Ben Greenfield [00:00:00]: My name is Ben Greenfield, and on this episode of the Ben Greenfield Life podcast.

Tina Anderson [00:00:04]: We created a whole entire new category. In the probiotic space, spores have the ability to survive the gastric system naturally. So it's not like we do any inter-coding or anything like that. They have this endospore shell around themselves that allows them to withstand the body temperature and also withstand the very acidic environment of the stomach. And when they get to the intestines, that's when they take their shell off, their endospore shell off, and that's when they go into their live vegetative cells state and where they start to work throughout the digestive system. And these strains, once they get to the intestines, they stay there for about 21 to 28 days, where most probiotics out there would just simply pass through. Similar to food, these strains actually stay there for about 21 to 28 days, making a true change in the gut flora.

Ben Greenfield [00:00:49]: Fitness, nutrition, biohacking, longevity, life optimization, spirituality, and a whole lot more. Welcome to the Ben Greenfield Life Show. Are you ready to hack your life? Let's do this.

Ben Greenfield [00:01:13]: Well, everybody, I get to invite and interview two pretty smart cookies on today's show. I have a research microbiologist who specializes in the human microbiome and wellness. Kiran Krishnan is my first guest. And Kiran is joined by Tina Anderson, who actually began her career as a trial lawyer. And now she is in the probiotics industry. So, as you probably have already guessed, based on Tina and Koran's background, we're gonna be talking all things probiotics in today's show. And I have plenty of my own stupid questions about probiotics to ask you guys. So what do you think? Are you ready for this?

Tina Anderson [00:01:55]: I'm ready.

Kiran Krishnan [00:01:56]: Oh, yeah.

Ben Greenfield [00:01:58]: Okay, cool. You guys are with a company called Just Thrive. I actually had some of your gummies. Do you have these Just Thrive gummies? I had them in my smoothie this morning. Believe it or not, basically every morning is a competition to see how many different things I can squeeze into a smoothie. But tell me about how Just Thrive got started.

Tina Anderson [00:02:16]: Yeah. So my husband Billy and I were in the pharmaceutical industry for several years, and we thought it was great. You know, we're thinking, oh, we're delivering life saving medications. We're making a huge change in the world, helping people feel better. But after being in the pharmaceutical industry for several years, we started to see a lot of the abuses in the industry, the over prescribing of medications. We saw it with our own family members. You know, we'd see one pharmaceutical, she'd be on one and then before, you know, she'd be on a different twelve different medications and never getting any better. And so we are really focused on mindset, we're deep thinkers and we just felt that we weren't doing our life's work.

Tina Anderson [00:02:56]: And so we. My husband was seeing a naturopathic physician who worked with Kiran. And through, I think, being at the right place at the right time and a lot of meditation, we were able to license these strains out of London University, these probiotic spores out of London University, and from there, that's where Just Thrive was born. And it's been the most amazing experience I've ever gone through in my career.

Ben Greenfield [00:03:21]: How do you license a probiotic spore? How does that work?

Kiran Krishnan [00:03:24]: Let me touch on my perspective on why I got into the probiotic industry and was fortunate enough to partner with Tina on it. So I started looking at the probiotic industry from microbiologist's perspective and a lot of things just didn't make any sense. And then I come along and I meet this functional medicine doctor who has a 95% gut practice, gut focused practice. He approached almost every chronic condition by dealing with the gut, and yet he didn't use a single probiotic in his practice. That was baffling to me. It caused me to ask a lot of questions. When I started asking him, why do you not use a probiotic? He was using ferments and prebiotics and lots of other things, he said, because I've tried so many of them and most of them don't really do a lot. Maybe they'll do something in the beginning, but then you'll see the effects fade and all that.

Kiran Krishnan [00:04:17]: And it kind of resonated with me because when I started getting into supplements and nutrition and all that for athletic purposes and for endurance and performance purposes, and I started looking at probiotics, I was like, the way they're formulating these things, packaging them, putting them in refrigerators, adding all these crazy capsules and all that, most of that doesn't make any sense. We wanted to rethink the idea of what a probiotic truly is and how you approach it from a formulation perspective. One of the ways in which you advance your project in terms of building your own proprietary probiotic is you have to find the right strains. And I'm sure we'll talk about what the right strain means and what it should be doing. But there are a lot of academic researchers that have spent a lot of time and a lot of grant money isolating strains from numerous sources. Now for probiotics, you want to isolate strains generally from the human gut microbiome, because these are strains that then have some familiarity with functioning in the gut microbiome, which is a very complex ecosystem. They isolate the strains, they characterize them properly and do full genomic sequencing, so we know every single protein and every single gene on those strains. Then they start to study what some of the strains' functions are.

Kiran Krishnan [00:05:43]: If you have connections with these academics, then you can approach them and say, hey, I know in your academic pursuits you've isolated these strains to try to learn about them, but we'd like to commercialize them. And if you can work out a deal with them, you can basically license the mother culture, if you will, the original strain of that they isolated. And then you get access to that and all of its genomic information to try to scale it into a commercial scale, commercial strain so that you can produce at a commercial scale. So that's the kind of deal we would do. And we did that with London University.

Ben Greenfield [00:06:16]: So when you say isolation, please don't tell me that that's just like random healthy donors pooping in a toilet bowl and the researchers collecting it with a spoon and I putting it in a food dehydrator or something like that.

Kiran Krishnan [00:06:29]: Unfortunately, that is. Yeah, yeah, really it's collecting a lot of poop, right? So if you think about a sample of poop, may have upwards of 2 - 3000 different species in there. And the idea is to collect maybe samples from all different parts of the world. So you get an understanding of what the population distribution looks like of microbes in different people from different parts of the world. And so then you take a stool and then you rehydrate it and you create a slurry. And then you actually spin-off using centrifuges, all the bigger, more massive things like the fibers and things that didn't get digested well or absorbed. And then you try to spin down what we call into pellets. These pellets are basically concentrated bacteria.

