The Microbiome and Skin: My Interview with Microbiologist Kiran Krishnan, PhD

In this episode of the Defiant Health podcast, I have a special guest: microbiologist Kiran Krishnan, PhD.   In addition to conducting research on microbiome and health issues, Dr. Krishnan also built a successful company called Microbiome Labs, a major provider of unique probiotic products.

Dr.  Krishnan has gained an international reputation for innovative thinking on microbiome issues pioneering, for instance, the science and application of spore-forming microbes. His studies have shown that such spore formers can reduce endotoxemia, minimize the damage done by antibiotics, and increase microbial diversity.

In this interview, Dr. Krishnan tells us about a novel approach to skin health he and his team have developed. 

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Transcript

William Davis, MD: 0:05

In this episode of the Defiant Health Podcast, I have a special guest, someone you might already be familiar with, as he has been prolific in providing education, built a successful company called Microbiome Labs and is an active researcher in studying microbiome issues.

William Davis, MD: 0:22

Our guest is Dr Kiran Krishnan, who has gained an international reputation for innovative thinking on microbiome issues, pioneering, for instance, the science and application of spore-forming microbes studies that have shown that such spore formers can reduce endotoxemia, minimize the damage done by antibiotics and increases microbial diversity. In this interview, dr Prishnan tells us about a novel approach to skin health he and his team have developed, and later in the podcast I'd like to tell you about Defiant Health's sponsors Paleo Valley, our preferred provider of many excellent organic and grass-fed food products, and BioDequest, my number one choice for probiotics that are scientifically formulated, unlike most other commercial probiotic products available today. Dr Krishnan, thank you very much for joining me in this Define Health podcast. I know you're doing a lot of work and off-camera. You mentioned to me that you're getting involved in the skin microbiome. Could you tell us more about what you're doing?

Kiran Krishnan, PhD: 1:26

Yeah, absolutely Well. First of all, thank you so much for having me. Your early books were some of the things that really got me inspired to put more focus in the microbiome. So you know the wheat belly and so on, and Supergut is a fantastic book. So thank you so much for having me. It's exciting to be here.

Kiran Krishnan, PhD: 1:47

So the skin microbiome is such an interesting area, right? So I've been working on the gut microbiome for more than a decade, probably published maybe 18 or 19 research papers associated with the gut microbiome. And then you know, as you start thinking about the gut microbiome and what that ecosystem looks like, how complex it is, but more so, how much the function of the organs are determined by the types of microbes that exist in the organ, right, we know, for example, the small bowel completely changes in how it functions. If you have dysbiosis in the small bowel, you have microbes in the small bowel that shouldn't be there in the case of SIBO, whether they come from the mouth or different areas, it completely changes how the small bowel functions, and then the small bowel no longer functions the way it should, and that's true for throughout the whole gut, the stomach as well, and we know that, you know. So then we started thinking about the largest, what should be the largest organ of the body, the skin. And is the skin a risk factor in chronic disease? And that has been a question that's been on my mind for some time. We know that the skin has a very complex ecosystem. We know that there are upwards of a thousand different species that can exist on the skin. We know that different parts of the skin have very different ecosystems. So the face, a sebaceous area like the face, where you have a lot of anaerobic environments, high oil and so on, compared to, say, the forearms and the legs that are much drier. They're very different organisms, very different ecosystems and thereby different functionality on the skin. And at the end of the day, one of my questions has been how much does the microbe population on the skin impact the function of skin? And the function of skin primarily is a barrier, right? That's one of the largest barriers in our body and it's a different barrier than the gut barrier in that it's less dynamic. The gut barrier has to let a lot of things through that need to get through, but then of course, cinch up a little bit to prevent things that shouldn't be going through. But the skin largely acts as a firm barrier. It doesn't let a lot of things through, if anything, a few things maybe. But that barrier function becomes really important.

Kiran Krishnan, PhD: 4:09

And then I came across this fascinating study called the Baltimore Longitudinal Study on Aging. And this was a fascinating study because, you know, it was the first time where they took individuals when they were young, in their early late 20s to early 30s, and these researchers decided, you know what, instead of aging studies where we take an older cohort and compare them to a younger cohort and look at differences, let's just take each individual and follow them for the next 50 years. Right, and that's fascinating because it really gives you now a whole different picture. Because if you take 80-year-olds today and compare them to 30-year-olds today, those 80-year-olds went through a very different life and system and ecosystem than the 30-year-olds have been going through. Right, when they were 30, the world was a very different place and their environment was a very different place. A very different place and their environment was a very different place. And so using each individual as their own control seems to be a really, really interesting way of studying aging, because you can follow that individual and other individuals that are similar to them and look at all their choices and the things that change within their system and how that impacts risk, and one of the things that they've concluded is that aged skin was an independent risk factor for chronic disease, and these are diseases distilled to the skin. So these are things like osteoporosis, alzheimer's, dementia, cardiovascular disease.

Kiran Krishnan, PhD: 5:39

Aged skin is a risk factor, and these researchers were able to use skin health and the condition of the skin as a very accurate predictor of morbidity and mortality in individuals, and so that became really fascinating to me, because then the dots started to connect, going okay, so as skin ages and loses its barrier function, it's now acting as a risk factor for chronic disease.

