May 16, 2019
Podcast from: [00:00:00] Introduction
[00:01:19] Podcast Sponsors
[00:04:44] Raja's Pups
[00:06:52] Guest Introduction
[00:08:28] Misunderstand Probiotics and Especially Probiotic Research
[00:12:51] Other Things About the Research
[00:23:45] What regulations or standardizations exist when it comes to the microbiome and probiotics?
[00:27:16] Flaws in Probiotic Research
[00:31:26] Podcast Sponsors
[00:34:27] Whether or Not Probiotics Interact with The Microbiome
[00:46:33] The Varying Effects from Different Species and Strains of Probiotics
[00:52:35] How probiotics affect males and females differently?
[00:56:10] Raja's take on companies who recommend particular probiotic strains to consume based on tests of the gut and microbiome
[01:02:59] Whether personalized microbiome testing will allow people to target a probiotic species for their specific gut profile
[01:10:29] The Importance of The CFU (Colony Forming Unit) Of A Probiotic
[01:18:10] What Raja is most excited about with his work?
[01:29:05] Closing the Podcast
[01:29:49] End of Podcast
Raja: Fermented food, fermented beverage, which is a very different category from a probiotic, uses the term because it's the fastest growing category in consumer health at the moment. No one's going to put over a year and a half into something and say, “Let's publish a non-interesting finding. This is a serious field. And if people want microbiologists to stick around and continue using the term, then companies, and even other scientific researchers need to start taking it seriously and need to start respecting the scientific definition.
Ben: I have a master's degree in physiology, biomechanics, and human nutrition. I've spent the past two decades competing in some of the most masochistic events on the planet from SEALFit Kokoro, Spartan Agoge, and the world's toughest mudder, the 13 Ironman triathlons, brutal bow hunts, adventure races, spearfishing, plant foraging, free diving, bodybuilding and beyond. I combine this intense time in the trenches with a blend of ancestral wisdom and modern science, search the globe for the world's top experts in performance, fat loss, recovery, hormones, brain, beauty, and brawn to deliver you this podcast. Everything you need to know to live an adventurous, joyful, and fulfilling life. My name is Ben Greenfield. Enjoy the ride.
I'm pumped up. I just started to record today's introduction for you and I got attacked by a wasp in my office. My heart is beating. I went to battle. I won. I killed the wasp. I killed it with a copy–what's this–I had “Paleo Magazine” on my desk and I killed a wasp with “Paleo Magazine.” I felt very ancestral doing that.
This podcast today is with Raja Dhir of Seed probiotics. I think they're the smartest most cutting-edge probiotic company. They're doing very cool things, a ton of clinical trials. I was absolutely blown away by this dude, and I think you're really going to love this show. We tackled a lot of myths in the probiotic space and talked a lot about the microbiome, as you can imagine, and a lot more.
This podcast is brought to you by Kion. Speaking of the gut, one of the things we have over there is the meal replacement powder that's kind of my go-to meal replacement powder. It's called MediClear, MediClear-SGS, and it is formulated with all your multivitamins. You don't even need to take a multivitamin if you use this. All your minerals, flavonoids, phytosomes, sulforaphane, a whole bunch of detoxification cofactors. It was originally developed for patients in hospitals to be able to get their full spectrum of nutrients, and also for folks who have gut issues to be able to support liver health and gut health.
A lot of folks will even use this on an elemental diet, for SIBO. It's like a shotgun formula and it works. Your gut just feels completely soothed after you have some of this stuff. I blend it usually with ice and a little bit of coconut milk or bone broth, throw some sea salt in there, sometimes a touch of olive oil just to top off the fats a little bit. It's good stuff. That's just one of the many products we have at Kion. But you can go to getkion.com and you get 10% off of everything on the site with the code BGF10. Use code BGF10 at getkion.com.
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Hey, so Raja, what do you have here?
Ben: You're taking out of this your paper bag.
Raja: Here we have some very meaty, very fatty bone marrow.
Ben: Is that for me?
Raja: These dogs eat better than me.
Ben: You'll give this bone marrow to your dogs?
Raja: Yeah. These are wild Arctic tundra pups. These are not bred dogs. These are dogs from a lineage which predates modern domesticated dogs from a village in Northern Russia where the people have lived the exact same way for thousands of years. And I've domesticated them–
Ben: So, if you try to give them dog food, they would literally rebel. They would eat you, probably. These are like wolves.
Raja: They are docile. They have been domestic–you know, with these animals, I've learned the process from wild type to domestication can happen within one generation. I found these puppies without having any history of domestication. Now granted, having been in proximity to humans means they've probably been pre-selected for traits or traits that were advantageous for living in proximity to humans. It might have propagated–
Ben: Right. Like not eating your babies. Yeah.