Kiran Krishnan [00:07:14]: So you're separating all of the matter and the debris from the fecal matter if you will, and you're isolating the bacteria. Now when you have these little bacterial pellets, then they start growing these bacterial pellets up in flasks and plates and things like that. And then you start streaking them and isolating colonies because every bacteria will have a slightly different colony. Then you pick the colonies, you do genetic sequencing and you try to figure out what they are. So it is a lot of shit work, if you will because these researchers are literally dealing with pounds and pounds of shit from all over the world.

Ben Greenfield [00:07:53]: And if I find a piece of, like, corn or carrot slice in my probiotic capsule, that means they didn't do a good job with the centrifugation.

Kiran Krishnan [00:08:00]: Exactly. But it's probably healthy for you, so I wouldn't be too alarmed. So.

Ben Greenfield [00:08:06]: Well, it's good to know that they can isolate it and grow it and that if you guys Just Thrive, becomes, you know, a $10 billion company, you aren't going to run out of people pooping in order to keep up with the probiotic production.

Kiran Krishnan [00:08:18]: So that's an important one. So a lot of people have a misconception that when you use a human isolate strain that the continuous supply of the strain continues to come from people. But it's not. Once you isolate a strain and you have the original strain, the original culture, you can keep that strain indefinitely in the freezer for thousands of years. So we have the original strain that was isolated something like 15 to 20 years ago sitting in a freezer and numerous copies of that strain sitting in little tiny vials in a freezer at -80 degrees Fahrenheit. And every time we do a production, we actually pull one of those little things and we inoculate a vessel with it and allow it to grow, and then we inoculate the next vessel and so on. So it's sitting there in the freezer. We never have to go back to the human source again.

Ben Greenfield [00:09:13]: That is so cool. Tina, when you came to Kiran, did you already have in mind what strain that you wanted?

Tina Anderson [00:09:20]: No, we didn't. We were looking at gut health because we had learned about the importance of gut health. That was shortly after the human microbiome project was launched by the National Institutes of Health. Told us more about the gut than we ever knew before. And we were, we just knew we wanted to get into the gut health space. But we had talked to the functional medicine practitioner that Kiran had mentioned, and he's like, the probiotics out there just aren't working. They're not working. And one day he called us into his office and said, you will not believe this, but we have the opportunity to, you know, license these strains at a London university.

Tina Anderson [00:09:53]: And he's like, this is the real deal. This actually, this works. And so that's kind of how it happened.

Ben Greenfield [00:10:00]: Okay, so tell me more about the strains.

Tina Anderson [00:10:02]: So they're Bacillus spore strains, and one of the biggest, you know, differentiators of it is it's their ability to survive the gastric system, we created a whole entire new category in the probiotic space. Spores have the ability to survive the gastric system naturally. So it's not like we do any inter-coding or anything like that. They have this endospore shell around themselves that allows them to withstand the body temperature and also withstand the very acidic environment of the stomach. And when they get to the intestines, that's when they take their shell off, their endospore shell off, and that's when they turn into a live vegetative. They go into their live vegetative cell state where they start to work throughout the digestive system. And these strains, once they get to the intestines, they stay there for about 21 to 28 days, where most probiotics out there would just simply pass through. Similar to food, these strains actually stay there for about 21 to 28 days, making a true change in the gut flora.

Ben Greenfield [00:10:59]: So could anybody just wander in like, like, could I just start whatever? Greenfieldprobiotics.com and go wander in and get that same strain and use it? Or are you guys able to somehow protect that at Just Thrive?

Tina Anderson [00:11:12]: Yeah, Just Thrive. We're able to protect it. We have, you know, a supply agreement and exclusivity, and that's what we've been able to secure.

Ben Greenfield [00:11:22]: Have you figured out a way to combine that strain with anything else that makes it more effective?

Tina Anderson [00:11:28]: Well, we have combined it with other Bacillus spore strains, and that's a really great question because one of the biggest problems in the industry that we're seeing is these kitchen sink formula to probiotics there, where they say they have 10, 15, sometimes 20 different strains in the product and they don't know what they're doing together. That is one of the biggest things we have been trying to push in the probiotic industry is get a study on the finished formulation. Because these are live microorganisms. We don't know how they're going to play with each other. UC Davis did a study, took 16 children's probiotics and found that only one of them met label claims. They tested them. Only one of them met label claims. So that means 15 of them either didn't have a strain that was listed on the label or they had even worse, they had strain that wasn't listed on the label that nobody knew about, nobody had studied, they don't know anything about.

Tina Anderson [00:12:21]: So we are very proud of the fact that we've done human clinical trials on our finished formulation.

Ben Greenfield [00:12:27]: What kind of stuff have you found out in your trials?

Tina Anderson [00:12:30]: Well, we did a leaky gut, a double-blind human clinical trial in leaky gut showing that these strains are reducing the LPS from leaking into the bloodstream by 42%. That study was profound because we also found people who were in the placebo group actually saw a 32% increase of LPS after 30 days.

Ben Greenfield [00:12:52]: Yeah. And by the way, LPS. Explain that to people who might not know what that means.

Tina Anderson [00:12:57]: Sure. It stands for lipopolysaccharide. It's a toxin that's found in our gut flora. It's not really problematic. It becomes really problematic when it seeps out of your intestines and goes into your circulatory system and causes this inflammatory response. The leaky gut study is profound. Kiran was super involved in that, in setting that up with the University of North Texas, so he could probably speak to it even more. But it's a really.

Tina Anderson [00:13:23]: It's the first study that I know of. I don't know of any other probiotic, or any other pharmaceutical, for that matter, that has a study on leaky gut or metabolic endotoxemia.

Ben Greenfield [00:13:33]: Any other cool trials?

