bacteria that are in your gut live. And that's where a, a lot of this ethanol is gonna be converted into acetaldehyde. We know that reliably the colon is where, when we look for instance, that after a night of heavy drinking, you'll see that colonic acetaldehyde levels specifically, so specifically the levels of acetaldehyde in the colon are 10 to 100 times higher than the acetaldehyde levels in the blood. So we're not saying that we're gonna get every molecule of acetaldehyde, but we know that if we could target that colonic sink of acetaldehyde, that's going to have an impact because that colonic acetaldehyde doesn't stay in the colon. It, it's a highly soluble molecule, so it forms there the initial sink, but then it, it will get absorbed and it will diffuse out into the bloodstream, recirculate the body, make its way to the liver, and then get broken down. But at that point, as I say, it's too late. So we're really targeting that major source and trying to have impact there.

Yeah. So that's why it's important to get it in first to get to the colon first.

Exactly. Exactly. Yeah.

Yeah.

Yeah. And did you test people? Can you test people for their acetaldehyde levels? Is that something?

So we didn't test people directly for acetaldehyde levels because it's hard to do that. It's pretty invasive. And specifically we're targeting colonic acetaldehyde to take colonic samples from people requires, I, I think a level of invasiveness that, that not a lot of people will volunteer for. Ultimately though, reducing acetaldehyde was a means to an end. And so even if we did reduce acetaldehyde, if it didn't result in people feeling better the next day after drinking, then it does, it doesn't even matter, right? Because the, the whole purpose of the product was to provide this end benefit. And so ultimately that's the endpoint that we cared the most about. We, we've done a lot of things to validate that taking this product or not taking this product has a very different, there's a very different outcome the next day for, for people when they take the product. And so in terms of perception of pain and the amount of things they're able to get done and all that kind of stuff. So those are the things that we targeted when we did— we looked in humans.

Okay. So what kinds of studies did you do on it?

There were several things we did internally that because they're not clinical trials, I can't really talk in detail about. But ultimately, I'd say that where we see what's consistent with the hypothesis, the things that we did internally to convince ourselves was we look at basically consumer satisfaction and we see that the vast majority of customers use the product. That's more than 95% say that they feel better the day after drinking. And so 95% is an extremely high number. And then we look at repurchase rates and those are also consistent with the fact that people really like the product. So, you know, none of these things do we report as definitive clinical proof. We're not a drug company. And so we don't have the ability to run lots of human clinical studies. But we say that all these things are at least consistent with the hypothesis that the product is providing value. And we allow people to experience or try that product for themselves and We offer, you know, a money-back guarantee, which we always honor. 0.3% of customers ask for a refund. It's, so it's, it's really uncommon, but of course we're more than happy to do that. And so all those things I say are consistent with the idea that product is working. There's definitely more that we can do to show that definitively in a clinical study. And as a scientist, I would never claim that we have clinical proof today, you know, so there is, there is an element of, of consumer experimentation with, in terms of how it affects you.

Yeah. And so what about the sugar to fiber? What would you see that would tell you that was working?

Yeah. And so that one is a lot more straightforward. We have very clear, we don't have to go into the colon on that one, right? You provide a sample every day, most people do, right? So we can use stool samples to look at shifts in the microbiome and, and a key outcome there is increased microbial diversity. And then we also can look at the transcriptome. So the, the genes that the bacteria are expressing, what we wanna see is upregulate. Ultimately we wanna see diversity, but we actually wanna see increases in in function. And so, you know, short-chain fatty acid production, fiber degradation, like we should see a shift, increased shift in those genes and their expression levels. And so this is a very straightforward thing to do. And these are, so we've already done preliminary studies that show that these things are, it's very consistent with those hypotheses. And, and so we are in the process, we've taken those and are, are designing like clear endpoints that we can do human studies that we, that we're gonna publish. So we're starting those studies in the next few months. So I'm really excited to get that data in. But the good news is here that we also have validated, obviously, and with first product as well, we've done a lot, we've done as much possible in vitro work as we can and ex vivo work. So simulating the gut environment in a test tube where we can more easily sample. And so we see with the first product that we get the breakdown of acetaldehyde at a physiologically relevant rate and physiologically relevant conditions. And then with the second product, we see sugar conversion into fiber again at physiologically relevant conditions and we know how much fiber we're making. We've characterized the degree of polymerization. So I think the chain length of those fibers and show that they have really long, really valuable chain lengths. And so all those things we know, and then we already have a lot of data that says that if you give somebody Liban, you'll see these changes, right? And so then, and they have bacteria that we know is making Liban. So yes, the two dots have not perfectly been connected yet, but it's a pretty small leap from A to B that we can, we can, and we are excited to show those in human studies.