Raja: Like gentleness.
Ben: Yeah. Okay. So, you got this bone marrow. They just eat this stuff raw, huh?
Raja: They just go right for it and–
Ben: I like it on sourdough bread with salt.
Raja: Yeah. And this is the stuff that keeps them occupied for about an hour and a half. If I know I'm doing something for an hour and a half and I don't want them bothering me, this is the–
Ben: So, this is basically getting sure that they don't chew my arm off while we're recording this podcast.
Raja: And there's good sound quality and not background wolf noise.
Ben: Dogs growling at the tall lanky man.
Raja: But I will save some for you, too.
Ben: Oh, thank you. Sweet. Now, I'm going to be salivating during this–watching these dogs eat their bone marrow. By the way, for those of you who are tuning in, the voice of the man who owns the dogs is that of my guest, Raja Dhir. You pronounce your last name dear, don't you?
Ben: Yeah, Raja Dhir. I met Raja a couple of years ago at this investment kind of syndicate that we were at because he was doing a lot of research in the field of probiotics. And I don't know if you remember. I was talking to you at the pool and you blew my mind with your knowledge of the gut, the microbiome, probiotics, bacteria. And like way back then, like two years ago, I was like, “Oh, I got to get this guy on the podcast,” and it's been–
Raja: I appreciate you saying that. From someone who I think understands the science and is as friendly with PubMed as myself, it's high praise. So, thank you.
Ben: Yeah, yeah. And quick intro to Raja, he's the co-founder and the co-CEO of this company called Seed, which is, of course, a wonderful name for a company that's focused on improving the health, people's guts and their microbiome. He leads the research strategy, academic collaborations, clinical trial design, the product development, the intellectual products or property strategy, all of that for Seed. He's kind of the architect of the Seed platform, and he's also the co-chair of their scientific advisory board where they focus on solving pretty complex ecological problems like honeybee colony collapse and plastic degradation and soil fertility, but all through the use of bacteria.
He basically spends his time researching microbes, the microbiome, bacteria, and specifically, probiotics. And I actually want to start off right there because yesterday in the Uber here in L.A., we're recording this in this little ranch that Raji lives at in L.A. Raja sent me a link to a paper that he had written that delves into why we misunderstand probiotics, and especially probiotics research. That's really, really interesting paper that I was reading in the back for that little [00:08:54] ______. But by the way, can I link to that for people in the shownotes? Is that going to be published, do you think?
Raja: You got a pre-publication draft, but it will be published in the scientific journal, Frontiers and it should be out within the next couple weeks. So, by the time this goes live, you absolutely can link to it. It's called “Probiotics: Reiterating What They Are And What They Are Not.“
Ben: And by the way, for people listening, it's going to be BenGreenfeldFitness.com/seedpodcast, like S-E-E-D, BenGreenfieldFitness.com/seedpodcast. I'm going to put the links to all the research and everything that we talked about. So, it's called “Probiotics: Reiterating–“
Raja: “What They Are and What They Are Not.” We went with a really translational title for it. So, the lead author on the paper is the chief scientist of our company who is a scientist by the name of Dr. Gregor Reid. He's a brilliantly charismatic Scotsman who now runs the Canadian Microbiome R&D Center.
Ben: [00:09:58] _____.
Raja: He's probably published more papers on probiotics a lot. I know he's published more papers on probiotics than anybody else in the world, something which when I sent him over my final–I actually sent him over the final version of the drafts and he didn't like one of the edits that I made and it was late and he was very tired. And he reminded me that he'd authored 530 more papers than me on the phone before begrudgingly accepting my final edits. But collaboratively, we got the paper to a really good place.
Ben: Nothing like [00:10:29] ______.
Raja: No. All in good fun. I mean, we have that dynamic together and we work really well together. But we wanted to really take–the central thesis of the paper is that we're coming up in a really exciting time in microbiology, and it's the time when novel organisms are being discovered, where we're understanding more and more about the gut on a day-to-day basis and other aspects of the human body, and microbiome as well; skin microbiome, vaginal microbiome, oral microbiome, a developing infants microbiome. These life stages are incredibly important. We're finally getting data back from proper intervention studies showing the effect that microbes can have on all these different organ systems in the body.
The paper kind of wants to clear up this idea that probiotics aren't just anything that's a result of–they have a very strict scientific definition, and it's a scientific definition that was defined by an expert panel for the United Nations and World Health Organization, which was chaired by Gregor Reid in 2001, which states that basically, organism must show in a human clinical trial for a specific indication that it has an effect in a randomized control trial before the term probiotic can be used.
