The Perfect Approach For A Child's Healthy Gut, How To Help Your Body Make It's Own Natural Antidepressants, The Problem With Probiotics & More With Seed's Raja Dhir.

Yeah, I mean, if you look at the structure of those polyphenols, like a structural biology or like organic chemistry standpoint, just actually look at them. They're so— they're very, very interesting. Also from the skin, also from the rind, like from the whole fruit. It's, it's a, it's a very, very, uh, exciting and interesting molecule, you know. And certain bacteria in the gut love it as well.

Fitness, nutrition, biohacking, longevity, life optimization, spirituality, and a whole lot more. Welcome to Ben Greenfield Life show. Are you ready to hack your life? Let's do this. Well, folks, it's been quite some time since I interviewed my guest today, Raja Deere. Raja, did I actually pronounce your last name right, by the way? I feel like I did this years ago when I first interviewed you. Dear. Dear. Got it. Nailed it. D-H-I-R. So anyways, Raj, if I recall properly, didn't we do our last podcast at some farm down in LA or something like that? Do you remember that?

I think we did. I think it was maybe a ranch.

I assume you're not surrounded by horses and dogs like we were last time.

No, though that That is an optimal environment for, for your health and microbiome.

Good for the microbiome.

Yeah, just trees. Trees and dogs.

Okay, cool. Well, if you didn't hear my first podcast with, with Raja, I'm going to link to it. If you go to bengreenfieldlife.com/seed2, that's bengreenfieldlife.com/seed, the number 2, because we talked all about probiotic myths and different forms of probiotics and longevity effects of probiotics and male versus female takes on different forms of probiotics and a whole lot more. But, Raja has been up to a ton since then in the whole realm of the microbiome and probiotics. So, he's one of the smartest guys I know when it comes to translating research and making it applicable, particularly for things like your gut and your digestion and your poops and everything that is related to your microbiome. So, he founded and oversees something called Seed Labs where they're actually solving a whole bunch of complex ecological problems with bacteria. But then, he also helps out with the company Seed Health, which is a microbiome science company that is pioneering some very cool probiotics. As a matter of fact, Raja helped to found that company and he does a lot with it. It's the same probiotic that I take daily. On a regular basis. I take 3 capsules a day of this stuff by Seed called a Synbiotic. And we're going to talk all about that and what you need to know when it comes to probiotics. So, Roger, welcome back to the show, man.

Thanks, Ben. It's good to be back.

Yeah. And if I recall properly, you, you have like a definition of what a probiotic actually is. That could be a pretty important way to start this podcast because I think the way you define a probiotic is, is interesting and perhaps even a little bit novel?

Well, it's mostly sticking to the international consensus of the term, the scientific international consensus, which defines it as a live organism. So, it has to be live, which confers a health benefit to its host. So, it could be probiotic for different types of hosts, it could have different health benefits. It has to be live and it has to confer a benefit to its host. And the range of that benefit is the degree of or the flavor of the probiotic.

So when you say that a probiotic has to be live, I don't even know, like if you were to go to Walgreens or CVS or whatever and grab a probiotic off the shelf, how likely is it that it's live?

I mean, what most products do is use very industrial and stable but low diversity strains. So, a handful of strains that they'll put a very high amount of, put it into a state of sleep, so to speak. It's a state of dormancy. And I don't know, I mean, let's assume that maybe 75% have the organisms that they claim that they have. Probably less, but let's just even assume that. That's just the first test. That's just the first stage. Those organisms then have to be alive through the gastrointestinal system and for the benefit have some activity most likely in the small intestines and colon. That is the most of the known mechanism by which how probiotics work. So, that step of the process is very important, but what you really want is to know how many live cells do you have that are metabolically active all the way through the pipe.

How do you test something like that?

There's a few ways. I think some people try to approximate that from animal studies. I think that doesn't work, that doesn't translate very well. The best system I'm aware of is a gastric simulator. It's a single simulator and then a twin version of it, and you can actually stack multiple of them to run different experiments in parallel. And it's exactly what you think. It has a stomach and 3 compartments, intestines and a colon. And actually, there's a microbiome transplanted in the colon. Oh my gosh. That's to measure metabolic effects. So, it's a biological system but it's assembled in vitro.

Okay. So, how big is a gastric— you call it a gastric simulator?

Yeah, that's, that's, that's a good term. Yeah. A gastric, gastric simulator. Intestinal simulator.

Okay. Is this, is this like the size of an average human gut or is this just like a huge machine in a factory?

It's probably about half the size of a car.

Oh, wow. Interesting. See, it seems to me like where my mind goes is, couldn't there be a future where you could have your own home-based gastric simulator that simulates your gut and you could just put stuff into it to see if it agrees with your gut before you decide to consume it yourself in the real world?

The good news is that you probably don't need it because microbiome, the level of personalization isn't that dramatic, I would say, that we can't get from other types of large population studies. But were you to do it, one interesting thing to do would be to keep your microbiome from infancy, from birth, as it developed, as it matured, as it diversified. And in times of distress, you could reinoculate yourself with your own original microbiome. I think I'd be interested in a chamber for something like that.

Oh, yeah. You mean like if you went on a stint of antibiotics or had an issue or I don't know, had your appendix removed or something like that, you could actually age or—

Yeah. As you age, you also lose a lot of the diversity from your younger self. So, I think there'll be many use cases of that. I think that'd be very interesting. If you start off with a good microbiome, which you have a better chance of doing if you follow some guidelines out of the gates.