Kiran Krishnan [00:13:35]: Yeah. So we've done a number, and I want to elaborate on the leaky gut study as well, a little bit. But some of the other trials are we did a study on liver function. So there's this endohepatic, circulatory, and protection axis, meaning there's a deep connection between your gut microbiome and your liver and how your liver functions as a result of your microbiome. Now, what we were able to see in this study is that the right type of microbiome and the right type of probiotic can protect the liver from damage. Now, this was an animal study because you can't induce damage in the liver, in humans. On purpose, at least what we did was we took animals, and then you overdosed the animals on acetaminophen. So this is a mouse study.

Kiran Krishnan [00:14:21]: Then in one group of animals, we used clinically graded milk thistle, and actually, which is a prescription drug in parts of Germany, and then we used the probiotic spores, the Just Thrive spores. What we saw was that the Just Thrive spores were able to protect the liver of the animals from damage from the overdosing of acetaminophen as well, and in some cases, better than the milk thistle did. So negating any of the damage from overdosing it. And that just goes to show, like, the intimate connection between all these other body systems and a healthy microbiome and having a healthy probiotic that facilitates a microbiome. And the leaky gut study that Tina mentioned, the reason we became so interested in that is, back in 2012, we were pondering and thinking, like, okay, if we had the best probiotic there is, what would we want it to do? What is arguably the most important function of a probiotic? Because there are lots of things probiotics can do. They can alleviate gas and bloating, and diarrhea or constipation, all the digestive issues and those are all important, but what would we want to do to really move the needle in human health? It became clear that we wanted it to resolve intestinal permeability because intestinal permeability comes about as a result of a change in the microbial environment in the gut. Your gut is naturally designed to not be overtly permeable. It has a dynamic permeability, meaning it allows things to go through, but then there are lots of things that it shouldn't allow to go through, including this LPS endotoxin.

Kiran Krishnan [00:15:55]: So when you lose that dynamic permeability and your gut becomes openly permeable, you start to get a lot of chronic low-grade inflammation, and that becomes one of the biggest sources of chronic low-grade inflammation. And as you know, that becomes the foundation for most chronic diseases. Right? So we saw a publication in 2015, which is a meta-analysis of this topic. They looked at something like 30 different published human clinical trials, and they concluded that the number one cause of mortality and morbidity worldwide in the developed world was intestinal permeability as a result of microbiome number one. Right? It's the number one killer worldwide, and it causes more mortality and morbidity than anything else worldwide, because it's the foundation of so many chronic conditions, like cardiovascular disease, dementia, Alzheimer's, diabetes, all of these things. Then the American Diabetic Association, which is normally way behind on advances, published a number of studies from 2013 all the way to 2018, showing that metabolic endotoxemia, that's the scientific definition of leaky gut, is the initial insult that starts the process of insulin resistance in the vast majority of people. So we said, okay, if we can get a handle on this issue of leaky gut if we can give people a tool that can stop that open permeability in the microbiome, then we're really moving the needle. On foundational health, they still have to do all kinds of other things to be healthy, but this moves the needle.

Kiran Krishnan [00:17:33]: We did that study, and we published it in a journal called the World Journal of Pathophysiological Gastroenterology. It doesn't roll off the tongue, but it's very good for gut nerds. It's an open-source journal, so we're able to share the study, and we, for the first time, showed that you can stop and reverse this endotoxemia. So it was published as a frontier paper in that journal, which was exciting to see.

Ben Greenfield [00:18:04]: Man. So when you hear about common causes of leaky gut, like eating too fast, eating in a stressed out state, eating these hyper hedonistic combinations of, like, vegetable oils and sugars, the fact that you just outlined that that is the leading cause for. For all-cause mortality, really, I mean, really makes you think about wanting to chew your food thoroughly and pay attention to gut health and not eating in a stressed-out stage, just as a base foundational practice.

Kiran Krishnan [00:18:30]: Totally, yeah, absolutely. And then, you know, overeating, one of the ways of inducing endotoxemia after a meal, so that it's probably. It's actually called postprandial endotoxemia because they measure the highest concentration of toxins in the body, and it's specifically, the LPS about 3 to 4 hours after the meal. And those meals that have a very high caloric density and very high volume tend to produce a very significant amount of endotoxemia. This is part of that overeating and the overeating and how that drives inflammation. What's the role of the toxin? Right. So let's talk about that for a moment. So people really wrap their head around, if you're not paying attention to your behaviors and your digestion and your gut health and your microbiome, what happens when the toxin leaks through? So LPS is really fascinating because it's very pervasive in the body.

Kiran Krishnan [00:19:25]: It can get into almost any tissue in the body. And the reason it can is because it looks like our lipid bilayer, right? So it's got this, like, fatty acid tail on it, and it's got this carbohydrate head very similar to that lipid bilayer that makes up all our cell membranes. So it can just scoot its way into almost any cell, almost any tissue after a meal. You find LPS in deep recesses in the brain, like the hypothalamus, and the frontal cortex. You find it in your liver, you find it in your joints, you find it in your heart and your pericardium. So you find it in all these different areas of the body. And wherever it ends up, it elicits a very profound immune response. Now, the reason it elicits a profound immune response is because your immune system is designed to monitor and detect the presence of LPS.

Kiran Krishnan [00:20:16]: Because to your immune system, the presence of LPS means that there are pathogens entering into the blood circulation. The reason is that because LPS is made generally by gram-negative bacteria, some people may have heard of gram-negative bacteria, a lot of them being pathogens. So your immune system is constantly monitoring for gram-negative bacteria entering into your system. It has a protein called LBP, an LPS-binding protein that it makes and sends out to look for LPS throughout the body. Wherever LBP finds LPS, it binds it. It activates macrophages and dendritic cells and causes those cells to go crazy and go holy crap, we've got a bunch of gram-negative bacteria in this region, like your brain, for example, your heart. And it recruits a massive amount of immune cells to that area that elicits an innate immune response. That's a cytokine-like storm that a lot of people heard about during COVID. So imagine these cytokine-like storms happening in your brain, in your heart, in your muscles, in your joints after you eat a meal, right? If you eat really bad fats, you eat oxidized fats, you eat high calories, you eat too fast like you said, and just overly processed foods that have a lot of pesticides and herbicides, all of those things are driving this postprandial response.

