Adapted from episode 146 of The Perfect Stool podcast edited for readability with Zack Abbott, PhD, the CEO and co-founder of Zbiotics*.
Lindsey:
So why don’t we start with how you got into developing probiotics?
Zack Abbott:
Absolutely. So I started from when I was doing my PhD, I was working with bacteria, and I really fell in love with all the things that bacteria were capable of doing as I started studying them on the cellular level. My research was really on how bacteria turn things on and off, and I thought that their capabilities were really impressive. Separate from that, being part of my program and seeing the research of other microbiologists, I saw there was a lot of really cool research on all of this, the good bacteria in and on your body and your microbiome. I think many people had been introduced to, as a kid, that bacteria were bad, they were germs. My initial interest in microbiology was really around preventing disease, infectious disease, specifically, which I do think is really interesting, but I really got 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 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 how I got into bacteria and probiotics, and eventually into engineering probiotics to do specific functions.
Lindsey:
Yeah, I was always surprised when I realized that when you say take an antibiotic or do something else to reduce the population of bacteria, you’re not getting rid of all of it. You never get rid of all of it. There’s always a little bit of it somewhere in there. Even when people have gut reports where it says “below detectable levels”, you can still bring those back; they’re hiding somewhere in there.
Zack Abbott:
Absolutely, yeah exactly. You’ll never get rid of all the bacteria. A. That’s generally a good thing that you can’t get rid of all them, and b. it also is what creates a lot of problems with things like antibiotics, 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 the gut microbiome.
Lindsey:
Right. And then, of course, 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 and bad things about them – neutral, let’s call it, bacteria. As long as that’s the majority of what you’ve got, you’re usually in good shape.
Zack Abbott:
Exactly. I mean, 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. 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 bacterial genes than you do human genes, on a pure number’s basis. Functionally speaking, you’re far more bacterial function than your human function, 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 your stress and the hormones and all the cholesterol, all these things they do, so many things for us as sort of symbionts or commensals, floating around. So the more of those you get rid of, and the fewer different bacteria you have, the fewer functions you have. You’re really reducing your own functionality, in a way. And so I think what’s important is preserving that diversity and functionality for human health.
Lindsey:
Yeah, and producing your B vitamins.
Zack Abbott:
That’s a huge one, sure. So many things, right? Extracting and or creating nutrients in the food you’re eating, yeah, so many things.
Lindsey:
And so, how do you actually, literally, turn something on or off with the bacteria? What are you doing to it physically?
Zack Abbott:
Yeah, that’s a really great question. I personally love this because this is what I studied for my PhD. So bacteria are these 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 not, if pH changes, temperature changes, sunlight, all sorts of things. They have, over the last 3 billion years, evolved in ways to essentially sense what’s happening, 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 proteins to swim. You want to stay put. You want to motor your boat. So bacteria, the way they do this is they have their DNA. They encode for these genes. There’s a string of DNA that encodes for a protein, but then in front of that gene is 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 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 the fact that this has been happening naturally for billions of years. We’re just 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, “okay, well, this promoter, this 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 basically leverage the bacterial promoters that already exist in order to modulate when we want a gene to be expressed.
Lindsey:
By exposing them to a certain substance, or?
Zack Abbott:
Oh, to change that promoter, or combine a promoter with a new gene or something? 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. The bacteria 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. 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. And then, we facilitate the interaction we want, but then the plant does all the work to cross over its DNA. And the same is true with bacteria. If we want to get a bacteria to turn on a gene, we just, we say, “hey, here’s DNA that we want you to intercalate and deal with.” In the case of Zbiotics, the technology we use is called homologous recombination, and it’s the way that bacteria already edit their own DNA. And so we can literally just mix the bacteria with a piece of DNA the bacteria already have naturally. The bacteria has the ability to take up that DNA from its running environment, and then it can scan that DNA against its own chromosome genetic code and then swap that piece of DNA in a super precise location. All of those capabilities are already things that bacteria can do. 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 mix them together, same as you would do plant cross breeding.
Lindsey:
And it does the job.
Zack Abbott:
Exactly. It does all the hard work.
Lindsey:
Is this what CRISPR is?