Right, just like banking your stem cells. We should probably go buy something like biomebank.com right now just to make sure we've got that when it becomes a reality. That actually reminds me of something I did want to ask you. If you are not born vaginally or if you're born via C-section, I should say, There's a lot of people who say that your gut is not really adequately populated with beneficial bacteria, the right amount of bacteria, for years later on in life. I've seen figures like 7 or 8 or 9 years old. Is there anything to that? Is that true or is that just kind of a myth floating around the internet?

Yeah, that's not entirely true. So, a better way to think about it is that the mode of birth vaginal versus C-section, the mode of feeding, breastfeeding versus non-breastfeeding, and the presence of antibiotics are kind of three equally and varyingly powerful lever, you know, cares of the stool. So try to get as many of those right as you can. And if you're able to do so, you'll have a very good chance at what is considered an optimal infant microbiome, which is dominated by a few different strains of Bifidobacterium infantis, making way for other Bifidobacterium to slowly start to build with diversification and acidify the gut as the rest builds on top. So, you'll have that if you follow those three. There are studies where people are born non-vaginally, but there's no antibiotics and there's breastfeeding and a little bit of luck that the right strains found their way there and they ended up with all known markers with a totally fine microbiome at 6 months and on.

Okay. What, what are the 3 strategies again?

Did you say, uh, vaginal birth, breastfeeding, and no antibiotics?

Okay. So if you aren't born vaginally, but you're not exposed to a lot of antibiotics and you breastfeed, arguably you're still going to have a decent biome as an infant or your child is going to.

I mean, if there really is no Bifidobacterium that finds its way there, you could kickstart the process by making sure that that infant has exposure to a few different strains of Bifidobacterium infantis. But it could be there, it could not be. The data is inconsistent on how B. infantis actually gets to infant guts in the first place.

Okay. Yeah, I was just curious the extent to which the vaginal flora makes a significant impact, or I guess even the fecal matter that they say that the child is exposed to going through the birth canal, if that really is as significant as a lot of people say.

I mean, I think it is important for other reasons. A perfect infant microbiome, let's say 2 weeks or 3 weeks out from being born, should be dominated by Bifidobacterium infantis, one bacteria. And you know why? Because it takes HMOs, it takes the sugar, the prebiotic fibers in breast milk, it engulfs them entirely and it leaves nothing else for any other pathogen to grow. There's nothing left over internally, entirely metabolizes HMOs internally. So, when B. infantis is there, it's not allowing any potential pathogens in that early period of life to take hold. Secondarily, it trains the immune system to promote tolerance. And so, it's a very big driver of minimizing what's called that atopic march, those conditions of allergy, asthma, sensitivity, inflammation, excessive inflammation. That tolerance we believe is taught from that bacteria. And so, for infants that are getting that bacteria initially from fecal content or very rarely a reservoir vaginally, that contact is very important. For others, maybe it finds its way in a different way, but if you want an optimal microbiome out of the gates, those are the conditions you need.

So, are you saying that the— what'd you call it, Bifidum infantis?

Bifidobacterium, that's the genus. Okay. It's a very interesting genus even in our research for many different stages of life, that's a very good one. And, the species is called infantis. I think it's a subspecies of longum, but it's Bifidobacterium infantis. That's the Latin name of the bacteria.

Okay. So, are you saying that Bifidobacterium infantis is the only important strain in a young human being up to a certain age?

I mean, at least one strain. There are other different strains that have different benefits, but as a baseline, Bifidobacterium infantis is. In fact, the healthiest infants in the world are dominated by almost exclusively Bifidobacterium infantis until diversification.

And at what age does diversification usually occur?

That depends on when you bring foods into the mix. So, as long as you're exclusively breastfeeding, you're pretty much going to be dominated by Bifidobacterium infantis in an optimal state.

Okay, I got it. And, these HMOs, that's human milk oligosaccharides, right?

Yeah, that's coming from mom's milk.

Is there a benefit to consuming HMOs after you've finished breastfeeding? Let's say for me, for an adult who wants a healthy gut, is consumption of human milk oligosaccharides something that's beneficial?

I mean, that's an interesting question. I think that it could be, but I think that if you have the right diet, it's not necessary. Because you'll still give plenty of oligosaccharide-like structures that you find in the food matrix. So, it's preferential, so it can in periods of distress probably tip certain communities in a more favorable way. But my perspective is that a rich and varied oligosaccharide composition in your diet should overpower any additional effect that HMOs would have in adulthood.

What are some other ways that you get non-human milk oligosaccharides, these other oligosaccharides that you mentioned from food?

From food, I mean, in virtually all plant, rough plant matter, you're going to find some version of them. I mean, they're in many, many different fruits, they're in many different vegetables, they're concentrated very highly in tubers. You're getting them if you're eating carbohydrates from plants, most generally, come in the form of, if they're not sweet, generally come in the form of variably digested oligosaccharides, varying chain length prebiotics. That's what you're getting, these types of fibers from your diet. Now, there's some that are, again, easier to get, there's some that are more useful in different periods of time versus others, but an optimal healthy microbiome at the adult stage should be able to tolerate and actually demands an extremely diverse portfolio of plant fibers.

Okay. So, you've got your monosaccharides, which are the single very simple sugars, then things like polysaccharides. Are oligosaccharides longer chains of carbohydrates that you'd find in fiber or are they just varying lengths like you said? I don't even remember what the word oligo means.

That's exactly right. That's exactly right. So, the number of polymers, the number of the degree of polymerization isn't 1, it's closer to like 6 or 7 or 8, like up and then above 10 I believe is like a fiber, like in a, like characterized as a fiber.

Okay. All right. Got it. What do you think about the carnivore diet though? Are they getting oligosaccharides from meat in some way?