Kiran Krishnan, PhD: 6:10

This sounds very similar to the gut, right? As your gut becomes more dysfunctional and loses its barrier capabilities, you get leaky gut, which then becomes a risk factor for disease. In the case of the gut, it's the microbial dysbiosis that leads to the dysfunction. In the case of the skin, it's the microbial dysbiosis that leads to the dysfunction. In the case of the skin, it's got to be the microbial dysbiosis as well. So that's when we started digging in, going oh wow, it is because there's a lot of really strong correlative data, some causative data that shows that certain changes on skin microbes affect the function and the structure of the skin, and that to me becomes really interesting, beyond the cosmetic aspect of it, because it's an independent risk factor.

William Davis, MD: 6:53

Any notions? What exactly is being mediated in the crosstalk between gut and skin?

Kiran Krishnan, PhD: 6:59

Yeah, so from the gut skin component to it, and so there's the skin, skin, what's happening between the microbes on the skin and then the resulting immune responses in that local region. But then there's also what is happening between the microbes in the skin and the gut, and the gut, of course, then dictates in large part how your immune system responds to things right.

Kiran Krishnan, PhD: 7:21

So one of the dots that we've been able to connect is when you look at inflammatory conditions on the skin, things like dermatitis, different forms of dermatitis, whether it's atopic, or a different version or even psoriasis, or even acne skin, where the immune system is playing a role in driving the inflammation and then, as a result, driving the damage to the layers of the skin, right, that we then can see the comedones that are developing in the case of acne are inflammation and filling in of the pores with immune responders, and all that, and then same thing with dermatitis and psoriasis, and all the redness and dryness of the skin, is a result of the immune system functioning there. Then the question becomes okay, why is the immune system going there and why is it doing that? Well, to me, it seems like there are two things that need to happen for an eczema-like response on the skin or a psoriasis-like response, or even an acne-like response on the skin. Number one there has to be a trigger on the skin that causes the immune system to need to respond to that area. Right, and often that trigger is microbial dysbiosis. Now, if you have, for example and this is why they've shown lots of very strong correlative data that staph aureus overgrowth in certain regions is associated with dermatitis, psoriasis and so on, in the case of the face, cutibacteria and magnesis is associated with increased risk for acne development, right, so there are these opportunistic or pathogenic-like organisms that are present in the regions where these lesions develop, which means that they are likely triggering the need for the immune system to respond. And then, sure enough, when you dig into the literature, it's true, they're immunogenic, they produce toxins, they produce things that cause the immune system to respond.

Kiran Krishnan, PhD: 9:18

But why is it that the immune system is responding in such a way that it causes all this damage to the skin? Right, the redness, the inflammation, the dryness and all that? Well, that's because the gut is also dysfunctional in many of these individuals, which means they've got an immune system that doesn't have proper tolerance messaging. Right, they're not expressing Tregs very well, the T regulatory cells. They're not expressing IL-10 very effectively, right, they're not expressing the regulatory components of the immune system that don't allow the innate immune responses to overreact, and so they tend to have an immune system already that's overreactive to things. So they may be histamine intolerant, from histamine from foods, for example. They may have environmental allergies, they may have chronic sinusitis, they may have lots of things where the immune system seems to be overreacting in response to stimuli.

Kiran Krishnan, PhD: 10:11

So these individuals have that double whammy They've got a microbe that's causing an immune trigger on that part of the skin and they have an immune system that tends to go full inflammatory, isonophilic, basophilic, inflammatory-type, damaging response, right. So they have the best of those two. And I compare it to individuals that don't have the second part. They don't have an immune system that is very pro-inflammatory, very IgE, very isonophilic, basophilic type responder. The difference between those two individuals is one could get staph aureus or get a physical stimuli.

Kiran Krishnan, PhD: 10:50

I give people an example of some people who wear a backpack all day and wherever the straps have been rubbing they get super red and itchy and inflammatory. What's the difference between that individual versus someone that can wear a backpack and be fine all day? Well, that's the immune system responding to that rubbing. Right, we call it contact dermatitis, right? Contact dermatitis is just well, your skin rubbed against something and was irritated. Your immune system responded in a very inflammatory manner. Now you have dermatitis and the difference there is that the individual that doesn't get that dermatitis has a well-tolerant, well-balanced immune response because their gut is healthier. The other individual doesn't, right? So that double whammy, I think, seems to be driving a lot of this.

William Davis, MD: 11:36

So if the skin microbiome can be the initiating factor, are you any closer to a microbial solution?