Kiran Krishnan [00:21:36]: And if it keeps happening meal after meal after meal, day after day, week after week, and so on, it sets up the foundation for disease. This is so profound and so important, and people just don't wrap their heads around it. And this is where the importance of those basic behaviors comes from.

Ben Greenfield [00:21:54]: Well, we've established that the most likely time of my life that I'm going to die then is going to be about 04:00 p.m. on Thanksgiving afternoon. All those boxes. You know, I've been learning a lot about the teeth and the jaw and the biomechanical structure of bite and also oral health. My dentist who's been on the show before, Dr. Eniko Loud down in Phoenix, she does salivary enzyme analysis of some of these gram-negative bacteria because of the association between your mouth bacteria and Alzheimer's, cardiovascular disease, etcetera. I'm assuming for many of the reasons that you've just described, because these then wind up in the gut, being absorbed through the buccal membrane, and winding up in the bloodstream. But could you make a case? Tina, you were talking about how the capsule can survive the gastric environment.

Ben Greenfield [00:22:44]: I'm wondering if you could make a case for actually, for example, breaking open a couple of capsules and kind of mouthwashing to start that population in the oral environment. Have you guys ever thought about that?

Kiran Krishnan [00:22:59]: Yes. So we've actually done, we do that quite a bit in clinics, and we recommend it quite a bit for people, especially during the cold and flu season, because there's a lot of association with the buccal immune response, because there's a lot of immune tissue in the soft tissue in your mouth, and it upregulates protective immune response in your upper respiratory tract, in your lower respiratory tract, and so on. So the spores do play a role there. Even Dr. Simon Cutting, almost 15 years ago, when we first started working with him on the spores, he always recommended taking some spores, mixing them in water, swishing it in your mouth and holding it, and then swallowing them. So, yeah, you're right on the right track. There's a huge advantage to doing that. I would do that kind of thing before bed, and I often do it because a lot of what's happening, especially for people who are mouth breathers and who tend to struggle with that issue, you want to have some sort of protection in your oral cavity. I also do it a lot during cold and flu season because that really helps upregulate some of the immune response.

Kiran Krishnan [00:24:06]: And the spores are really good at something called quorum sensing. This is one of the ways in which it helps against gram negatives, and it helps against leaky gut, is they have the ability to read other microbial signatures, so they can identify dysfunctional bacteria like Enterococcus. That's a type of gram-negative bacteria that tends to be found in the mouth. It can identify enterococcus and elicit, cause your immune system to elicit an immune response against the presence of enterococcus. So releasing more secretory IgA that neutralizes the bacteria, or even directly getting the immune system to go after that bacteria, or the spores themselves will directly negate and kill off that bacteria. We've seen that, and we've published a couple studies on the ability of the spores to do this quorum sensing. That's a really important thing now. You can use it on your skin, you can mix it in with lotion, you can put it on your skin.

Kiran Krishnan [00:25:01]: The spores are ubiquitous in the environment, and we've evolved to actually have this ongoing relationship with them where they're transient to our body, they show up, they clean up different systems, and then they leave again. And go back into the environment.

Ben Greenfield [00:25:16]: So here's something that I'm interested in based on what Kiran was explaining about acetaminophen and liver injuries. Tina, I know you're kind of a fellow health enthusiast and do some biohacking and stuff like that. You and I have had a glass of wine before at some of these conferences and health events that we're at. Have you ever kind of tried it prior to maybe a cocktail and a glass of wine and assessed how you feel afterward as an n equals one? Or have you guys seen anything done on alcohol in these specific strains?

Tina Anderson [00:25:48]: Yeah, I mean, anecdotally, I do it all the time when I'm going to drink. I usually have my probiotics every time at the same day, but then if I'm going to go out and I know I'm going to have a glass of wine or two, then I'll take extra for that reason exactly. I also take our IgG product, which is an immunoglobulin g that we don't want to distract the attention of what we're talking about today, but that's another great product that I have taken before. Before I'm going to engage in any alcoholic consumption.

Ben Greenfield [00:26:18]: Isn't that the same type of stuff you could find in Colostrum, the IgG?

Tina Anderson [00:26:22]: Actually, it's way more. I mean, IgG. Yes, IgG is found in colostrum, but the IgG that we work with actually has 25% to 50% more IgG than most continent colostrums out there.

Ben Greenfield [00:26:35]: Oh, wow. So for the leaky gut scenario, that could be a one two combo. If you take that and then the lactoBacillus strain at the same time the Bacillus spore strain. The Bacillus spore strains, yeah. Interesting.

Kiran Krishnan [00:26:46]: And in fact, there have been, you know, one of the things we really liked about the IgG is in the condition of HIV. There's this. There's this marked thing that happens called HIV enteropathy. This was actually a large-scale published study by the NIH that showed that the biggest thing that affects HIV patients in terms of progression from being HIV positive to AIDS is the development of a leaky gut. And part of it is because the virus attacks the gut and gut lining it, of course, kills off the CD4+ T cells. It causes CD8 cells to come in and start fighting it. And those CD8 cells are very inflammatory. So just choice aligning of the gut, makes the gut very, very leaky in HIV patients.

Kiran Krishnan [00:27:34]: So they have leaky guts in a very profound manner. Right. So it's a very accelerated, profound model for leaky gut. It's a very similar pathology that occurs in people with just poor lifestyle choices and lots of antibiotics. And you're a common American. Right. But it's a good model to study accelerated decimation of the lining of the gut. They did studies on the IgG, and we worked with them with the spores and the IgG, and what they were able to show with the IgG is even in that condition of accelerated leaky gut damage, that they were able to start to repair some of that lining.