Certainly, certainly not. Really? Certainly. Yeah, certainly not.

Is that a problem, do you think?

I think people could survive on a carnivore diet, but I think that every 100 out of 100 academic microbiome scientists would answer that question by saying that you're introducing a massive deficit to the host microbiota, a massive deficit. And first, and second, that you probably dramatically shift it from a saccharolytic state, which means breaking down carbohydrates to a proteolytic state, which is very adversely associated with metabolic and cardiovascular health outcomes just from the microbiome standpoint. Now, I'm not talking about in the blood.

Yeah, that's, that's interesting. I was talking with Dr. Steven Gundry, who was poking some holes during our interview, which might be released at the time that this interview comes out. Again, I'll put the show notes at bengreenfieldlife.com/Seed2. He was bringing up some statistics on true long-lived populations, or at least longer-living populations than some of the popular blue zones. And he was talking a lot about the process of fermentation of meat, dry aging, wet aging. There's even like on Lifehacker.com, they've got recipes for speeding up that process via fermenting the meat and fish sauce and kombu. Would the fermentation process applied to meat help to skirt some of these issues with inadequate fiber?

There's no way. Fermentation can't make a fiber. Spontaneous fermentation can't assemble amino acids into a fiber-like structure. It just doesn't work that way. I mean, fermentation can take a very long fiber and transform some chain lengths of that into different compounds. That's basically the The basis of fermentation is we break it down and convert it into other interesting compounds that your body might like. That's how acetate is made, for example. So, there's an interesting role for fermentation, but fermentation itself can't take amino acid chains and make fibers out of them. Fibers have to start from carbohydrate. Actually, mucin and some of the intestinal sugars, some of the backbones of mucin, of the mucosal layer, are actually more similar to that type of oligosaccharide-based fiber structure. And that's why you see that like mucin-degrading bacteria, they like those fibers because they're able to have all the environment that's necessary to also adhere to mucin and to degrade marginally mucin. But be careful, if you degrade too much mucin, that can also take you to a bad place.

Stephen Gundry, in the book, by the way, that he just wrote that I talked to him about, it's called Gut Check. I think his main argument was that there are some potentially harmful sugars associated with chronic disease in meat. I believe they're called Neu5Gc, and the process of fermentation somehow deactivates or predigests those sugars. And I don't think he was making the argument that the fermentation somehow causes the non-existent fiber in meat to somehow benefit the biome. I think it was more the elimination of potentially harmful sugars. I mean, That is—

I've heard that hypothesis. I don't have a definitive opinion on it, but it's certainly plausible that subjecting meat to microbial fermentation could alter it in a way that could make it less harmful. That hypothesis could definitely be true.

Now, a lot of people are sensitive to fiber. Way back in the day, I interviewed this guy, You'd probably find him fascinating. He wrote a book called "The Fiber Menace" and his name was Konstantin Kaborotsky, something like that. Anyways, totally vilified fiber and talked about how it causes gastric distress in a lot of people. And, I think people who have had, for example, small intestine bacterial overgrowth or SIBO have certainly reported having issues with the whole idea of resistant starches, inulin, green banana starch, et cetera, causing bloating and digestive distress. Even after I interviewed Konstantin, yeah, I was doing the giant blender bowls of kale. And, I learned this from Mark Sisson, I don't know if he still does this, but big-ass salads with just tons of nearly pounds of vegetables for lunch when I began to reduce that amount of specifically raw fiber intake, my gut did feel a lot better with respect to bloating and indigestion, irritation, gas, et cetera. I think that a lot of people have kind of tuned into the idea that maybe excess fiber might not be that great, especially if you have those issues. And some people have even cut out fiber quite a bit, maybe not gone with a full carnivore diet, but they're limiting fiber. Now, what I'm wondering is this. If, let's say, I'm traveling and I'm not eating as much vegetables and fruit and fiber or I've got digestive issues and I've decided to try lowering the amount of fiber that I take in, could using a probiotic actually allow for you to get all the benefits that you're looking for in fiber? Like, even if I was eating just meat, what if I were to just take a probiotic, would that replace a lot of what it is that I'm missing from fiber?

I think, I think reduction of fiber for people that have symptoms from it is fine. I think, I'm not sure if that's optimal. I think that maybe speaking to microbes that are in regions of the intestinal tract that maybe not the best suited or are at the right place, I think that that field is still developing, but that can also explain some of those symptoms is that, you know, there's, other organisms that are causing those symptoms that would normally be crowded out or in an optimal microbiome wouldn't be there at all but have already been outcompeted. So, I think that's an interesting area to explore. What are those organisms and how can you fix that? Why then would there be several studies where people take antibiotics and actually their ability to eat fiber goes up, right? So, there's validation for this hypothesis that there's a microbial component to fiber intolerance or to resistant starch intolerance. I think that to dramatically cut down fiber without replacing it with a very biologically relevant amount of other substrates, so like flavonoids, polyphenols, there's certain carotenoids that structurally are also able to be metabolized by the microbiome, also enriched for very interesting pathways and also keep that organ, that microbiome metabolically active in a positive way. And so, I think any dramatic reduction of fiber intake should be cautiously paired with something of that type, right? And you have to take this seriously. I'll give you one example. So, a paper came out in a leading scientific journal a few months ago on acromancia, And, it found that in the presence of a low-fiber diet, it went from protective to inflammatory and triggering food allergy. So again, thank God it was a very well-designed— I think it was even a Nature paper, but it was an animal model. And so, it was a very mechanistic paper. But yeah, that was the takeaway, which is if you have akromancia or if you take akromancia, should be paired with a high-fiber diet. Otherwise, it'll probably— my hypothesis is it'll start to degrade your mucins, induce more inflammation at that local site, and actually increase the inflammatory signaling coming out of the microbiome.