Kiran Krishnan, PhD: 11:44

Are you any closer to a microbial solution? Yeah, that's a great question. So we developed this quorum sensing product to effectuate the population of microbes by directly competing with or producing compounds that inhibit the growth of dysfunctional microbes and or enhancing or producing compounds that enhance the growth of beneficial microbes. On top of that, some of these quorum-sensing microbes also do a great job of recruiting the immune system in the right way to flag and deal with problematic microbes, right? So the class of microbes that we worked on in the gut for a number of years in that are the spores, the Bacillus endospores. Now, bacillus endospores are fascinating because we have a long history with them, right, we've co-evolved with these organisms because they're pretty ubiquitous in the environment. Some of the early recordings of the use of Bacillus endospores for quorum sensing comes from the 1950s, for example, when the German army was in North Africa in World War II, a lot of the soldiers were dying and getting sick from dysentery, more so than the war, and one of the things that they observed was that the locals, when they would get an upset stomach, would actually seek out and eat dried camel dung as a therapeutic to help the gut, right? So then, research studies started in the late 1940s, early 1950s to look at what's in this camel dung that actually seemed to be helping with gut infections. And what they found out was this Bacillus subtilis, a quorum-sensing, competitive exclusion microbe that was coming out through the stool in these camels that were ubiquitous in the environment. If you consumed enough of it, it would actually seek out and identify the dysfunctional microbes and bring their numbers down specifically. So Sanofi Aventis, a pharmaceutical company, launched that product as a treatment for dysentery in 1952. And that product is still in the market today as a treatment for traveler's diarrhea, dysentery, chronic upper respiratory symptoms and so on, and it's called entro germina and that product has been in the market now for well over 60 years as a prescription drug in Europe, latin America and so on. So Bacillus has this long history of being able to read other microbial signatures, identify dysfunctional microbes and then bring their numbers down.

Kiran Krishnan, PhD: 14:29

We published a couple of studies like that on the gut. So it got me to thinking OK, bacillus is pretty ubiquitous. We find it on our skin, we find it everywhere. Maybe they can do the same thing on the skin. And so we developed a product with a specific carrier that was skin memetic, so it didn't interfere with anything with the skin. And then we put two bacillus endospores in it, a coagulant and a subtilis, and we started doing some studies on it.

Kiran Krishnan, PhD: 14:54

We started with some initial skin swabs on people with acne. So we would see really high cutibacterium magnesis in these individuals right. So they have inflammatory lesions all over the forehead. You swab the forehead, they've got 80% cutibacterial magnesis and of course that's why the forehead looks the way it does. Then they start applying this quorum sensing serum on their forehead once a day. In 14 days, 21 days, you know, 60 days, and so on, we took samples and what we saw was a dramatic reduction in the cutibacteria magnesis and, as a result, the lesions go down as well. So the first individual that we did this with, in a 30-day period we saw more than 50% reduction in inflammatory lesions and the cutibacteria magnesis went from almost 80% to about 30% prevalence on the forehead right to about 30% prevalence on the forehead right, and so we started.

Kiran Krishnan, PhD: 15:45

Then a whole other thing We've just completed 317 subjects on acne and inflammation. We saw the same thing. So the product is actually called this. It's called Sib. Oh, where is that camera? It's a we call it a biome balancing serum, because what we've been able to show is that when you add the spores onto your skin just once a day, they seem to effectuate change. Now we don't know exactly what mechanism they're doing the change through. That's going to require more study but we know the change is happening and we know that the skin is improving dramatically as well.

William Davis, MD: 16:24

Is it you're thinking that you apply this as a spore and it germinates on the skin? You know.

Kiran Krishnan, PhD: 16:30

I would hesitate to think that it actually germinates on the skin, because we know that spores themselves are immunogenic and even as a spore, even though they're not metabolically active, they do have receptors that are expressed on the outer spore coat that on its own can modulate immune responses in a given area. We actually, a long time ago, while we were working on the gut, did a simple study and looking at quorum sensing and competitive exclusion. For those that are listening, competitive exclusion if you're not familiar with it, that means one microbe competing with and thereby eliminating another microbe, right? Spores do this really well against pathogens. And so we did a competitive exclusion study on the surface of a cell phone, right, because we know that cell phones are probably one of the filthiest things we all have around us, right? There's so much fecal matter and other things on it from everything that we touch and other people touch, and we set it down everywhere. And so we took a couple of the spores and we just mixed it in a little bit of water and a tiny bit of alcohol and we swabbed a couple of phones with it, and then we did kind of before and after swabs of the phone. After about a week we found compared to phones that were handled in very similar ways that did not have the spores on it. The ones that did had much fewer environmental and pathogenic organisms on it. So the spores somehow prevent the establishment of pathogenic organisms, even on an inanimate surface like the phone. And so then it starts thinking like okay, maybe there are some ways in which the spores, even in the spore form, can effectuate biofilm formation and so on. Right, we know they themselves are good biofilm producers. They produce enzymes that can break down other pathogenic biofilms. So that part of the mechanism to me is very fascinating.

Kiran Krishnan, PhD: 18:33

I would guess that the spores are not necessarily germinating on the skin and living on the skin, because what's interesting about the skin swabs is we add, you know, a billion or so CFU to the skin once a day in a given area like the forehead. You would think in seven days, once we swab to look at the changes in the microbiome, we'd pick up a lot of bacillus. But we don't. So we hardly pick up any bacillus at all, which means that they're not actually hanging out on the skin. They're there for a period of time and I think they transit, they leave the skin, but they effectuate an immunological difference or they may affect something like staph epidermidis, which is a good beneficial bacteria, because we do see the beneficial bacteria on the skin increasing in growth, right. So some really interesting things there. Now you go back to the evolutionary biology significance of that and it comes back to like, well, the benefits we all know being in the outside environment playing in the dirt, you know getting dirt on us, desert dust blowing across different parts of Europe and the ability of the desert dust to sit on the skin and provide some transient microbes to the skin that can effectuate change. So I think a lot of those things kind of help explain some of the empirical value of doing something like this. But we're super excited to keep digging into the research.