Kiran Krishnan [00:28:10]: So the combination is a powerful one-two punch because it worked a little bit differently. And it's a great way of continuous protection on the lining of the gut and the liver thing. I've been thinking about this a lot because I do enjoy a cocktail from time to time in some nice high-end spirits. And when you think about, okay, liver protection, how do you negate some of the negative effects of alcohol? We know that a lot of the negative effects of alcohol come from the formation of acetaldehyde, and acetaldehyde can be very inflammatory. So I have two thoughts in mind. Number one is, okay, what drives some of the acetaldehyde production? There is some evidence that a dysfunctional microbiome actually produces more acetaldehyde than a more diverse microbiome. And so there is a small case to be made with early evidence that the spores may be able to help with lowering some of that acetaldehyde. Number two is the inflammation associated with the acetaldehyde and clearing it.

Kiran Krishnan [00:29:12]: That's where the liver comes in, and that's where all the flushing and all the disturbances to the rest of the body. The spores are anti-inflammatory, and they're profoundly anti-inflammatory. And this is a very important distinction between different types of probiotics. It'd be surprising to learn that a huge number of well-known probiotic strains are actually inflammatory. That's exactly what was shown. Yeah. And this is a fascinating thing, where there was anecdotal evidence. Then I was able to work with researchers at University University College Cork in Cork, Ireland, one of the biggest microbiome research institutes in the world.

Kiran Krishnan [00:29:54]: And what they were able to show is that the vast majority of probiotic strains that are widely used, that they tested, when you take them, they elicit a huge spectrum of immune responses, including three different mechanisms of systemic inflammation. Right. So they up-regulate inflammation. Your body sees these strains coming in. They don't necessarily recognize them. And as a result, the immune system gets fired up. Now here's the thing. For a healthy individual that is trying to ward off colds and flu and things like that, you just want your immune system kind of irritated and upregulated so that in case you encounter a virus or something like that, it deals with it faster.

Kiran Krishnan [00:30:39]: That may be a benefit for the vast majority of people who are dealing with health conditions, with inflammatory conditions. It actually can make it worse.

Ben Greenfield [00:30:47]: Right, right. It'd be similar to, like, if you have chronic fatigue or stress issues, the same ice bath practice that might help some people develop cellular resilience. And stress resilience would kind of push you overboard.

Kiran Krishnan [00:31:00]: Totally. Yeah, exactly. And so when you look, when you work, and I have the pleasure of working with lots and lots of functional medicine practitioners, I have a whole other thing that I do in the functional medicine world. And what I've come to find out is that a lot of holistic health functional medicine practitioners don't use any probiotics for their mast cell activation patients, their SIBO patients, their histamine intolerant patients, people with all kinds of sensitivities, because these people tend to have a proclivity towards inflammation. And in their experience, most probiotics make it worse. And now we have the answer. We go, ah, that's because most of these probiotics, you wouldn't think, but they upregulate inflammation. Now, the spores are what we call in the probiotic research world, silent probiotics.

Kiran Krishnan [00:31:47]: That means that they don't upregulate any of the pro-inflammatory pathways. In fact, they upregulate the anti-inflammatory pathways in the body. And that's a really, really important distinction between different probiotics. This is where I get nervous when I see kitchen sink formulas with 15 strains in them and no research behind what the immune impact is, what the microbiome impact is, and so on, because many of those, especially in their combinations, could be quite inflammatory.

Ben Greenfield [00:32:14]: So when you hear about people getting gas and bloating and sometimes a deleterious response to a probiotic, paradoxical, because they thought it might help their gut, you're saying that it might not be due to what I kind of always thought was the case. Right. Like throwing off the microbial balance in a way that causes gastric upset, but it may actually be inducing an inflammatory response.

Kiran Krishnan [00:32:36]: That's right, yeah. It could be inducing an inflammatory response in the lining of their gut, just like a food that they may not be tolerant to would. Right. If someone's intolerant to a particular type of food, say dairy. They can't tolerate dairy. Well, they eat dairy. They're going to get gas, bloating, loose stool, and so on. Now, there's, there's a small sliver where there are certain people that might experience something called a Herxheimer reaction, a die-off reaction, or naturopaths will call it a healing crisis.

Kiran Krishnan [00:33:06]: That is a change that's happening, that's positive but has a negative symptom in the beginning. And normally you work through that for two or three days. But if you're taking the kitchen sink probiotics and the stuff that just doesn't have clinical studies behind the finished product, and you're having a negative effect as a result of it, you could probably lean towards the idea that, okay, this is just not agreeing with my system. It's upregulating too much inflammation, and it's probably not doing me any good.

Ben Greenfield [00:33:35]: The qualitative way to differentiate between the two inflammation versus some kind of a Herxheimer reaction and die-off of bad bacteria, I assume, would be the length of time of the symptoms, a few days, versus, say, several weeks. I suppose from a quantitative standpoint, could you actually get an inflammation marker test and see if you had higher levels of homocysteine or interleukin or something like that? And that would give you a pretty big clue that your probiotic might have contributed to an inflammatory spike.

Kiran Krishnan [00:34:07]: Yeah. So IL-6 would be one that would be good to check. If you have a big spike of IL-6 after using a probiotic, that generally means that your immune system doesn't agree with that probiotic, and it's not really helping you. But if you have, for example, some die-off-like reactions, but your IL-6 isn't elevated, and then on top of that, you might see Interleukin-10 elevated, that means the probiotics actually going to work trying to induce an anti-inflammatory response. But what is actually causing the discomfort is the microbes, the dysfunctional microbes that are present in your gut trying to fight against the presence of that probiotic. Right. This is why they call it a die-off response.