Ben Greenfield: Well, that's actually really good to know too because I interviewed Colleen Cutcliffe of Pendulum that makes an acromantia-based product. And, she brought forth some data that indicated that acromantia may assist assist with fiber digestion in people who tend to get some of these bloating and gas type of issues in response to a high-fiber diet. So, I suppose it makes the case that if you're going to use akkermansia, A, don't avoid fiber, and B, maybe be less scared of fiber because it might actually help you to digest it.

I think there's many bacteria that serve that function. So, there's many Bifidobacterium, there's many Bacteroides, there's many lactobacilli. The interesting thing about Akkermansia is that it does do that, but you don't normally have a lot of it. There's not a high abundance of Akkermansia normally. And so, when you think about rounding out your microbiome to be able to handle high fiber production, I would consider open the question of what is the best cocktail of organisms to actually accomplish that. You probably want a diverse cocktail and you probably want them all to have pathways for fiber degradation.

Ben Greenfield: I want to backpedal for a second back to babies. Since the last time I interviewed you, you've sent me a few packets of this powdered— I don't know if it's a symbiotic or a probiotic or how you would define it, but it's a pediatric product. It's different than the one that I've been taking on a regular basis. What's different about the pediatric product that you're making and why?

Sure. So, DS-01 is the adult product and that is a 24-strain mixture, but that's not the most important part. The important part is that there's multiple strains of— from within the same species in that composition. So, it's what's called a redundant consortia. So, it's a very interesting transient probiotic consortia designed for adult consistent usage. That's the intention of it. And, with activity across different organ systems, across many different biological systems within the body.

Okay. And I don't want to derail you. I don't want to derail you from the pediatric thing. I want to come back to that. But what do you mean when you say transient? Do you mean these, these probiotics go through the gut, washed away, and they're gone?

They're transient in the sense of they don't result in long-term chronic shifts of the composition of the native microbiome. So they don't displace or modifiably alter in a healthy state the native microbiome.

Why is that important?

I mean, the microbiome is an ecology which is quite varied between people. And so, certain organisms and certain microbes work in what we call networks. They work with other organisms that they're used to working with. Akkermansia, just to drive that point home, is part of a network of 4 or 5 organisms that when you look in people that have Akkermansia are typically co-localized and co-located with. So, the microbiome is a a resilient yet also fragile ecology in the sense that there's shifts from time to time and especially in periods of duress like after a course of antibiotics in a condition that microbiome may play a role like IBS. Those are two areas that we've studied. You have to be very careful and considerate about which microbes you're introducing into that ecology and what you're trying to do. So, transient can be good for the goal of that. If you're trying to cure depression, you probably don't want a transient Konsortia, you probably want to take very high amounts of Copperococcus and Dialister, different bugs. And, you'd want to take probably antibiotics first to wipe everything away so you have the best chance of making those new bugs actually take over and build a new ecosystem as a foundation of that ecological recovery. I mean, that's how it works in drugs. If you have a C. diff infection, you take a course of antibiotics to wipe everything out then you're transplanting a stool, a whole stool from another person, and then you let that try to recover. But if you just take the stool from another person and you just put it in without the antibiotics, you have much lower engraftment and long-term colonization rate. So, it can be good, it can be bad, it depends on what you're trying to do.

So, if the transient product is designed not to disrupt the presence of an already arguably healthy microbiome, If I've got a healthy or good microbiome, why would I even take it in the first place? Specifically referring to the DS-01 that you guys make.

It's a very good question. So, there's two parts to think about what you want a probiotic to do. You want a probiotic to do things to other microbes in your microbiome like microbe-microbe interactions. And then, there's things you want it to do to the host. So, microbe-host interactions. Now, what we learned as we were progressing was that most of the microbe-host interactions actually don't happen in the colon. The colon is a lot more protected. It has a much thicker mucosa. It has a much more dense community. But actually, there's something different about ingesting, about that daily inoculation of microbes and their transit and passage through the body that we believe seem responsible for many of the host side effects, the microbe-host side of those two interactions. And, one good example is Probably a lot of intestinal immunity is regulated there because the immune cells that reach out and sample it are big drivers of T-cell differentiation of immunity. And other examples like the gastrointestinal barrier, the epithelial barrier is more permeable in the small intestines and the end of the small intestines than you'd expect it to be in the colon because it actually bypasses that. So, it actually gets absorbed in the intestines on their path down. So, most of your microbiome or most of what's already in your microbiome isn't going to interact with those other parts of the gastrointestinal system on a day-to-day basis. And so, for that, you have to look more to probiotics. And if they're human native strains, it's just a different level. People have also for some host side effects tried to look to fermented foods. There's a very interesting way to think about fermented foods as well, but you have to really dissect what you're trying to look for and what you're trying to deliver. There's an independent benefit of daily inoculate microbial inoculation than what your microbiome is to begin with. That's probably the most important part.

Okay. So when I take a probiotic, even if I've got a good microbiome, what I'm doing is upregulating the function of things like the gut immune action, the mucosal lining, the potential of something like a permeable gut and some of these things that just having a healthy microbiome might not be sufficient to allow for.