Kiran Krishnan, PhD: 19:55

The next phase of research with this because we've gotten a lot of empirical reports on this is age-related changes. So one of the things that a lot of people have reported we probably have 30 cases on it at least on dramatic reduction in fine lines and wrinkles in a short period of time and improvements in the tone of the skin. So hyperpigmentation of the skin and what people are expressing is texture of the skin. So one of the things we know that occurs over time, if you look at the topography of the skin, the pores start to increase in size, right, so they become more visible, and then the skin looks like it's not smooth anymore. It doesn't have that nice smooth, baby-like texture, because our pores become bigger and you see more creeks and valleys and things like that. So we're starting to see people reporting uniformity on the skin as well, and the microbes must be making that change.

William Davis, MD: 20:52

I recognize this is not a drug, but do you plan to explore other conditions like psoriasis or rosacea?

Kiran Krishnan, PhD: 20:59

We are. Yeah, we actually have a couple of conditions that, in speaking with dermatologists, friends of mine, are difficult to treat. So one of them and this is a condition that seems to have popped up in higher prevalence since the pandemic and it may be related to people wearing masks all the time. But perioral dermatitis, that seems to be something that a lot of people are struggling with. You know, and my dermatology friends tell me that it's really hard to treat. They use a lot of steroids, they go through Nystatin and different antibiotics and many of these patients they seem to be pretty resilient.

Kiran Krishnan, PhD: 21:38

We've done a few cases with perioral dermatitis and it seems to dramatically help. And then we also have done a number of cases with just your standard eczema, you know, and we also have done a number of cases with just your standard eczema. You know your run of the mill eczema dry, flaky, red, irritated, itchy skin. We're seeing a much higher prevalence of that now in kids, you know, and you know that if you're, if you've got a five, six year old with eczema and you're treating their skin with steroids, long term it's going to impact the structure of that skin right. That area of the skin will become thinner, like most people say, there'll be a lot of more inflammatory response in that area.

Kiran Krishnan, PhD: 22:15

There's some rebound responses with steroids and all that. So one of the things we want to do is provide parents with something else they can look at and do to try to help that. So I think we would stick with the kind of cosmeceutical route. We wouldn't look at doing a drug route with it, but it'd be similar to, like you know, cerave, which is a lotion that seems to be used quite a bit with people with dermatitis because of the additional ceramides that they've added in there. That can help. So we'd look at doing something like that ceramides that they've added in there.

William Davis, MD: 22:50

That can help. So we look at doing something like that. What's your suspicion? If those two microbes the coagulants and the subtilis applied topically are beneficial, do you think there might be an additional effect if taken orally concurrently?

Kiran Krishnan, PhD: 23:01

I 100% feel that that's true Now, because in part because we've done a number of case studies that way as well. You know, when I was at microbiome labs, one of the last technologies I developed before we sold to Novozymes and then I exited was a product called Serene Skin, which is a specific for spore formula. That was for acne and for inflammatory conditions on the skin. In fact, we got issued a US patent on it. We've published two papers on it, one of the papers I think you know don't quote me on this, but I think it's published in the British Journal of Dermatology. So a pretty high-impact paper and what we showed was that just from oral consumption of the spores and these were a specific formula to increase the production of acetate in the gut, one of the things that we figured out was that acetate production, which is one of the short-chain fatty acids, acetate production in the gut is really important for skin health and in part for people who are very prone to acne. And the reason for that is acetate seems to, of course, leave the gut. It's butyrate as opposed to butyrate that stays predominantly in the gut and functions in the gut with all kinds of important things. Propionate comes in and out. Propionate also goes outside of the gut and functions in other areas, but acetate seems to be able to build up in a good amount and then leave the gut and function outside of the gut and functions in other areas. But acetate seems to be able to build up in a good amount and then leave the gut and function outside of the gut.

Kiran Krishnan, PhD: 24:33

We saw that acetate production can actually reduce the amount of sebum that's being produced by the sebaceous glands and can actually reduce inflammation in the skin, and so we looked at okay, what does the gut of acne individuals look like?

Kiran Krishnan, PhD: 24:50

And there's a lot of really good data showing that people with acne tend to have low ruminococcus and low microbes that produce acetate and other forms of short-chain fatty acids.

Kiran Krishnan, PhD: 25:00

So we formulated this product, we created a version that can create higher amounts of acetate, and what we saw in the 12-week study that published was that we saw a 75% reduction in lesions all lesions, inflammatory and non-inflammatory in that 12-week period, without the use of antibiotics, and that's right on par with any antibiotic that's used for acne. It's about 70% reduction in that period of time. So that was very exciting to us, and so then, when we first launched SIV, what we did is we took some of our estheticians and skincare professionals and said do both Do the serene skin orally and then do the SIV topically, and then in some cases just do one or the other. And we always saw better results with doing them both. Because I think it comes down to that modulating the trigger on the skin right, the pathogenic organism, and then also modulating the immune response, and doing that through the gut is the most effective way of doing it.

William Davis, MD: 26:06

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William Davis, MD: 27:44

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Kiran Krishnan, PhD: 29:05

You know we see that they do, but for a short amount of time. They're really interesting in that in the gut modeling studies that we've done we've used a system called a SHIME system, right, the simulated gastric system and it's really interesting because it has all the components of a digestive tract, starting from the stomach, small and large bowel. It has all the specific components of those structures and then it's inoculated with the full human microbiome and then you stabilize the microbiome in there over a two, three week period. You continuously feed it food like you would an individual and then it has a mucosa and an immune system and all that. So you really get really great insights in what's happening with the microbiome as you add substrates into the system.