Zack Abbott:
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 has an ability to basically do “a find and replace” function like you would do in a Word document. So it gets educated by being infected by a virus, and says, “okay, this sequence is viral.” And so then it can take that sequence and then scan its genome, and then every time it finds that sequence, it can cut there, 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 is in terms of editing or inserting something new into a very precise location. So it’s a bacterial process that we’ve rejiggered or utilized in a unique way. And so homologous recombination is very similar. Also, homologous stands for homology, right? There’s a level of identity. So, 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 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.
Lindsey:
And why would a bacteria choose to change its own DNA?
Zack Abbott:
Yeah, that’s why they’re so successful. Bacteria have been around 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 play a numbers game, right? So bacteria divide very quickly. They have many brothers and sisters that are essentially identical. And so if bacteria are swimming around the environment, there’s always bits of DNA floating around everywhere. When cells die, they release their DNA and its strategy is, “okay, I’ll grab this piece of DNA and see 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 it’s bad, and maybe I’ll die, but whatever, it’s okay, because I have many other brothers and sisters who didn’t take this piece of data. And 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.” 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 in the last 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 will be useful for us or for humanity.
Lindsey:
Yeah. And how quickly can they do this homologous recombination?
Zack Abbott:
Bacteria do that pretty much instantly, in a matter of minutes. But for scientists that are the director of that process, 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. So that whole process takes a few weeks or a month.
Lindsey:
Yeah, okay, so I understand that you’ve got a couple interesting products based on this whole concept. Tell me about the first one. You started with the Pre-Alcohol* (use code PerfectStool20 for 20% off) one, because I have a couple of clients that use that, and they say it works for them by preventing hangovers. So tell us how it works.
Zack Abbott:
Yeah, absolutely. That’s a great lead up to that. So we took probiotic bacteria, safe, edible bacteria that you already eat every day, called Bacillus subtilis, and then using homologous recombination, we inserted a gene that encodes for a protein that can break down acetaldehyde. Acetaldehyde is this toxic byproduct of alcohol that forms largely in your gut when you drink alcohol. The alcohol or the ethanol is converted into this very toxic byproduct called acetaldehyde, and then usually that gets absorbed in the bloodstream. Its sort of rehabbing 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 too late, and so it has already had this damage. The idea was that your liver expresses this protein and has this gene that can help combat the acetaldehyde. And actually, most life on the planet contains a homologous version or a 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 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. So that’s the idea with the first product.
Lindsey:
Cool, and I know it comes in a little bottle of liquid, right?
Zack Abbott:
Right, yeah, it’s about a half ounce liquid shot. The idea is, there’s the bacteria, add 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 come prepackaged with the ability to tolerate your stomach acid and become active 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.
Lindsey:
So when you say it’s expressing the enzyme, does that mean it’s putting it out there into your digestive tract?
Zack Abbott:
Yeah. So in the case of the first product, Pre-Alcohol, what we actually did was, instead of having a bacteria make and then secrete the enzyme out into the lumen of the gut, we decided to actually have the bacteria because 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 molecules been detoxified, so all that happens inside the cell.
Lindsey:
Yeah. So it’s best to take it immediately before you start drinking?
Zack Abbott:
Yeah. So this fundamentally is why I really was excited about the idea of engineered probiotics. 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 Zbiotics. 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 they take it several hours before you started drinking and and that would also be fine, because the bacteria would already be in there, and they’d be persistent for say, about a day.
Lindsey:
Now, I’m not encouraging heavy drinking, but maybe someone knows that when they go out, they do it up, and they’re having, say, eight drinks. I don’t know, six drinks. Should they re-up their dose somewhere after the first four? I mean, how much can it handle, really?
Zack Abbott:
Yeah, so as you said, to be clear, the product is built for, as another tool in the toolbox for a responsible drinker. This isn’t a “Get Out of Jail Free” card. 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, and that ethanol is processed goes from alcohol to acetaldehyde, and then subsequently, immediately from acetaldehyde to acetate. So you don’t get a lot of acetaldehyde formulation 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 cause causes poor sleep. It monkeys around with some of your hormones, like your hunger and satiation hormones and your ability to process sugar 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 especially as we get older, many of us probably, anecdotally, have noticed that two to three drinks when you’re 45 hits a lot different than two to three drinks when you’re 25 and that’s in part because we get worse at dealing with that acetaldehyde, 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 to handle as much acetaldehyde as you’re likely to be exposed to in the 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 it 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 going to drink more than you normally would, and you know that that’s going to result in you not feeling great the next day, having Zbiotics will help make sure that when you wake up the next day you feel better than you would have otherwise. And your results in terms of what better means is going to 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 a little sluggish, but the majority of what I’m dealing with is is gone, or is much better.