Yeah, well, that was actually the primary finding of our, of our placebo-controlled trial on DS-01 after antibiotic, of course, a broad-spectrum antibiotics. That was a clinical trial that we did. And the first and strongest and probably most striking finding was concurrent to antibiotics, which actually disrupt the epithelial barrier. They disrupt the gut barrier. So, that was a very interesting finding. The second one was that DS-01 rescued that gut barrier disruption in almost 90% versus 10% to placebo. So, it was a very strong effect based on this lactulose-mannitol test. And the third thing was that that effect persisted out to 2 weeks after taking the original course of antibiotics. And so, that's kind of the host side of it. And then, if you ask about microbiome, there's a lot of other findings I think are very interesting. But, But I think that that framework for people might be interesting to think about.

So, if I were going to use that strategy, if I were, God forbid, to have to get on some kind of a hefty antibiotic regimen, would I begin to use the DS-01 synbiotic during my antibiotics or would I wait until I'd finish the course? Concurrent. Okay, concurrent. Take it at the same time.

That's how the trial was designed.

Okay, got it. Now, I kind of derailed you as you were beginning to explain why the pediatric blend is different than the DS-01.

Yeah. It's different on outcome, it's different. The pediatric product is fewer strains but also multiple strains from comprising different strains of the same species. So, more redundancy, more representation of the diversity within individual species and paired with a fermentable prebiotic. And so, the primary outcome for that was that when consulting pediatricians, In designing the trial, we were told that this trial were to address pediatric constipation or regulate the GI system of children would address the single most common reason for pediatrician visits, which is pediatric constipation. I think it's like 1 in 3 or 1 in 4 kids see a doctor for it, have it.

Yeah. Useful for a parent's sanity too, because no parent wants to be waiting there 15 minutes to use the bathroom themselves when their kid's on the toilet. Yeah, I'm sure. Yeah. The, the age though, what's the age at which you'd take or stop taking something like this?

Well, that you could start as early as 3. You should continue for as long as regulation of the gastrointestinal system is a primary benefit or goal that you have. And then I think, you know, maybe even post-adolescent onwards, I would recommend, I don't know what the official recommendation is, but from a biological standpoint, I would say as soon as you're highly diverse and if you're able to balance out your carbohydrate and your fiber intake in a somewhat meaningful way, you could switch over.

Okay. Do you have kids?

I do. I have one 5-month-old son.

Okay. Knowing what you know, if you were to kind of have the gold standard feeding or probiotic or or breast milk consumption or human oligosaccharide consumption, human milk oligosaccharide consumption for a young human being coming into this world to give them as many advantages as possible from a microbiome standpoint, what would it generally look like in terms of what you'd feed a young human being to optimize that?

I mean, I think about this all the time now. So, I have as detailed and intricate of an answer as you want to that question. I think I'm very, very interested in the development of the gut and the brain, and they're kind of related. There's a lot of compounds that drive that, either comprise the structure of it or drive the development of it. I think for the first few months, as much as possible, one should exclusively breastfeed at least through 4 months, try to get to 6 if you can, but at least through the first 4 months if there's no Bifidobacterium infantis. So, I didn't do a test per se, but I gave him early inoculation of Bifidobacterium infantis around week 3 or week 4.

Wait, wait, wait. What do you mean early inoculation?

I mean, I did it myself. I work with and grow a lot of different strains. So, I took 2 or 3 strains from our library of Bifidobacterium infantis and I put it on the tip of his tongue and then he breastfed right after.

By the way, look at you. You got your library of probiotics, you got your gastric stimulators. Geez, everybody's going to be envying your setup at home. So, you inoculated your son with those strains. What else do you do?

Yeah. Well, that's first, then get to breastfeeding. When you get to diversification, you want to get carotenoids and N-3 fatty acids as early as possible. You want to make sure that mom is taking very, very high dose, at least DHA, but ideally DHA and EPA. That's going to directly pass through the breast milk. And, even during the breastfeeding phase, you want to make sure mom's eating an incredibly diversified diet in carotenoids. Carotenoids are very unique in that they actually are stored in, are broken down in the gut along like polyphenols and flavonoids and some other plant-based compounds, but they also make their way directly into the eye and into the brain. And, that's very interesting to me that there's this very precious class of compounds that crosses the placenta, it crosses the blood-brain barrier, it's allowed to aggregate in the brain of your offspring. And so, I'm very, very interested in some of these types of plant-based compounds.

You're going to sell a lot of mini carrots to pregnant and breastfeeding women with this. What other food sources are rich in carotene, by the way, that you like?

Not just carotene. So, I should clarify that the class are carotenoids and there are a wide variety of compounds. There's about 40 or 50 in the human diet that are found across the spectrum of color. Basically, they comprise color in in certain vegetables by having an absorbing effect on the light spectrum and reflecting out others. So, that's their relationship. They function alongside chlorophyll as a relevant molecule in plant biology that just turns out to be very interesting for humans too. I mean, we benefit a lot from that.

So, just colorful vegetables.

Yeah, as rich and deep. Most pigments in vegetables are driven by something in the carotenoid family. Or also in the marine environment, things like astaxanthin or zeaxanthin, there's few in the sea as well.

Got it. Anything you go out of your way specifically for your son or that you recommend folks avoid?

I mean, I'm pushing for him to get onto polyphenols as quickly as possible as well. So, blueberries, bilberries, you know, just most of your bright low— relatively lower sugar berries, I think, are— you, you're just gonna get so much of it, so much good stuff from that.

Fantastic. You've just described the diet that my sons grew up on, so I feel very good about that. And I'll still probably forward them this podcast in a few years, so I've got healthy grandchildren.

But yeah, okay, that's great. I see them also probably drinking the oil of the fish straight out of the pan in addition.

So, they're not that extreme although I have to admit they probably get their fair share of chicken fecal matter from doing an inadequate job washing the eggs they go down and harvest every day from our chickens. So, they are getting an adequate microbiome, that and licking the goats.