Okay.

So you mentioned that within a day or so, you think both of these products will pass through people's guts.

Mm-hmm.

So they won't settle.

Right.

Have you done the shotgun sequencing on people's guts who've been using 'em to see if they're there and, and how long after they've completely disappeared, or?

Yeah. Yeah. Again, this is something where we can tap into a lot of existing research. Bacillus subtilis is one of the most well-studied bacteria on the planet. There's lots of data on transit times of bacillus. So one of the things is that you likely eat this bacteria every day of your life. It's everywhere. And even though that's true, when we sequence people's microbiomes, just generally, we rarely see this as a member of the microbiome. So we already know that even though everybody's ingesting it every day, it's something that's just passing through. And then specific studies with bacillus is a common probiotic bacteria as well, both for people and for animals. Lots of studies have been done to show how long it persists and nothing we've done to this, this bacteria, as I say, is just expressing more of a single enzyme. So nothing about that should affect its transit time. So we're already leaning on essentially a lot of data. That being said, of course, with the studies we're, we're looking to do on the effects of microbiome, we also look to see is our bacteria there? How long is it there? And preliminary results are consistent with what we see in, in the scientific literature already on that.

That it's gone within a day.

Yeah. That the majority is gone. Yeah. You might be able to detect it for a few days, but you're taking however many million or billion CFU, The vast majority of that, 99.9% of that is, is out within like the first day.

Yeah. So people can't hope to be able to seed their own community of this and keep being able to drink their alcohol without rebuying the probiotic. That's, that's probably a pain point.

Yeah, exactly. I mean, it'd just be really inconsistent. And so I think that this is another area where I, as a microbiologist, feel that the probiotics industry is sometimes predicated on some false hopes around the idea that these bacteria are gonna, A, that they can seed the gut. Reliably, and B, that that's even a good idea that, that they should, you should be trying to see the gut. One of the analogies they use is the life of the party, you know, a college frat party, and then picture somebody walking into that party and that the total life of the party, they're very valuable to that community. And then now picture that same person going to a hipster party in Brooklyn. That person will no longer be the life of that party. They will be bad for that community, probably in most, in most situations. So the idea that, well, everybody's microbiome is totally different. Your microbiome and my microbiome are two totally different parties, totally different communities. The idea that this probiotic bacteria is going to come in and just uniformly beneficial to everybody's microbiome is not a really strong hypothesis microbiologically speaking. And if you could cram it in and you could force it into that community and have it persist for a long time, that would probably disrupt the network of interactions that are happening in your microbiome already. And so having a transient passerby that overlays a single function is a much more safe and responsible approach to trying to deliver benefit to the microbiome rather than trying to force in a bacteria wholesale forming thousands of functions. You're probably taking it because you either want something very specific to happen or you want this sort of generalized gut health benefit, which you can't deliver with a single bacteria. You have thousands of different bacteria in, in your gut performing all kinds of different functions. And so there's not really silver bullets with, with gut health.

Mm-hmm.

I was just thinking about glutathione and because it's depleted, probably typically after drinking, that might be a good way to measure the effect of pre-alcohol is to see if levels are depleted or not after using it.