Lindsey:
Yeah, I’ve actually never had a hangover in my life, I don’t know why.
Zack Abbott:
Well, you are one of the chosen ones.
Lindsey:
I think part of it, though, is because my own body will not let me drink too fast. I’ll just get to a point where I need some water. I have to keep flushing it out. I cannot force myself to take another sip until I’ve I’ve diluted it a little bit. It’ll help my body process it.
Zack Abbott:
Totally. That’s a big thing that you’re hitting on there, which is that one of the biggest determinants of how you feel the next day is the rate of alcohol consumption, how much alcohol per unit time, and so pacing yourself is one of the best things you can do to set yourself for a good next day.
Lindsey:
Yeah, and I’m drinking a lot of water with it.
Zack Abbott:
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 going to be able to handle this exposure time you’re going to have with these toxins. So definitely, drinking water is also really good for pacing yourself. So yeah,
Lindsey:
Yeah, okay. Let me ask you this. So some clients pointed out, and 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 have all the concurrent symptoms like brain fog.
Zack Abbott:
Yeah, I think it’s a really interesting and reasonable hypothesis. We didn’t test for that specifically, so I couldn’t say for certain, but the bacteria are intended to deal with gut derived acetaldehyde. So I think that the most common reason that we experience gut derived acetaldehyde is from consuming alcohol. But of course, theoretically, another source of gut derived acetaldehyde would potentially be a target of this as well. But I couldn’t say for certain, because the dynamics are different. So I’m not certain, but certainly a reasonable hypothesis.
Lindsey:
Okay, so then your other product is called Sugar to Fiber* (use code PerfectStool20 for 20% off), which comes as a prebiotic drink mix. So tell me about that one.
Zack Abbott:
Yeah, so I’m really excited about this. We just launched this one a month ago. So we launched pre alcohol back in 2019, and,
Lindsey:
Oh, it’s been that long?
Zack Abbott:
Yeah, yeah. And it’s been really fun these last, five plus years of us learning what it’s like to try and tell people about the product and get people interested in all those sorts of things that I had to kind of 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. 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 do. But our second product, as you said, it’s called Sugar to Fiber, and so we’ve engineered this bacteria, 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 fructose together make a long chain of fructose fiber, and that fiber is called Levan. Levan is a fermentable fiber that helps feed your microbiome. And so that’s the idea behind the second product.
Lindsey:
Okay, and when it feeds your microbiome. Does it produce butyrate or is it what kind of what kind of fiber is it?
Zack Abbott:
Yes, the kind of fiber Levan is, as I say, a soluble, fermentable fiber, and so it’s a prebiotic fiber. It’s primary goal this product is about increasing the amount and diversity of fiber that’s hitting your microbiome 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 going to be good for short chain fatty acid production and diversity first and foremost, just like the first product, it’s not a get our of jail fee card. You can’t just go out and eat a bunch of cotton candy 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 a lot, but it’s not really about sugar reduction so much. 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 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 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 around 10 grams of fiber, you’re getting that all as one bolus all at once, 10 grams that goes through and hits your gut all at once. It’s sort of a feeding frenzy, and your body 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, we’re pulling small amounts of sugar out of each meal, converting that into small amounts of fiber. So it’s a slow drip of fiber that kind of hits the gut and maximize utilization. So maximize 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, beginning diversity. Diversity of microbes means give them, giving them diverse food for bacteria, the 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 is not all one thing. You need to have 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 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 an absolute value is good, it also is giving you a fiber that you’re unlikely to be getting elsewhere. So it’s kind of increasing the diversity of your fiber as well.