That's it. You see in the first 2 years of life, you'll see introduction of all kinds of things that kids eat. You'll see everything that they eat. Show up, but it doesn't last very long. It just passes through and signals to the host to teach it tolerance. That's the hypothesis behind early, early rich microbial exposure and its effect on the immune system is that you're born inflamed. Microbes and certain ones are better at teaching your immune system tolerance over time that benefits you, that benefits your immune system. It makes it more calibrated.

Yeah, that makes sense. Hey, back to antibiotics. A lot of people get on antibiotics and finish and feel like their brain has changed. And, I don't think it's any secret the existence of the gut-brain axis, but are there certain things like natural antidepressants or something like that that your body is churning out that just get nuked by an antibiotic regimen? Is there something to do about that?

I mean, definitely. I think the last library had about around 500 different neuroactive metabolites that come just from the microbiome. So, it's so powerful that if you take your blood and you do metabolomics like broad-spectrum untargeted metabolomics on every metabolite in your blood and you do that to 10 people and then you give all of them a very high-dose broad-spectrum antibiotic and subsequent to that, you do that again, you won't be able to match people back to their own sample after. It's the only time, it's the only event where you're not able to do that in the field of metabolomics. It's the only event that renders you incapable of matching your sample back, your own biological sample to itself. So, there's many of them. And so, after a course of antibiotics, absolutely, but it rebuilds, right? In our trial, we saw that after 12 weeks it builds, but it comes back differently, right? So, this is where I think there's an opportunity to guide that recovery of the microbiome. In the case of DS-01, we had a rescue effect on what are called low abundance microbes. So, this means low abundance microbes that were already in someone's gut coming in that took the antibiotic and took a placebo were gone, more extinct in comparison to the DS-01 arm where it enriched and kind of protected through what we believe is a very strong cross-feeding function, right? So, it donates that cross-feeding consortia function to let some of those microbes tap into those networks to get back up and going again. And remember, some of these bugs need very specific network of other bugs around them to be able to grow. So, you see these things cluster together a lot. That's another very interesting finding that we found where DS01 in particular could be— it could be an optimal time to start DS01 is alongside the completion of a course of antibiotics.

Ben Greenfield: A lot of people will use, I guess, it's Xanax or diazepam or something like Valium. And, I think it was— by the way, you guys have a fantastic article database on your website at seed.com. I think it was there that I was reading up on a natural compound. I want to say it was like nor— nordazepam, something like that, that the body actually makes that is affected by an antibiotic regimen.

That's gut-mediated. Yeah, absolutely.

Yeah, that's just crazy that your body can churn out natural antidepressants and you can nuke them with an unhealthy microbiome. The other interesting thing, and I think I also learned this from your website, is that if you have been on an antibiotic you can be far more susceptible to heavy metal absorption from things like sushi, tuna, et cetera. Is there something to that?

Yes, there is. Microbes, they can bind to metals and metabolize them or excrete them or at least lower their absorption rate. But again, remember the system. So, if that absorption of that metal is happening up before your microbiome, that's out of reach. It's just different chambers. It's a different game. So, only for colonically absorbed areas, that's the case. The other way that not the microbiome but that probiotics could benefit is that, and more than just metals but things like even microplastic, right, which varies between 0.1 to 1 nm in size. If it's above a certain threshold, I think it's 0.7, it generally shouldn't enter into the body. Like, 90% of the microplastics that we consume, and there's a lot of them, they're in fish all the time now, they're in water, they're in anything we eat, in takeout that's heated. Like, no one doubts that we have tremendous exposure to very small particles of plastic now. That's only going to get worse. The amount of plastic that's being produced and how much it decomposes and where it has entered into the oceans, this— it's a matter of time before it actually permeates many, many more things. So, but a lot of that won't get absorbed if you have the right intact barrier and a barrier that supports it. So, I think there are periods of distress that allow the body to be more permissive or more tolerant of things that in an optimal world we would excrete or we wouldn't even have to endure.

Yeah, it makes me think about in microbiology lab, I spent one summer as an undergrad doing fluorescence assays on potential bacteria that could bioremediate. In this case, we were looking at, I don't think it was plastics. I think in this case, it was actually metals. I don't recall. It was too many years ago. I'm getting old. But, the idea behind bioremediation using organisms like bacteria, from what I understand, that's kind of one of the fundamental premises of Seed Labs, yeah?

Yeah. I mean, Seed Labs is an ecological division of the company, is the ecological division of the company. And so, it's considered a wide variety of microbial applications that relate to ecologies and certain environments, marine environments, pollination environments, waste degradation, nutrient uptake, and even marine diversity and symbiosis in marine ecosystems like densely populated coral reefs. So, we've had 4 or 5 very big projects there that are all ecological of nature, and plastic degradation was one of them.

Well, selfishly enough, I'm interested in something else because I love to put bee pollen in my smoothie. I do a ton of raw honey. I have it with salmon a lot, probably too much. I do a bunch of different bee products. What's that one company? Beekeepers Naturals. I even suck on beekeepers lollipops while I'm playing tennis. The impact on bees though, what are you guys doing as far as that's concerned? Because it's my understanding you're doing some kind of work between bacteria and bees.