It probably still would be because glutathione is really recharging the enzymes that the vast majority of your oxidative stress is happening from the ethanol. So you're still having to deal with all that ethanol. Mm-hmm. And glutathione is still recharging those enzymes to deal with ethanol. And so we're really just targeting specifically this small amount of dose makes the poison here, right? Very small amount of acetaldehyde that's being formed in the gut. It's not really meaningful in terms of alcohol and, and intoxication, but it has a really outsized effect on how you feel the next day because that small amount could lead to the blood. So we're really just dealing with that.

Yeah.

I think that there are biochemical or physical readouts we could do. Okay. I just think that ultimately, as I say, what I think people care about is whether or not they're gonna feel better the next day. And so I think that that's the most valuable outcome that that we can show.

Yeah. And what are people saying with the Sugar to Fiber?

I mean, it's too early to say. We just launched it a month ago. So far so good. I'll say the difference between the two products is really, this conversation's been a microcosm of that. A lot of skepticism, a lot of questions, a lot of how does this work with the first product and the second product's like, okay, yeah, I get that. Like Sugar to Fiber. So we, we've had a, we've had a lot of positive feedback on the product so far. A lot of people say, how's that possible? That seems That seems too good to be true. Understanding the basic biochemistry of the relationship between sugar and fiber can really help with that. And so in terms of people's experiences, we did a lot of beta testing before we launched several months, and we saw that with those people that the most common benefit that people were excited about was that it was just such an easy way to start. We see this a lot that it, it was a way of crystallizing a, a good habit. You do this one little thing, which is just pour this powder into your breakfast cereal or your morning coffee or whatever, and then it's like, hey, I just did something good for my health. Then I actually started pouring it into a glass of water. So I get another glass of water. So now I'm getting more hydrated. Or, and then started making sure that I ate more fruits and vegetables to make sure that I was stacking more fibers on top of it. So we saw that it crystallized a lot of good behavior for people cuz it was such an easy way to get started. I think that that's one of the things I'm, I'm most excited about because as I say, the goal of the product is not to be a fix-all. It's meant to just be something easy to do to help your health, another tool in the tool belt. And so I love that it was a crystallization point or nucleation point for other really good habits, which is what you want.

And I have to mention that these are not cheap products. Well, I mean, I should say in particular, the pre-alcohol, like a 12-pack is $108. So $9 a bottle. So it's basically like buying another cocktail.

Yes.

Yeah.

So yeah, that's exactly right. It's the cost of a drink, right? I would argue that for our customers, I think that, and people who are excited about the products, you know, how much is your next day worth to you? Is it like for the cost of one extra drink, you get your day back the next day. And I think that that's the real benefit. It's not so much about pain avoidance, getting away with something. It's about, look, I want to be able to enjoy drinks with friends or celebrate in this way, but I also— I have my morning workout, or I want to meet up with friends for a hike, or I want to be fully present at my kid's soccer game. It's these things. It's not like they'd be impossible without the product, but the opportunity to ensure that you're going to be able to maintain all those healthy habits and routines and those obligations is, is worth it for the cost, like you say, of a cocktail, at least for our customers. Yeah, yeah, yeah. But we try to, we try, you know, that's an ad hoc product and that's giving you a day back with the other product. It's really more of a habit or routine is meant to be a daily. And so obviously the daily price had to be different. And so we had to think of ways to make that possible. They're manufactured differently and things to make sure that like second product, it's, you know, $2 a day, which is I think more in line with people, people can afford on like a daily.

Yeah. I see if you subscribe, it's $60 for 28 packs, I guess. Yeah. You could also subscribe on the other one. And then I think it was what, $86 or something? Yeah. $86 for the 12-pack.

So over $7 a bottle.

Yeah. Yeah. It's not for alcoholics. They're not going to be taking this every day or they'd have to be a bitch alcoholic.

Yeah. Right.

Right.

You know, and that's not the point, right? The point of the product is—

right, right. It's for the, it's for the responsible drinkers.

Right.

Okay. Uh, anything else you'd like to share with us, uh, like any new products on the horizon or?