Lindsey:
That’s interesting because I just got a nattokinase supplement for my husband because of fibrolinic activity of nattokinase and breaking down a fibrin in the blood vessels to try and prevent clots and calcification of the arteries, etc…..
Zack Abbott:
Oh interesting. Yeah, exactly. So that nattokinase is an enzyme that’s made by bacillus subtilis. And of course, it’s called nattokinase because it was discovered in natto which is the bacillus is the fermentative agent of natto. The fiber, Levan, it’s the string of sugars. And then the nattokinase is a protein made by the bacteria. So different mechanisms, different functions, different mechanisms. But nattokinase is a 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, as 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 it, 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. We’re really excited about the potential of nattokinase in its own right.
Lindsey:
Yeah. So how, when you’re creating genetically modified bacteria, can we be sure they’re not going to take over a microbiome and do something they weren’t intended to do, or, even worse, mutate and do something else. How long was that studied? And don’t bacteria mutate pretty easily?
Zack Abbott:
Yeah, that’s what we’re talking about, the beginning of bacteria do mutate all the time. That really isn’t a problem, because that’s happening no matter what. So if you eat a native bacteria, it’s got to 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’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. But acetaldehyde is a molecule that doesn’t really provide a competitive advantage for the bacteria. 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, you’re already expressing 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 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 that 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 making more of that enzyme. But again, that’s not really going to provide it with any advantage. It’s unlikely to mutate that direction. But even if it did, it wouldn’t really be a problem, because that enzyme just breaks down acetaldehyde, which is a molecule you should have none of. It’s a very toxic molecule. 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. 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. 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 aciddehydrogenase gene came from another, so bacillus subtilis is a soil microbe, that’s why you eat it every day. It’s on the surface of fresh fruits and vegetables. And we took this gene from another soil microbe. So 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 Levan sucrase is the name of the enzyme, this is already a native enzyme of bacillus subtilis. All we’ve done is increase its ability to express enzymes 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 you.
Lindsey:
So if there was already a bacteria that converted acetaldehyde to is it acetate?
Zack Abbott:
Yes, yeah.
Lindsey:
Why not just make a probiotic with that bacteria?
Zack Abbott:
Well, because, and this is sort of the state of the probiotics industry as it is, we scour nature, and then we say, “here, we want to deliver to you as the function, the ability to break down acetaldehyde” And so we say, “oh, here, here’s a bacteria that can do that, you should eat this,” 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 your gut is probably very likely an anaerobe, so manufacturing would be very difficult. And then once it gets into your gut, it doesn’t necessarily turn that gene on in a reliable situation. So even though it has the ability to do that, and occasionally it will turn that 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 time that that it might need it. So that’s where engineering is valuable. When we genetically modify something in the context of Zbiotics, what we’re doing is just delivering reliability of that function, essentially about the function that already exists.
Lindsey:
So how do you know that while it’s sitting in the bottle getting delivered, it’s not already turning off that gene?
Zack Abbott:
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 really great bacteria that I love is that it forms a spore, which is a dormant form of a bacteria. 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 1000s of years old. And those bacillus spores are still alive, so they’re in that spore form, and then we can put them 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, how long it’s in there, as long as I don’t put any nutrients in that bottle. So the bottles 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 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 part of its normal life cycle, right? It’s on the surface of some vegetable, and it’s in spore. You eat it. It passes through 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 out of the environment. And so we just took advantage of that life cycle that already existed and then engineered it. While it’s passing through that river, it expresses 1000s of enzymes. And so we’ve just engineered it 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.
Lindsey:
Yeah. So for the Pre-Alcohol, we’ve got long intestines. What is it something supposed to be the length of a tennis court, or the covers an entire tennis court? I can’t remember what the analogy is, but, what’s to say that if you take it at 6pm, that what’s coming into your intestines isn’t going to absorb into your bloodstream and already cause damage before it gets to the spores?
Zack Abbott:
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 going to be absorbed very quickly. As you say, it’s going to 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. 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. Both those steps are really efficient in the liver, a small amount of alcohol that is not absorbed very quickly like you described, is going to 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 lot of this ethanol is going to 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 level specifically, 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 going to get every molecule of acetaldehyde, but we know that if we can target that colonic sink of acetaldehyde, that’s going to have an impact, because that colonic acetaldehyde doesn’t stay in the colon. It’s a highly soluble molecule, so it forms there the initial sink, but then it will get absorbed and it will diffuse out into the bloodstream, recapitulate the body, make its way to the liver and then get broken down, but at that point, it’s too late. So we’re really targeting that major source and trying to have impact there.