Yeah. So, this program was based on the discovery that bees have a kind of microbiome in their hindgut and that some of those strains that are resident there, it's actually a type of Lactobacillus that are native into honeybees, perform a valuable function in detoxifying just what's called xenobiotics, which just could be referred to anything that's toxic from the environment. But the class of xenobiotic in particular was pesticides. And the class of pesticides in particular was the neonicotinoid pesticides, which are super destructive to honeybee colonies. So, this is a very interesting finding. And so, the premise was, well, could you enrich for those and build a small little honeybee microbiome ecology that optimizes for this detoxification pathway? And so, after a lot of enrichment experiments, found a mix including Lactobacillus kunkkii, that one native strain. And I think it's had 4 field trials now in 3 different continents. It's quite impressive how that body of literature has progressed and been very efficacious for pesticide-induced death of the bee, but also in other pathogen that gets to young bees in the first few days of life. It's a type of pathogenic infection that if you actually find it as a beekeeper, if you find it, you have to torch your whole hive and all the surrounding ones because it's so toxic, it's so bad, and it could spread so quickly. So, prevented young bees from having infection of that pathogen.

That's interesting. When you talk about nicotinoid pesticides, it makes me think about this interview I did a few weeks ago with Jonathan Otto. He discussed pesticide like compounds winding up in medical supplies, plastic tubing, even vaccines, and mentioned that the use of nicotine products such as a nicotine patch may actually bind to some of the same receptor sites and make you less susceptible to damage from pesticides and herbicides based on the fact that apparently they're somewhat similar to nicotine itself. I don't know if that has anything at all to do with the honeybee research, but it's interesting.

They are somewhat similar in the sense that if you give honeybees the choice of glucose water or this neonicotinoid pesticide, over time it'll begin to prefer that pesticide because of exactly that same pathway than the sugar water. So, in that respect, it is. I can't comment on if that means you should start taking nicotine to protect yourself from pesticides, but I do. I don't know how far I'd go there.

I have a few of the 14-milligram nicotine patches in my pantry and I'll occasionally put one on if I need a little bit of energy or if I'm going out to a dinner party at night that'll keep me out past my bedtime.

But it is a nootropic and it does access brain chemistry in a very clear way.

So, yeah, that probably works. And by the way, this is probably a little bit relevant. There's a lot of people who use nicotine gum and lozenges and all sorts of oral nicotine products. You ever come across anything that shows the impact of nicotine on the microbiome specifically?

The impact of smoking but not separated out for nicotine per se, but the impact of smoking affects several different microbiomes. And women, actually, it affects a different one. It affects their vaginal microbiome in a very destructive way. Smokers in particular are most likely to not have an optimal CST1, which is the most protective state.

Ben Greenfield: I think you mentioned to me as we were leading up to this podcast in the past few weeks that you have something you're working on for the vaginal microbiome. I find that interesting. I know a lot of women who will use vaginal suppositories for the microbiome, but what exactly are you guys working on?

So, the vaginal microbiome is quite unstable, but when it is optimal, it is very stable. And, it's typically only a couple different strains of the same species and of one species ideally. And, the best of those species would be Lactobacillus crispatus. That is the hallmark of an optimal vaginal microbiome. It protects, inhibits pathogens from existing. It has anti-inflammatory benefits and it's associated with fertility. It's associated with reduction of spontaneous preterm birth. It's associated with positive outcomes in STIs. We have an IND approved by the FDA to actually study R composition on cervical cancer as a result of HPV. So, we think that it would clear the therapeutic product that we're developing. We think that that would clear HPV more consistently and faster, which is a very prevalent viral infection, which is also learning to escape vaccines. So, very important reason. And also, if you've just given birth, for example, you have a very disrupted vaginal microbiome because your estrogen levels are low and prolactin is up. And, And also if you're perimenopausal or postmenopausal, it's far more likely to be disrupted and out of that state because of changes in circulating estrogen levels. So, it's a very interesting space. So, what we developed is actually an entire ecology that comes— that represents the entire genomic content. Again, remember that multiple strains of the same species that represents the entire genomic content of that optimal genome. And it also is optimized for stability and resilience. And so, the idea here is that you can actually take it and over time, well, we know that you can rapidly in the first month induce this community state type CST-1. And with minimal ongoing maintenance monthly, you can sustain it.

What's the strain again? I missed it when you said it. Start with a C, I think.

It's called Lactobacillus crispatus. It is also referred to as CST-1. There's 5 different CSTs, which is like the type of vaginal microbiome that any given person may have.

Got it. And, when that product is released, is that going to be a vaginal suppository?

Yeah, that is.

Okay. And, is there a retention time that's necessary?

Uh, the first month is a little bit more involved. Where you need to take it every other day for the first week and then once a week for the rest of the month because what you're doing is you're inducing that colony formation. So, unlike gut applications, here you want colonization. Here you want to actually displace anything that's there, outcompete it and engraft and be the only player in there. You want to have the entire metabolic activity restricted to this bacteria. That would be the most optimal state.

Ben Greenfield: Okay, that makes sense. Not related to the vaginal biome, but I guess back to the Synbiotic, I get your monthly refill pack of that. And occasionally, I've broken open the capsules and it's kind of like a capsule inside of a capsule. What's going on there?

Raja Chaudhary: Many human native strains are quite sensitive to water and other plant materials. So, in a big smoothie or a yogurt, for example, or a nutritional powder, greens powder, or a fermented food. It's very unlikely that high amounts of these human— many of these human native strains will stay viable over a long period of time. So, to protect those strains, first and foremost, they're in a capsule just for themselves. So, the probiotics and all the live organisms in DS01 are kept by themselves in that inner capsule. That capsule is then flooded around with a punicalagin-rich prebiotic polyphenol. So, this is a high punicalagin load.

Wait, I know this by the way. Punicalagin, that's found in pomegranate, right?

That's right. That's right.

I aced that.