Kiran Krishnan [00:34:52]: Like the spores, for example. When they go in, one of the first things they're gonna do into your gut is they'll do quorum sensing.

Ben Greenfield [00:35:00]: You mean the Bacillus spores that's in the Just Thrive stuff?

Kiran Krishnan [00:35:04]: That's exactly right, yeah. The Bacillus spores that are in the Just Thrive, when they first enter into the gut, what they do is they start reading the microbial environment when they identify dysfunctional bacteria, they'll sit next to them, and they'll produce antimicrobials, or they'll elicit an immune response to try to get rid of those particular bacteria. Now, those bacteria, when they're being killed off, will release a bunch of toxins, and those toxins can feel like discomfort in certain people. And so that's a die-off reaction versus the probiotic coming in your immune system going, I don't know what this is. Let's just attack it, and then attacking it and causing a bunch of systemic inflammation in the individual. That will happen over and over again. For a probiotic that's incompatible to an individual, the die-off response will go away in a day or two after those dysfunctional microbes are gone from the system.

Ben Greenfield [00:35:56]: So here's something I'm curious about. When it comes to antibiotics, some people say, take a probiotic when you start an antibiotic regimen to help to replenish what you're killing off, some people say it doesn't have any benefit. And now I'm seeing research that suggests that probiotics might slow down the recovery of the gut microbiome after antibiotics. Do you have any thoughts on this?

Tina Anderson [00:36:18]: Yeah, that's, I think the Weissman Institute study that recently came out telling us that, yeah, like some of these, the kitchen sink formula type probiotics that we're talking about will compete with your gut flora and hinder your own immune cells to actually fight off the effects of the antibiotic. And so one of the things that we're so excited about with this that we studied is it actually, you know, we are huge believers that you should be taking a spore-based probiotic while you're on an antibiotic. We've studied this. We know that the spores actually survive the presence of an antibiotic, which is huge. They actually will not be killed off by the presence of an antibiotic. We've studied this with some of the strongest antibiotics out there, and we know that these spores are not competing with our natural gut flora. They're actually working together with them cohesively. So.

Tina Anderson [00:37:12]: But, yeah, that Weissman study was kind of interesting because it told us that, you know, this is what we've been preaching for years. You know, we don't want to be. We have to be careful when you're taking these, you know, multi-strain probiotics without a study on the finished product.

Ben Greenfield [00:37:27]: So the study that showed that probiotics could hinder the recovery from antibiotics from a gut microbiome standpoint, they were using, like a multi-strain formulation. Was it like an off-the-shelf? Or were they just using a random set of strains that they had at Wiseman's lab? Or do you know?

Kiran Krishnan [00:37:43]: So what they did is they actually bought strains from a data bank that are commonly used probiotic strains? So, you know your acidophilus and those types of strains that are typically found in a probiotic, and they assembled a formulation that mimicked your average multi-strain probiotic on the marketplace. They didn't want to go and buy any given commercial product. What they were trying to do was create one that was a representation of your typical generic probiotic combination. Now, what's really important to note here is, and this particular study tells a really important story about understanding why probiotics are different. When you think about a probiotic strain or things that people call probiotic strains, there are really two distinctions. Number one is, is it a resident strain naturally? Is it naturally a resident strain to the gut, or is it a transient strain to the gut? Now, probiotics in general should be transient strains because transient strains have a way of coming in, interacting with the microbiome, with the immune system, doing positive things, and then leaving because their job is not to stay there and take up space. Right? Now, when you take probiotics that are actually resident strains and try to put them into your system, they're going to go in and compete with your other resident strains.

Ben Greenfield [00:39:09]: Yeah. That makes it be like having a plumber who I wanted to come over and clean my toilet and then leave when they're done, versus them setting up shop in the master bedroom closet with a sleeping bag. And it vastly changed my lifestyle, one versus the other.

Kiran Krishnan [00:39:23]: That's exactly right. Yeah, that's exactly right. The thing about it is that what happens to the gut microbiome when you take an antibiotic is with the first dose of the antibiotic, within about 90 minutes or so, it knocks down almost all the strains in your gut microbiome, down to just a few cells of each strain. So the volume of bacteria drops down quite dramatically, which means there's now a lot of real estate open for microbes to start taking over binding sites and campsites and so on. Now the bacteria start to grow back. Right? That's the beauty of bacteria, is you can't kill them off completely. They're going to start to grow back. But what grows back and in what proportion is where you start to see the dysfunction?

Kiran Krishnan [00:40:09]: Now, what happens is if those get knocked out, then you take 15 billion of these other resident strains from other sources, those 15 billion are going to start competing for binding sites with your own residence strains that are trying to grow back. That's where we see the big problem. That's why to me, when I think about this as a microbiologist, I'm like, the best probiotics and the safest ones are always going to be transient strains because that's actually how we interact with microbes in the natural environment. All of the microbes we come across in the natural environment, whether it's in the dirt or, you know, rivers and streams or foods that we forage for and pick and so on, or microbes that we get from each other that we interact with are going to be transient in your system. They're going to go in, they're going to be that plumber, they're going to fix a thing or two, and then they're going to leave when they're done. Right? That's really what you want at the end of the day.

Ben Greenfield [00:41:03]: Now, we are able to test our gut. I recently did a Genova, three-day stool panel, which kind of tells you parasites and yeast and fungus, some bacterial balance. There are other companies, like Viome, for example, that are doing these bacterial profiles of the biome. Why can't you look at the results of a test like that and literally customize the type of bacteria that you're replenishing based on what each person's unique biome is? And based on that, how do you know that one specific strain is going to be good or bad for just the general population? Does that make sense?