Lindsey:
Yeah. So that’s why it’s important to get it in first, to get to the colon first.
Zack Abbott:
Exactly, yeah.
Lindsey:
Yeah. And did you test people? Can you test people for their acetaldehyde levels? Is that something?
Zack Abbott:
So we didn’t test people directly for acetaldehyde levels because it’s hard to do that. It’s pretty invasive. Specifically, we’re targeting colonic acetaldehyde. To take colonic samples from people requires a level of invasiveness 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 doesn’t even matter, right? Because the whole purpose of the product is to provide this end benefit. And so ultimately, that’s the end point that we care the most about. We’ve done a lot of things to validate that taking this product or not taking this product has a very different outcome the next day for people when they take the product.in terms of perception of pain and the amount of things we’re able to get done, and all that kind of stuff. So those are the things that we targeted when we looked in humans.
Lindsey:
Okay, so what kinds of studies did you do on it?
Zack Abbott:
There were several things we did internally that, because they’re not clinical trials, can’t really talk in detail about, but ultimately, I’d say that where we see what’s consistent with hypothesis, and things that we did internally to convince ourselves, was we look at basically consumer satisfaction. We see that the vast majority of customers that use the product, that’s more than 95% say that they feel better that they have to 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 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. We also offer a money back guarantee, which we always honor, .3% of customers ask for a refund. So it’s really uncommon, but of course, we’re more than happy to do that. And so all those things 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 an element of consumer experimentation with, in terms of how it affects you.
Lindsey:
Yeah. And so what about the Sugar to Fiber? What would you see that would tell you that was working?
Zack Abbott:
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 the key outcome there is increased microbial diversity. And then we also can look at the transcriptome, so that the genes that the bacteria are expressing. What we want to see is upregulate. Ultimately, we want to see diversity, but we actually want to see increases in function. And so, in short chain fatty acid production and fiber degradation, we should see a shift, increased shift in those genes and their expression levels. 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. We’ve taken those and are designing clear endpoints that we can do human studies that we that we’re going to 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 that with 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, in physiologically relevant conditions. We know how much fiber we’re making. We’ve characterized the degree of polarization. So I think the chain length of those fibers ensure that they have a 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 Levan, you’ll see these changes. We have bacteria that we know is making Levan. And 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 and we are excited to show those in human studies.
Lindsey:
Okay. So you mentioned that within a day or so you think both of these products will pass through people’s guts?
Zack Abbott:
Mhm.
Lindsey:
So they won’t settle?
Zack Abbott:
Right.
Lindsey:
Have you done the shotgun sequencing on peoples guts who have been using them to see if they’re there and how long after they’ve completely disappeared?
Zack Abbott:
Yeah, yeah. Again, this is something where we can tap into a lot of existing issues. Bacillus, subtilis is one of the most well studied bacteria on the planet. There’s lots of data on transit times of bacillus. 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 as a common probiotic bacteria for people and for animals, lots of studies have been done to show how long it persists, and nothing we’ve done or nothing about that should affect its transit time. So we’re already leaning on a lot of data. That being said, with the studies 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 the scientific literature already on that is that it’s gone within a day, yeah, 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, that 99.9% of that is out within the first day.
Lindsey:
Yeah, so people can’t hope to be able to see their own community of this and keep being able to drink their alcohol without rebuying the probiotic.
Zack Abbott:
Yeah, exactly. I mean, it would just be really inconsistent. 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 going to A. that they can see the gut reliably, and B. that that’s even a good idea, that that they should, be trying to see the gut. One of the analogies I 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 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 those situations. So the idea is that 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 1000s 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 1000s of different bacteria in your gut all performing all kinds of different functions. And so it’s not really silver bullets with gut health.
Lindsey:
Mhm. 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* (use code PerfectStool20 for 20% off) is to see if levels are depleted or not after using it.