Kiran Krishnan, PhD: 29:51

So when we've done studies with that, we've hit the system with lots of spores and then we look at the microbiome changes throughout the small and the large bowel. What we always see, no matter how many spores we're given whether we're dosing it at 5 billion a day, 50 billion a day didn't matter what we always see is a certain threshold of the spores that are reached in that gut that doesn't get exceeded. So the spores have their own limiting factor within the gut right. So in the gut, what we normally see is around 10 to the 6 CFUs per gram of stool right or per gram of you know, whatever we pull out the titrate or whatever we pull out of the gut.

Kiran Krishnan, PhD: 30:37

So 10 to the 6, for people that aren't familiar is one with six zeros right. So it's not a lot of bacteria, but they don't exceed that level in any given area, which is really fascinating. Even if we hit it with a lot, we actually just get more coming out. So the spores have a very interesting transient quality where they do take up residence for a period of time. But then if you follow any individual spore, what it does is it tends to take up residence in certain parts of the gut and then re-sporulate and move on and then take up residence re of the gut and then resporulate and move on and then take up residence, resporulate and move on. We know, for example, that when you consume the spores in the duodenum itself, the spores come out of the spore state right, so they're a vegetative cell in much of the duodenum and the jejunum. Then when they move to the ileum, as they're kind of tumbling through and they're rolling through, they resporulate in the ileum, which is really fascinating, because the ileum has that huge area called the Peyer's patches, right, massive immune sampling area, and in fact one of the characteristics of the Peyer's patches is that they're dendritic cells, these immune cells that reach across the lining and they grab onto certain microbes and pull it across and they can take those microbes to the mesenteric lymph nodes and then do things with them that may be beneficial. One of the microbes that we've done a lot of studies showing that that happens is a psychobiotic, the Biflongum 1714. We can talk about that if we have time. But what we see is that the spores, if they resporulate, if they leave the vegetative state and become a spore in the ileum, they're actually more immunogenic to the immune tissue in the ileum. They trigger more immune responses in a positive way. They upregulate tolike receptors, they upregulate Treg and so on Pardon me a little dryness in the throat and so they upregulate these immune factors and then in some cases they can actually get phagocytized or consumed by dendritic cells and pulled across and then transported to mesenteric lymph nodes where they can upregulate the proliferation of T cells and B cells, which is fascinating, right. So they have a very interesting life cycle throughout the GI tract. They enter then the large bowel still in spore state, but then by the time they move past the sigmoid they become a vegetative cell again and then they spend much of their life in the large bowel as a vegetative cell. Within two to three weeks they tend to leave, and part of that, I think, is their evolutionary adaptation of being a ubiquitous yet transient organism in lots of different guts. Right, they are what we would call universal colonizers. They're found in the digestive tract of virtually every animal that they've been looked for, including insects, including honeybees and so on. They're in every mammal in the digestive tract. They come in through eating and interacting with the environment. They do some things in the gut and then they leave through defecation. That's how they spread across the globe.

Kiran Krishnan, PhD: 33:55

There was a really fascinating study on glacial ice cores and these scientists took ice cores from the Tibetan Plateaus, from the North Pole, from the South Pole, and they take these, you know, mile-long ice cores and they can take slivers out of the ice core to look at what was in the environment during that time.

Kiran Krishnan, PhD: 34:14

That's now captured in the ice and they find that even three to five million years ago these bacillus endospores were ubiquitous in the environment, even in the South Pole, north Pole, tibetan plateaus and so on. And the most fascinating part about it is most of the strains that they identified in the glacial ice cores that were three, five million years old. Not only were they still alive, they could still be plated, but they had more than 95% genetic homology to the strains that we have around the environment today. So they haven't changed much in the last 95, in the last three million years, they have barely changed, and that's fascinating for bacteria, because, as you know, bacteria mutate and adapt all the time, right, which then leads us to believe that, okay, they're pretty supremely adapted for this environment, and part of that environment includes our digestive tract.

William Davis, MD: 35:08

Have you had a chance to explore the change in microbial composition in the GI tract with implanting Bacillus coagulans and Subtilis?

Kiran Krishnan, PhD: 35:18

Yeah, so actually that was one of the papers we published that I thought was the most fascinating. We had a hypothesis because there was a lot of studies before that done by other people since the 1950s showing the competitive exclusion capability of the spores. Right, you could put the spores next to a pathogen. They're going to reduce the amount of the pathogen through one mechanism or the other. Actually, there's a fascinating study that we did ourselves with Cleveland Clinic on C diff that I'll mention after this. It just speaks to the utility of the spores, their arsenal of capabilities that they have. But we saw that and we said, okay, they're quorum-sensing microbes, they can identify and bring down dysfunctional bacteria. Maybe they can do the opposite and bring up beneficial bacteria.