Kiran Krishnan [00:41:43]: Yeah. Yeah. So that is the ultimate goal of microbiome science, is can we get to a place where we can look at an individual's microbiome and understand what they need specifically? Now, we're not there yet, and it's for this reason. The reason is that at the species level, right? So if you look at bacteria, we've got, you know, everything that lives starts with kingdom, order, and all that, and everyone knows that there's genus and species. Just for people who may not be familiar, we take lactobacillus acidophilus, or in our case, Bacillus subtilis. The lactobacillus or the Bacillus is the genus, and then the specific species is the subtilis or acidophilus. In humans, we're homo sapiens sapiens.

Kiran Krishnan [00:42:31]: So we're the same almost genus in species. Now, what we don't know yet is why, at the species level, we are all vastly different in our microbiomes. You and I, Ben, could have maybe 25% similarity at the species level in our microbiomes. And yet we may have 98% the same functionality out of our microbiomes. Now, the reason for that is because there's a lot of functional redundancies among bacteria. I may have a certain set of bacteria that's producing short-chain fatty acids for me, and it's doing it at the right levels. You may have a slightly different set of bacteria, but they're still producing short chain fatty acids. Both of us have preserved the function of producing short-chain fatty acids.

Kiran Krishnan [00:43:22]: You just have different players that are doing it than me. At the species level. It becomes very complicated to understand how to modulate the microbiome. So when you look at the microbiome and you look at function rather than species population, that's where we can start to make changes. Now, the other problem is a given individual's microbiome can have up to 1000, 2000 species in it. The vast majority of those species have never really been isolated well, and they're not available from a commercial standpoint to repopulate the gut. So most probiotics, as people are familiar with, have bifidobacteria lactobacillus as genuses. And then in our case, we have Bacillus.

Kiran Krishnan [00:44:06]: Just looking at those, that makes up 99% of the probiotics out there. That's only three genuses out of thousands that could exist in an individual's gut. We look at an individual's gut and we go, oh, my God, they're missing this particular genus. Well, there's no source of that genus out there to replenish that individual's gut. So then you have to look at how do we upregulate the endogenous level of that bacteria. This is where transient microbes come into play. As it turns out, one of the things that the Bacillus spores can do is they can naturally help some of the underrepresented genuses and species in the gut replenish themselves by producing compounds that those particular bacteria feed off. So we saw, we did a study where we published a study showing that when you add Bacillus endospores to your gut microbiome, it increases the diversity of all species by almost 30%. So species that were there at such low levels that we could barely detect them, are now flourishing.

Kiran Krishnan [00:45:12]: We've all heard of Akkermansia. Akkermansia is becoming so important now, and people are starting to understand the benefits of Akkermansia. Your endogenous Akkermansia especially. We did a study where we showed that we can add Bacillus subtilis in and Just Thrive probiotic combination. In individuals where Akkermansia was not detectable because it was at such low levels, we were able to see a thousandfold increase in as little as three weeks.

Ben Greenfield [00:45:40]: So what do you think would happen if I started breaking open a couple of the Just Thrive Bacillus spores and putting them into my yogurt before I ferment the yogurt? Do you think it would help with the growth of the other bacterial strains in the yogurt?

Kiran Krishnan [00:45:54]: It will, yeah. In fact, Bacillus is used quite a bit for fermentation. Part of it is because Bacillus will acidify the environment. They will produce lactic acid. The acidified components will actually help some of the beneficial bacteria grow and prevent the growth of yeast mold and so on. They will also produce a number of peptides. And these peptides actually help other beneficial bacteria grow. That's one of the ways in which they do it in the gut.

Kiran Krishnan [00:46:18]: So we had for a while some recipes for fermenting fruits. For example, with the Bacillus. One of the things you can do that's simple is take a mason jar and fill the bottom third of the mason jar with any kind of fruit that has sugar in it. So pineapples, berries, and so on, and then the rest of it with water, you open a capsule of Just Thrive. You put it in the mason jar, stir it up, and then seal it shut and then leave it on your kitchen counter for three or four days. You'll start to see some bubbles forming in there. And you're basically getting a fermented fruit juice that now has even higher nutritional value because there are organic acids, there are peptides, there are all kinds of wonderful things in there now.

Kiran Krishnan [00:47:00]: And it tastes good, right? So you can absolutely do that as well as a side.

Ben Greenfield [00:47:03]: You might have just saved me a bunch of money on my water kefir grains for making fizzy water kefir. That's. I'm gonna have to try this. Tina, you guys need to do a cookbook too.

Tina Anderson [00:47:12]: Yeah, well, we do send out recipes on our blog.

Ben Greenfield [00:47:15]: Oh, I didn't realize that. Okay, now, kind of a logistical question. You know, it's like 100 degrees outside right now. What happens if I order from your company? It arrives and, like, the bottle's hot.

Tina Anderson [00:47:26]: Yeah, it's. That's not a problem at all. These spores are so hardy that they're able to withstand. We've tested them up to 455 degrees. They will withstand heat of up to 455 degrees, if not hotter. But we tested it at 455 degrees, so that's not a problem. We get that question all the time. But you could open the capsules and mix them with food and bake with them.

Tina Anderson [00:47:48]: You know, if your kids are picky or a spouse is picky, or somebody doesn't want to take them, you could actually bake with them. So they are. That's how hardy they are. That's the same ability that they have to survive the presence of an antibiotic. Actually, that shell on them allows them to survive the high temperatures, and low temperatures as well.

Ben Greenfield [00:48:06]: That's actually going to surprise a lot of people, including me, that you can get them that hot. That's actually pretty cool.

Kiran Krishnan [00:48:10]: You might think this is interesting, Ben. The oldest Bacillus spore that's been found was found in a cave in California. So if people aren't familiar, what's happening is that we're approaching this post-antibiotic world because of the overuse of antibiotics. A lot of the pathogens have developed resistance to antibiotics. And that's a very scary thing. If you get, for example, a MRSA infection where no antibiotics can help you. So what researchers are doing is they're going deep into caves that have never been explored, looking for bacteria that may make a unique antibiotic that we haven't even thought of to be able to try utilizing it to create the next generation antibiotics. Because, again, all antibiotics originally came from yeast, mold, and other bacteria.