Zack Abbott:
It probably still would be, because glutathione is really recharging the enzymes. The vast majority of your oxidative stress is happening from the ethanol. So you’re still having to deal with all that ethanol, 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, a very small amount of acetaldehyde that’s being formed in the gut. It’s not really meaningful in terms of alcohol and intoxication, but it has a really outsized effect on how you feel the next day, because that small amount can really affect you. So we’re really just dealing with that. I think that there are biochemical or physical readouts we could do. I just think that ultimately, people care about is whether or not they’re going to feel better the next day. And so I think that that’s the valuable outcome that we can show.
Lindsey:
Yeah, and what are people saying with the Sugar to Fiber?
Zack Abbott:
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 has 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 more “okay, yeah, I get that, sugar into fiber.” So we’ve had, we’ve had a lot of positive feedback on the product so far. A lot of people say, “how’s that possible, “that seems too good to be true” and 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 was a way of crystallizing 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 for my health. “Then I actually started pouring into a glass of water, so I get another glass of water, so now I’m getting more hydrated, 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, because it was such an easy way to get started. I think that that’s one of the things 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 related habits, which is what you want.
Lindsey:
Yeah. You have to mention that these are not cheap products. Particularly the Pre-Alcohol, a 12 pack is $108 so $9 a bottle, so it’s basically like buying another cocktail.
Zack Abbott:
Yes, yeah. So yeah, that’s exactly right. It’s the cost of a drink, right? I would argue that for our customers, and people who are excited about products, how much is your next day worth to you? 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, you know, I want to be fully resent 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 costs, like you say of a cocktail, at least for our customers.
Lindsey:
Yeah, yeah.
Zack Abbott:
Yeah. That’s an ad hoc product, and that’s giving you a day back with the other product that’s really more of a habit or routine. It’s 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 other things to make sure. It’s the second product it’s about $2 a day, which is, I think, more in line with people, people can afford on a daily basis.
Lindsey:
Yeah. I see if you subscribe, it’s $60 for 28packs, I guess, yeah. You could also subscribe on the other one. And then I think it was what, $86 for the 12 pack?
Right, yeah. A little over $7 a bottle, yeah.
Yeah. It’s not for an alcoholic. They’re not going to be taking this every day, or they’d have to be rich alcoholics.
Zack Abbott:
Yeah, right, right, you know. And that’s not the point, right? The point of product is…
Lindsey:
Right, right. It’s for it’s for the responsible drinkers. Okay, anything else you’d like to share with us? Any new products on the horizon or?
Zack Abbott:
I think that the mission 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, bacillus and stuff, and that we’ve kind of like hoped, will provide some tangential benefit for us. 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. 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 really not a nuanced approach to a technology. With 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 antibiotics 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 say “that that sounds scary, that sounds bad” and by 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 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 into something more rational and nuanced and acceptable, because I think that ultimately, genetic engineering 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. 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 genomes are good. It’s just as irrational as 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.
Lindsey:
That gives me an idea for your next product, a bacteria that eats glyphosate and turns it into something harmless.
Zack Abbott:
Well, 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’re going to say, engineering bacteria to basically eat or fix greenhouse gasses and turn them into very useful products. So we can literally turn pollution into useful products that are more sustainable than how we typically make them with, which is with oil. 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. Hopefully we can decouple the two, 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.
Lindsey:
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* (use code PerfectStool20 for 20% off) on the show notes.
Zack Abbott:
Thank you so much. I really appreciate it, Lindsey
If you’re dealing with gut health issues of any type (diarrhea, constipation, bloating, SIBO, IMO, H2S SIBO/ISO, IBS, IBD, gastritis, GERD, H pylori, diverticulitis, candida, etc.) or have an autoimmune disease and need some help, I see individual clients to help them resolve their digestive issues or reverse autoimmune disease naturally, You’re welcome to set up a free, 30-minute breakthrough session to see if you’d like to work with me. I also have my own two products, Tributyrin-Max, which is particularly helpful for loose stool and diarrhea as it slows your motility and firms up your stool, and SBI powder, which is an all around gut pathogen binder, which is super safe and won’t harm beneficial bacteria, and is usually the first line of treatment I educate my clients about in order to avoid stronger antimicrobial herbs.
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