Kiran Krishnan, PhD: 36:06

And so we did a SHIME study on a somewhat dysfunctional microbiome that had very low keystone species. So this uh, many of the uh, the individuals had, um, almost no detectable acromantia, low bifidol longum, low bifidol adolescentes, low uh, fecal and bacterioposnitza and so on, um, you know, low and no root array. Of course nobody has root array anymore. Uh, we, we basically uh, somehow eliminated that that very, very important strain out of our normal guts. And so then what we did is we took, okay, normal diet three weeks. Look at changes on the gut microbiome no real changes, nothing dynamic. And then we started supplementing with spores, and what we saw at the end of the three-week period and this is using a Simpson diversity index, which is one of the very accepted diversity scoring mechanisms for the gut we saw almost a 30% increase in diversity, right, which is fascinating. Now the first question most people ask is okay, we know, diversity is the number of viable organisms, but the index also looks at uniformity of the organisms. Right, you might have 700 species in there, but if 100 of them make up 90% of the population, your diversity score is still going to be low. So the index looks at both the number and the uniformity. So we can increase diversity not only by having more viable species, but also improving the uniformity of the ecosystem, which then stabilizes the ecosystem more, makes it more resilient, because it creates more competition, right, which is a good thing for any ecosystem.

Kiran Krishnan, PhD: 37:45

And so what we saw, though that was fascinating, was that the uniformity was increasing. So, to a certain degree, the spores were kind of going hey, these guys are too low, these guys are too high, we're going to modulate their levels to a certain degree and I think, as the spores start to do that, it creates a rolling effect where the other microbes then start to rebalance themselves out. We know that many of the keystone species play a role in balancing and creating stability within the microbiome. So, let's say, the spores even increase one or two keystone species, then they start to take over the job of creating uniformity and stability in the microbiome. But we also saw microbes that were not detectable in the baselines that were now present at really high levels. Right, acromantia is one of them.

Kiran Krishnan, PhD: 38:32

Now some people say, well, okay, well, where did that come from? Because you didn't put it in. Now some people say, well, okay, well, where did that come from? Because you didn't put it in. Well, then it becomes important to understand how some of these genetic analysis work. Is that anytime you're doing a stool genetic analysis, you're really looking at a probability of finding an organism, right?

Kiran Krishnan, PhD: 38:48

Because organisms aren't uniform in any sample, and so if an organism is very prevalent, there's a high chance that if you take three or four samples, you're going to find the presence of that organism in at least two or three of those samples right. But if an organism is so low in its prevalence, then you take three or four samples, there's a lower chance that you will even pick it up in that sampling right, because you're not sampling the entire stool mass. And so what we hypothesize is that likely in these cases where there was no detectable acromantia and then all of a sudden we see 10 to the 8, 10 to the 9 CFUs per gram. Is that acromantia was always there? It was just at such low levels we couldn't even pick it up. The probability was too low, presuming that if we sampled enough we would find it. But the level was so low that now the spores and the changes in the microbiome increased its prevalence so much that now we have a much higher chance of picking it up right. So we do see this amazing dramatic increase in keystone and other beneficial species and a general increase in diversity and, if I can make a point on that, competitive exclusion with C diff. This is fascinating and this is a study done by Gail Cressy at Cleveland Clinic, and she published two studies on this. So what we took?

Kiran Krishnan, PhD: 40:10

She has a very well established C diff model in mice. She was one of the few people that can stabilize C diff for long-term infection in mice and, as it turns out, one of the ways she does it is by actually treating the mice with vancomycin, funny enough. So you use the treatment for C diff and it makes the mice more susceptible for long-term infection of C diff. So she treats the mice with vanco, she then inoculates them with C diff and then she stabilizes the infection over a short period of time. Then she can add in any other substrate. So then she added in the spores and what she found was a dramatic reduction in the amount of C diff in these animals, especially when using antibiotic treatment as another arm. We could reduce the level of C diff as much as an antibiotic can, but what she was able to discover was a mechanism by which the spores went after C diff. Right.

Kiran Krishnan, PhD: 41:11

So spores can produce antibiotics. We know that they can produce antimicrobial antibiotics in their little microbial environment which can bring down certain bacteria. They produce things like subtilisin and so on. Now, clostridium is also a spore former, so they likely can be resistant to antibiotics. So the spores don't use antimicrobials to go after Clostridia. What they did is they effectively surround the Clostridia, like kind of circling the wagons around them, and they produce a chelating agent to starve the Clostridia of iron.

Kiran Krishnan, PhD: 41:49

And we know that Clostridia, like many pathogens, require iron as part of its metabolic process, right? This is part of why Clostridia eats through your tissue to get to the blood, right, and people get bloody diarrhea, and so Clostridia is looking for iron. The spores are starving it to death by keeping iron away from it, by chelating the iron. Right? That's just the mind-boggling brilliance of nature. Right, we can't engineer bacteria to do this, no matter what our budgets are and how many brilliant researchers you give us. That's where a lot of my philosophy around research and therapeutics and all comes from is. A lot of these things have already been figured out by nature. We just have to be smart enough to know where to look and verify that it's working and then utilize it Right. And so, yeah, it's fascinating that these microbes can adjust our microbiome better than we can try to do it ourselves. That's fascinating.

William Davis, MD: 42:48

I know you're a lover of spore formers. Have you had a chance to work with any of the beneficial clustering like Bitericum?

Kiran Krishnan, PhD: 42:56

I have.