Kiran Krishnan [00:48:57]: So they were going in these caves in Southern California and they found these salt crystals, and then they were able to melt down salt crystals and isolate Bacillus endospores from the salt crystals, and they were still alive. Those microbes were 250 million years old sitting there, right? 250 million years old, still alive. And they've pulled out Bacillus endospores from glacial ice cores that were 40, 50 million years old. And there's a study showing that Bacillus subtilis, one of our key strains that are in the formulation, can survive in the vacuum of outer space for over seven years and may be one of the earliest forms of life on Earth because there's this concept of panspermia, where the fundamental building blocks of cells were seeded on earth during the bombardment period from meteors and all from outer space because they find proteins and amino acids and all that on meteors. And so they looked at microbes that exist today that could have made a journey on a meteorite across from, say, Mars and landed on Earth, and they found that Bacillus subtilis is one of the few that could have made that interstellar journey. So these are phenomenal organisms and they're all around us, and you just have. In our case, we kept thinking we were just smart enough to figure out what nature already has for us. We're not trying to recreate nature.

Kiran Krishnan [00:50:24]: We just have to know what she has for us and how to utilize it and how to put it back into our system.

Ben Greenfield [00:50:30]: Hey, you talked about the oral microbiome, maybe put in a little bit of the broken-up capsule and swish it around the mouth prior to sleep. But could probiotics help with sleep, do you think? Or do these specific spores help with sleep?

Tina Anderson [00:50:40]: Yeah, absolutely. I mean, we know that there's. That the gut-brain access, and so, so much of what's going on in your brain is affected by what's going on in your gut. So we say that all the time, so many people will come to the product because of the common digestive reasons, you know, gas, bloating, diarrhea, constipation, and then, you know, three months into it, they're like, I'm sleeping better. Oh, I have more energy, or I have better weight management. We see that a lot too, but it just makes so much sense if you're going to the bathroom more regularly and you're getting rid of toxins and. And if you're taking care of all those neurotransmitters that are in your gut. 90% of our serotonin is produced in our gut.

Tina Anderson [00:51:16]: Gaba is produced in our gut. Dopamine is produced in our gut. So all of these important neurotransmitters are helping us, and definitely we see that all the time. People have improved sleep from it.

Ben Greenfield [00:51:26]: Didn't you send me something that says calm on the label? Did you just put other stuff in it that also helps with sleep?

Kiran Krishnan [00:51:31]: Yes.

Tina Anderson [00:51:32]: So our Just Calm product is a psychobiotic. So a psychobiotic. It basically is the friendly bacteria that are supporting that gut-brain access. And that's a strain called Bifido longum 1714 that has eight clinical trials on it about how it basically has shown to balance out cortisol, so lowering cortisol levels, lowering your perception of stress, even changing your brainwave activity, so putting you more in that theta wave state where you're calmer, more in that meditative state, not where you're in, you can't function, but it's just where you're more focused. And so the studies on that product are amazing, and obviously we've had a ton of success with it because we've seen some great results.

Ben Greenfield [00:52:15]: Well, this is super interesting. I know there are a lot of research studies and a lot of product information that you guys have on Just Thrive. I got to check out these recipes, by the way. I had no clue you were putting those out. But what I'm going to do is for the show notes, they're going to be for everybody listening in. BenGreenfieldlife.com/justthrivepodcast that's BenGreenfieldlife.com/justthrivepodcast. I'll link to the Just Thrive stuff. We've got discount codes.

Ben Greenfield [00:52:44]: I'll put studies in there, other podcasts I've done on the biome, Tina and Kiran. Anything else you guys want to throw in?

Tina Anderson [00:52:51]: Thank you for bringing up that, that link. We have a coupon code for 20% off for the 90-day product because I just feel so passionately that when you do the 90 days, that's when you start to see all the magic happen. When you start taking care of your gut and you start seeing the difference, it takes about that time to start seeing the magic happen. So the code is BEN for 20% off. So yeah, and just, you know, give yourself grace along the way as you're going through your gut healing journey.

Kiran Krishnan [00:53:18]: One of the things I want to say is that gut health and I think most people listening are probably in tune with this, but gut health is so paramount to overall health and wellness, and longevity. When you think about gut health and what is the healthiest marker of your microbiome? Based on all the studies that have been published out there over the last ten years, and we're talking probably two or 300,000 studies on the microbiome, the really key foundational thing is diversity in the microbiome. The higher the diversity of your gut microbiome, the longer you live, the more resilient you are to disease, the more cocktails you can enjoy without all the negative effects, the better your muscles function, the better you perform in every single way. And so maintaining and increasing diversity is a critical step in having true foundational health. And the thing is, when you look at all of these listed known healthy behaviors, like eating healthy foods, being outside, exercise, and meditation, all of these things have been shown to actually increase the diversity of your gut microbiome. Another thing that helps with maintaining an increasing diversity is taking the right probiotic, but you need a probiotic that has the ability to impact the rest of the microbiome is transient in that way and is designed by nature to improve the diversity of your gut microbiome. That's where these Bacillus endospores come in. So we're super excited to be to have been working with these for like ten years now and we'll continue to work with them and put out more studies and more information.

Ben Greenfield [00:54:54]: That's awesome. If you heard that part about diversity and you're listening in, that means if your idea of your vegetable intake is the all too common cucumber, carrot, tomato, lettuce and maybe throw in some chicken and rice, then read my cookbooks or branch out wide variety of herbs, spices, fruits, vegetables, fermented foods, meats and that's going to back up the use of these type of spores that we've talked about. Alright, guys. Thank you so much. And again, for those of you listening in the show notes are at BenGreenfieldlife.com/justthrivepodcast, the 20% code that Tina mentioned for that 90-day supply is Ben, and have an incredible week.

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