That's right. It's part of the ellagitannin family. So, these are these big, big, big molecules. Only about 3 or 4% of them actually get into your blood. So, most of them flood the microbiome and they can feast on it. And, they break it down into these secondary and tertiary metabolites that are actually really interesting and we think can signal into other organ systems by being bioconverted by your microbiome.

Ben Greenfield: Yeah. It's kind of interesting because one of the reasons that I first started taking the Seed Symbiotic was a little bit prior to first meeting you, I had listened to a 2-hour-long podcast on pomegranates and the pomegranate oil and seed. And fiber and skin and juice and had pretty much made up my mind that come hell or high water despite living in inland Washington, I was going to try to figure out how to eat a pomegranate a day. And then, I looked at the profile of the Synbiotic. I'm like, "Oh, wait. I could just take this, get all of that stuff with less fuss and less unwrapping and less figuring out how the heck do you get all the seeds out of the pomegranate." So, I started using DS-01, but that was what originally kind of got me turned onto it.

Yeah. I mean, if you look at the structure of those polyphenols, like a structural biology or like organic chemistry standpoint, just actually look at them. They're very, very interesting also from the skin, also from the rind, from the whole fruit. It's a very, very exciting and interesting molecule. And certain bacteria in the gut love it as well. And so, I think it's a little bit more rare than— you can get certain classes of tannins from things like teas and and dark chocolates and, and you know, there's tannins you can induce through toasting and through other methods. But I think that this structure in this class along some flavonoids alongside some carotenoids are very interesting, right? Like astaxanthin I think is a very interesting type of carotenoid. And similarly, I would say that punicalagin and other pomegranate polyphenols are very interesting amongst polyphenols.

It's fascinating. The laundry list of ingredients on the back of this probiotic I think rivals any that I've seen. Is it pretty much what I described that I do? Is it 3 a day? Because I just wake up and I take 3. And, maybe I'm not doing that correctly in terms of with or without a meal, but what's just general best practices if I get the symbiotic?

Best practices is do 2 a day as a daily regimen for maintenance.

Maybe that's why I'm running out early. I'm doing 4.

Oops. No, we've had some people that have taken as many as in certain periods. I mean, off just on their own, they've decided to experiment with dosages, but 2 gets you most of the activity that you're looking for. It's the dosage that we studied in our antibiotics trial against the placebo, dosage that we studied in our IBS trial against the placebo. But I think there may be some people, you know, that at least I've heard people come in that have more gastrointestinal issues and following a certain regimen will experiment with higher dosages to kickstart certain metabolic pathways. So, I can't comment on that with data for too— I can, but I have heard of it. Yeah.

With, without a meal, doesn't matter?

I mean, it doesn't actually dramatically matter. It's a very small difference between— we used to think that 10 minutes before a meal would give it the best delivery, the most viable cells. But actually, after interrogating that research question, we found that it's the same number in more or less in both the fed and a fasted state. So, it doesn't really matter for efficacy. I think what's most important is, at least from what I've heard from people, is sometimes they can tolerate it better after a meal versus on an empty stomach. And, that's normal. I always feel a bit strange telling people like, "First time I took it, I threw up and I have a little bit more of a sensitive gut," but that period doesn't persist very long or slight modifications if there's discomfort, a little bit of distress, you can power through it very quickly. Me and 2 out of the 5 other people that were the very first when the research was being done in 2014, 2015, some of the earliest, earliest work on this. I think 2 more years of research around 2017 is when it came out to market. But yeah, I threw up.

Wow. Got to put the warning label on there, may cause barfing. And by the way, Definitely use it when you travel. It's stable, non-refrigerated stable. I think you and I may even talk about this in our first podcast, Raj, the impact of airline travel on the microbiome, on jet lag symptoms related to microbiome. I'm heading out to India on Monday. I'll have my packet with me. I take 3 before I fly and 3 when I land just based on the impact that airline travel and radiation and stress and circadian rhythm disruption has in the biome. So if you're listening, this stuff is great for travel too.

I've just heard that from so many different places now, including members of our scientific advisory board that go back and forth between France, go back and forth between the UK. Like, they use it regularly in between California and New York. And that's something you can see actually right away.

Yeah, incredible. Well, if you're listening, listen to my first podcast with Raja too, if you like to geek out on this stuff. We covered a bunch of new material there. On probiotics and Seed and the development of this stuff. The Synbiotic, it's one of the best-formulated probiotics, probably the best-formulated probiotic, possibly also breast-formulated, I don't know, that I've ever used. I'll put a link to it. We've got special offers, discounts, et cetera, over in the shownotes where you can leave your comments, your questions, your feedback. You can also, of course, get linked out to the first podcast that I did with Raja. BenGreenfieldLife.com/SEED2. BenGreenfieldLife.com/SEED, the number 2. Raja, thanks again for coming on and giving me my every 5 years probiotic dose of wisdom.

You got it. Thanks, Ben. It's great to be here. Alright, folks. I'll see you soon.

Ben Greenfield along with Raja Dhir from SEED signing out. Have an amazing week. Hey, guess what? If you want me to interview bigger and better guests, the number one way to do that is to get this show a rating or ranking or review wherever you're listening to it. That helps out the show quite a bit across all levels, including delivering to you amazing, amazing guests and episodes. So go check out anywhere that you listen to this podcast. There should be a big shiny button somewhere where you can leave a ranking, leave a review. If you got a little extra time. Thank you so much. Do you want free access to comprehensive show notes, my weekly roundup newsletter, cutting-edge research and articles, top recommendations from me for everything that you need to hack your life, and a whole lot more? Check out BenGreenfieldLife.com. It's all there. BenGreenfieldLife.com. See you over there.