Kiran Krishnan, PhD: 42:57

Yeah, so we actually worked with a couple the beneficial Clostridia like Butyricum I have. Yeah, so we actually worked with a couple of other species. One of them is a it's a Butyricicoccus polycecum. And then the Clostridia Butyricum is another one that I think is a fascinating organism. You know, I would say that the majority of Clostridia you find in your gut are probably beneficial, and we know many of them are very important for proper immune function.

Kiran Krishnan, PhD: 43:24

But we did work with the butyricum and the butyricicum, which is another genus, all of them because we're working on metabolic health and we're trying to see okay, how do we naturally increase butyrate production in individuals? Right, Because of course, that goes a long way for diabetes and weight management and all that, but then also it plays a significant role in dealing with really inflammatory conditions in the gut like IBD. So I've had a chance to work with Clostridia as well, and I think it's a fascinating, amazing organism. We didn't end up coming out with the commercial product. We had it in the pipeline, though, but I left before we could come out with it as a commercial product.

William Davis, MD: 44:10

Any thoughts or opinions on what's going on in the Akkermansia world?

Kiran Krishnan, PhD: 44:15

Yeah, you know it's fascinating, right? So a lot of people ask me about that because of course, there's a brand that's done a really good job from the marketing standpoint of really talking about Akkermansia. Now, I've been talking about Akkermansia for a long time because there's clearly some really good population longitudinal data showing a correlation between good levels of acromancia and protection against metabolic syndrome and lots of things under that metabolic syndrome umbrella. I do believe it's an important keystone species that is likely low and missing in many missing and when I say missing I typically mean not detectable, so at such low levels that it's not functional in many individuals. When I was at Microbiome Labs, I think we had done somewhere around 15,000 to 20,000 stool tests in the US, and so I had a good sense of the collated data and we would always, I'd say I would say 60, 70% undetectable Akkermansia in individuals, right? So I think it's such an important microbe and I think a number of our behaviors make sense in why Akkermansia itself would be low. I think number one is we're overfed, right, Akkermansia is one of those microbes that tend to do well in a fasted state. Number two Akkermansia does really well with polyphenols, right. It's really good at metabolizing polyphenols, and these are colored fruits and vegetables and certain types of nuts that have a lot of agalic acid and so on. So things like almonds and macadamia nuts and so on, we don't consume those things right. We consume processed food mostly. So Akkermansia doesn't have the food that it needs and we're overfed, so it doesn't have enough period of time to do what it's supposed to do as a mucinophilia microbe and live in the mucus and eat off the mucus to some degree. So I think it makes sense why our numbers would be low.

Kiran Krishnan, PhD: 46:17

Then the question I get is can you supplement with Akkermansia right? To me, that's where it becomes really, really, you know, questionable. Because Akkermansia is an obligant anaerobe right. Oxygen is basically toxic to it, same with the polycecum microbe that we worked with. There's lots of microbes that are obligate anaerobes 15 seconds of oxygen exposure and they could be dead. And so can you actually grow an anaerobic bacteria in a facility? Because you can build an anaerobic facility we did that at a pilot scale to grow anaerobes but then you have to encapsulate it in an anaerobic facility. You have to store it, ship it. Everything has to be anaerobic right or it's going to be dying in the bottle and then the moment you consume it.

Kiran Krishnan, PhD: 47:10

Akkermansia was never designed naturally to go through the digestive tract over and over again, especially not a mature digestive tract like an adult digestive tract that has lots of acid in the stomach and bile salts and all the gauntlet that microbes have to go through. So I don't think you are engrafting or inoculating yourself with Akkermansia when you take the supplement form. With Akkermansia, when you take the supplement form, I think there could be some metabolic response based on what may be receptors or stimuli on the outer membrane of the Akkermansiaa cell when it dies and goes in, and I think the company has shown some beneficial effects. They're pretty minor but there may be some beneficial effects.

Kiran Krishnan, PhD: 47:56

But to me, when it's a keystone species and it should be there in your gut, we should always focus on how do you grow it endogenously right? How do you increase your own acromantia? And that to me, is a really important thing and I've put out a few videos on this saying that hey, there's data showing polyphenol intake increases Akkermansia. Fasting increases acromantia. Exercise increases Akkermansia. Increasing diversity in general increases Akkermansia. So instead of taking what would be, you know, the perceived shortcut of going, I'm just going to try to take this as a supplement and hope that this is engrafting in my gut. I would rather see people you know try to grow their endogenous levels, especially with the large bowel anaerobic microbes they're just so hard to take as supplements?

William Davis, MD: 48:52

Mind if I ask you a personal question. Yeah, I mean, everyone knows you're a microbiologist and how do you manage your intake for you and your family of fermented foods?

Kiran Krishnan, PhD: 49:04

Ah, okay, so we don't eat it as regularly as I would probably like to. So I grew up in India and Malaysia and in both cultures fermented foods are a staple part of your diet. Right In India, most of the breads and all that are made from fermented flour. There's lots and lots of different fermented dishes that are commonplace, so fermented foods were a normal part of my diet. Now, moving here, it becomes hard, because one to really get the benefit to me out of fermented foods is you should be doing the fermentation yourself, right, I've I found very little benefit in grabbing what is a fermented food out of grocery store shelves because in most cases you know they're not taking the fermentation to its, to its ultimate end, where it should be taken to, because of course economically that's not viable.