Ben: Does everybody do that? Like when you see a probiotic on a store shelf, they'll fit that criteria or can people just say probiotic?
Raja: The term in the United States is completely unregulated.
Raja: And so, in the scientific literature, the term is defined as such, but because there's no regulation unlike the European Union around using the term, every product or every food, fermented food, fermented beverage, which is a very different category from a probiotic, by the way, uses the term because it's the fastest growing category in consumer health at the moment. Gut health is exploding, and in many ways, consumers are way ahead of the science.
Ben: So, it needs to technically be, you said, live microorganisms, which when administered in adequate amounts confer a health benefit on the host. That's technically–
Raja: That is the scientific definition of probiotics.
Ben: –what a probiotic need to do to properly be qualified with probiotic?
Ben: Okay. So, what else do you get into in this paper?
Raja: Well, we start with the definition, clearing the air. We go into couple areas where over the past three years, the field itself has been gotten a lot of bad press and it's become discredited in ways that in the paper, we discuss as very unscientific. And so, the core of this is the idea that taking one single data set or one product or one study that's not causative, that is just even correlative if thought, and then applying the findings and generalizing them to the entire field is an unscientific practice. And so, in the form of shepherding the definition, we go through two or three case studies of the last year where the term has been totally demonized, a press cycle ensues, and then everyone is left holding–when the dust clears, not sure whether they should stop taking probiotics–
Ben: I think that one of those demonizations, a couple of months ago, it was basically this idea that if you use probiotics after someone has been on an antibiotic regimen, probiotics could make the microbiome worse or aggravate that person's gut.
Raja: That is the third example that we address and respond to in this paper. That was the study that was published in the Weizmann Institute of Israel. The scientists that led that research group are, in general, doing very interesting work in the field of microbiome science. And so, it was a pedigree group. What was really unique about that study was that they got, subjects to consent, to do invasive small intestinal biopsies or tissue samples to try to see the effect of what's going on in the small intestines rather than just the colon. I mean, just by virtue of publishing that finding and those results, the paper was very novel. The problem is that–
Ben: Yeah, because usually, you're just looking at the large intestine.
Raja: Usually, you're just looking at the large intestines. You're just looking at the colon. And more importantly, you're not even looking. So, if you think about the body as a big doughnut or a big cube, right–I mean, a lot of people are–there's a gold rush right now to go into stool and try to find out what you can find from it and lean from it and the activities that that's having in the body. But most people don't realize that–
Raja: Any diagnostic company. Even researchers in the lab. So, it's not even about companies, but yeah, there are a lot of private companies now that are looking at stool and trying to find pathways or patterns and have implicated that to health effects or to dietary lifestyle choices. But even scientific researchers in the microbiome field that are very obsessed with looking at stool, I can see why it's very attractive because big data people can come in and run bioinformatics on the data set and then look for correlative patterns and pathways between individuals, cluster them very nicely and neatly. And the problem with big data people in biology is that they assume that data, if you get enough of it, will give you an answer.
Raja: So, classical science or classical biologists think very differently, which is have a hypothesis, narrow down an intervention, and then test it in either animals or humans in a large enough sample size and look for biomarkers or functional endpoints that changed in that host. And so, there's a huge uproar when this Israeli paper came out because all the medical doctors and practitioners and gastroenterologists are saying, “Well, hey, we've used probiotics in our practice for a very long time and we see dramatic changes in individuals, whether it's their presenting with constipation, whether it's a constellation of symptoms like IBS, whether it's inflammatory cascade that could result from a gut barrier being [00:16:52] ______.
I mean, the gut is a very hard to reach place. And so, sometimes mechanisms are a little bit elusive, but you see very clear functional changes in the population that you're studying, right? Doctors said, “Well, hey, let's take a pause here. We can't just make broad assumptions that any microbe that you ingest is going to be bad for you because a combination of 10 or 12 organisms delayed normal reconstitution of the gut microbiome.”
There are a lot of reasons to question those findings in the first place. So, if you look even deeper into the study, the group that started with the probiotics had about 20 species less in the gut than the one that started in spontaneous recovery. And so, the same rate of recovery occurred but they just happened to cluster back to a level that had lower species. I mean, that was something that wasn't explained in the paper, right? At 90 days, everything lost statistical significance, whether you got the FMT. So, basically, for people listening that want to know how the study worked, they took the three groups of people and gave everybody antibiotics, massive doses of Cipro and metronidazole. Then they gave one group probiotics.
Ben: I hope they paid the study participants for that.
Raja: Yeah. They gave one group probiotics. They let the other group just recover spontaneously, what they called watchful waiting. And they gave the third group, actually, FMT of their own stool injected back up inside rectally.