I mean, always. I think that the mission and, and the vision of ZBiotics and why I'm really excited about it is just all the incredible things we can do. There's so much excitement around the microbiome and around probiotics, and I think that that's all well-placed excitement. We've discovered this other organ system of the body that's so foundational to all of human health. That being said, I think that the products that deliver on that are rudimentary. Often most probiotics are kind of the leftovers of the dairy industry, like to Bacillus and stuff in that, that we've kind of like hoped will provide some tangential benefit for us. And so the opportunity to refine that thing that we pulled out of the ground and shape it into a very specific tool with a very specific function, I think is a really exciting promise. And so I'm just excited about this new category of genetically engineered probiotics that have very specific benefits. This is the first two of what I hope to be many by us and other companies. We're approaching this understanding that people are really concerned around GMOs and for good reason. There have been some applications of that technology that have been unsavory or that don't align with people's values and understand that. As a scientist, it's been really tough for me to see is that unfortunately the technology is being conflated with the applications of the technology. People say, I really don't like Roundup Ready corn, and so therefore all GMOs are bad. And that's just not really, you know, not a nuanced approach to a technology. Most technologies The technology itself is not good or bad. It has mixed products which can be good or bad or align or don't. And so one of the things that I'm excited about doing at ZBiotics is like the conversation we had explaining how we've used genetic engineering, what it is. I think a lot of people just hear genetic, genetically modified or GMO, and they just like, oh, that sounds scary, that sounds bad. And, and so just explaining that we're simply directing normal bacterial evolution to give a function that is very safe. And so, and by, and then by building a product that actually provides a benefit to you that you want and saying that the reason that benefit exists is because we engineered the bacteria to be able to perform that benefit. We hope to kind of elevate the conversation about good or bad or is it or isn't it into something more rational and nuanced and acceptable, because I think that ultimately genetic engineering is a— and biotechnology in general are really important tools in humanity's toolbox. We deal with a lot of existential crises facing this planet. I think that when we look at climate change and feeding a growing population of people and dealing with emerging infectious diseases, biotechnology is going to be an incredibly important tool for us to use to combat these problems that in large part we've created for ourselves. And so there's no going backwards. We have to move forwards. And so I'm excited about helping to present another facet to this conversation so that we can ideally, hopefully move forward. And I'm not certainly advocating to say all GMOs are good. It's just as irrational saying that they're all bad. I think it's more what can we do with this that aligns with our values and that we believe is safe and responsible? I think that's a really important question to ask.

That gives me an idea for your next product.

A bacteria that eats glyphosate and turns it into something harmless.

Uh, we, you know, that would be a really interesting idea. I think that there's some really cool companies out there that are engineering bacteria. That's what I thought you were gonna say, engineering bacteria to basically eat or fix greenhouse gases and turn them into very useful products. Oh, that's— so we can literally turn pollution into useful products that are more sustainable than how we, what we would typically make them with, which is with oil. So, I mean, there's all these incredible things that people are doing with GMOs. And unfortunately, that shouldn't be a bad word. What should be a bad word is whatever application people don't like. And so hopefully we can decouple the two. And, and that's one of the things, that's one of our goals is really advocating for a really, really amazing and powerful beneficial technology if used correctly.

Okay. Well, thank you so much for sharing about this with us. This was really interesting, and I'll put links to your homepage and your products on the show notes.

Thank you so much. I really appreciate it, Lindsey Parsons.

Well, I'm excited to recommend ZBiotics to people who I know have issues with hangovers and such and see if it helps. Please use my affiliate link in the show notes for either product if you're going to try them to support the podcast. You can also support the podcast by buying supplements at a discount from my FullScript Dispensary, ordering tests at a discount from my Rupa Health Lab store, or using my affiliate links to iHerb, which is available worldwide, or Amazon. And just a note that you can use my Amazon link to buy anything, not just supplements, and support the podcast. So I'd love it and really appreciate it if you'd bookmark my link and use it for regular Amazon purchases. If you'd like to connect with me online, you can follow my High Desert Health Facebook page, join my Gut Healing Facebook group, or join my newsletter list at highdeserthealthcoaching.com, as well as follow me on X, Instagram, TikTok, and Pinterest. Links for those are in the show notes. Thanks for joining me today, and here's wishing you all the perfect stool.