Kiran Krishnan, PhD: 49:56

You look at the kombuchas on the market. They cut the fermentation short by 50% at least, right, and then, and also the flavor profile of a fully fermented product is probably not broadly appealing, so they cut it short, they add sugars and flavors and things like that, and so it's less desirable. And so I've always looked at OK, can I do some of my own fermentation and make it easy, make it not something that's been overwhelmingly difficult to do. So I started with fermentation with the spores. What we did is we bought these regular old jars right that can do anaerobic fermentation and we started this about eight, nine years ago. So I fill the bottom third of the jar with fruits you know things that have good amount of sugar, so so berries and pineapple and things like that Mash it up just a little bit and then I add about a tablespoon of sugar and things like that, mash it up just a little bit and then I add about a tablespoon of sugar and then the other two thirds. I add water and then I add some bacillus spores, normally subtilis and or subtilis and coagulants. You mix it up and you let it sit on the counter and normally in about three or four days you start to see a little bit of bubbliness and things like that to it. It becomes a nice little fermented beverage that we've enjoyed. So I've been able to do that from time to time.

Kiran Krishnan, PhD: 51:22

But actually in our last conversation with your recommendation for using root to ferment the yogurt, that's something I've been able to do and that's been super easy but also really beneficial. So that to me was one of the easy things to do and you know that gives you the closest thing you're doing as home fermentation and you're controlling what all is going in it, and you know you do it, and you do it at your own pace and leisure. So that's the extent of the fermentation that we do. I would love to be able to do some natto or sauerkraut or kimchi on my own, but we just don't have the time to do it. You know I wish we did but we just don't. Yeah. But the yogurt fermentation, though, with the root rice, is phenomenal because it's easy and it doesn't take much and it tastes good.

William Davis, MD: 52:17

Can you share what kind of experience you and your family have had with it?

Kiran Krishnan, PhD: 52:21

Yeah. So my my reason for wanting to do it was twofold, actually threefold. One was you know our conversation about the emotional impact that rooterai has, right, that bonding. I actually think the work that I was able to learn from the researcher out of the APC in Ireland his name is skipping me now but he's done a lot of work with the tribes near New Zealand and Australia, the Papua New Guinea tribes, right and he's looked at ruderi Ruderi is one of his favorite things and one of the things he's noticed about those tribes is that they tend to have very high levels of ruderi and they have very high bonding. They have very high expression of oxytocin and Westerners we tend to have very low expression of oxytocin and so to me that hormone is so important in terms of the stability, emotional stability, in a household with the family, right. That was one of my goals and one of my targets.

Kiran Krishnan, PhD: 53:33

The second thing was weight management. We all always have to look at weight management. I think root or rye plays an important role in helping with digesting resistant starches and things like that right to get more benefit out of them. So feelings of satiety and maybe even increasing fat burn. And then the third thing was reduction in bloat after you eat. Right, I think through our conversation I had recommended to a number of people who have SIBO that, hey, they take a really high root-oride dose. They do some of it fermentation, some of it through supplementation, and normally what people report is they see a lot of reduction in the bloat. Normally what people report is they see a lot of reduction in the bloat. So those are the three motivations and I could say and this is just you know our own NF4 study that certainly the emotional aspect is improved.

Kiran Krishnan, PhD: 54:29

Right, you notice that you notice a different type of bonding. You notice a different tolerance, I would say, for the things that you would normally be irritated of with your family members. You know the things that trigger you. Your tolerance level for those things tends to improve. And then the other side of it for me, the bloat.

Kiran Krishnan, PhD: 54:52

Especially when I eat certain foods, like if I have a big Indian meal right and I'm eating lots of bread and naan and rice and all that, I tend to feel really full and bloated after that. That reduces quite dramatically if I take a high dose of either the root-or-iron capsules or the fermented product afterwards and, funny enough, one of the staples in India is, after a big meal, you eat curds, right, you eat fermented dairy, and that is a way of settling the stomach and reducing the bloat and the discomfort. And you walk right, that's what they do. They go for a walk and they eat their curds and it's kind of the same thing the fermented dairy here in this case and it really helps through the gut. So that's been our experience.

Kiran Krishnan, PhD: 55:39

The emotional part is really fascinating to me, you know. I think that that's a fundamental issue in society today is you mix a reduction in the bonding and love hormones that people can produce and then you add anonymity through social media and all that. You're going to get the worst out of people, right, because now they don't have the judgment of society the same, because they can be anonymous with their trolling comments and all the crazy things that people do and say, right. So I think that's a fascinating area and I think that's one area that I would love to see more research on.

William Davis, MD: 56:19

Dr Krishnan, I will take it away your time. Always a pleasure. I learn a hundred new things every time I hear you speak and, as you know, this is a really exciting time. It's like AI and changing technology. Microbiome is changing everything and I hope I can interest you in coming back again everything and I hope I can interest you in coming back again.

Kiran Krishnan, PhD: 56:39

I would love to. I've always been a fan of you and your work and your teaching and all that, and I think when we met recently, over the last year, I'd mentioned to you. We met briefly when you did a lecture at a conference, I think maybe 10 years ago, and maybe your first book was just out at the time and I'd always admired the work you've done in educating people and all that.

William Davis, MD: 57:01

So it would be my pleasure to come back.

Kiran Krishnan, PhD: 57:03

So yeah, absolutely. Thanks, Kiran.