Ben: A fecal microbiota transplant.
Raja: Autologous. So, their own original community. And they wanted to test the hypothesis, “Well, what's the fastest way of returning back to your normal baseline, to the exact alpha diversity of your microbiome before you took the antibiotics?”
Ben: Take a probiotic. Don't do anything or shove your crap back–
Raja: Or shove it right back up in there, yup. So, first of all, forgetting about the limitations of shoving your crap back up commercially, look at all three groups. At 90 days, everything lost statistical significance, everything. That means that the recovery, whether you took probiotics, whether you took an FMT, or whether you just did nothing at all at 90 days, all three groups are indistinguishable from one another.
Ben: Meaning, indistinguishable that it didn't change their bacterial profile?
Raja: Yeah. Meaning, you couldn't pick which person was and which group after 90 days because the error bars were all overlapping. And so, for all intents and purposes, the paper should have said, “Ten species are delayed for up to 90 days on probiotics, but we don't know about how much.” But that's much less exciting of a paper than saying probiotics delay the gut microbiome recovery.
Ben: Are there any other studies that show that if you're on antibiotics and you take probiotics, it's useful?
Raja: Absolutely. So, we discussed two examples in the paper, in the Frontiers paper. And actually, within that same month, two new large-scale studies came out showing after antibiotics, a group that was given probiotics and compared to watchful waiting, one was in infants that were given antibiotics and had a C-section, cesarean born birth. And they showed that probiotics actually improve the composition of the gut microbiome in this very vulnerable infant population. We link to that in the paper.
Ben: That's important, too. I was at dinner last night with a couple that just had a baby and did a C-section and they had no clue about the idea. And I think it's like seven years that it takes for an infant's gut who's born via C-section versus vaginal delivery for their gut flora to repopulate the same as if they'd been born vaginally and be able to breathe in mom's fecal matter and be repopulated.
Raja: We'll jump into that in a second because that's a really deep field in microbiome science. And there are two kinds of arch nemesis in the field that have competing viewpoints. The short answer is there are three things that you can do; have a vaginal birth, not have antibiotics during birth or give it to a child in the early stages and breastfeed. And if you do two out of three, correctly, you dramatically increase the chance of the infant's microbiome developing normally.
Ben: So, you could have a C-section, but then also just don't use probiotics and breastfeed?
Raja: Don't use antibiotics and do breastfeed.
Ben: Or antibiotics, breastfeed. Yeah.
Raja: Breastfeed, I think the research now shows that breastfeeding in the human milk, oligosaccharides, from breast milk are a lot more contributive to developing infant microbiome than mode of delivery.
Ben: Probably, the colostrum helps too, right?
Raja: And now we know that there are even communities that are passed down that colonized the mother's areola. So, even contact with the breast, human skin to skin contact is important.
Ben: Or skin microbiome. Yeah, it's a good point.
Raja: But the second study that came out that same year–or sorry, that same month, was double the intervention period. So, instead of four weeks, they did eight weeks. They did 700% the dosage of probiotic when compared to the Israeli study, and they found that there is no change in some cases trending on a higher alpha diversity in the probiotics group than compared to the watchful waiting group. And we linked to that paper as well. But the point is really, we try to not be sensationalistic. I mean, science in general, it shouldn't be a very sensationalistic field. And so, one of those studies had really good PR behind them and ended up penetrating into everybody's phones in the mainstream.
Ben: You mean, the study that probiotics don't really work [00:22:48] ______?
Raja: That they don't work or it could be dangerous because they had a really good proven lab. I mean, they spent a year and a half gathering these samples. For God's sake, they put shoved fecal transplants back up the patient's rectum and invasively scrubbed their small intestines. Of course, they're going to want to get a meaningful publication out of that, right? There's this human bias and everything, and there's human error, and people want their work to get of wide reach because it–I mean, no one's going to put over a year and a half into something and say, “Well, let's publish a non-interesting finding.”
Ben: Yeah. It's physically insignificant. I think one big part of this too is that, and correct me if I'm wrong, whatever probiotic strain that they use in that paper or in any other probiotic studies, it's also different. I mean, how do you even know when you're looking at probiotic research? What strain they use versus the bottle that's in your cabinet?
Ben: Like, is there any regulation or any standardization at all when it comes to that?
Raja: What I will tell you is that your supermarket probiotics, for the most part, are–there are five or so contract manufacturers that just produce these species. In many cases, there are species, not even strains.
Ben: Can you describe that for people who aren't familiar with the supplement industry or contract manufacturers?
Raja: A contract manufacturer is just kind of a manufacturing facility which produces–I mean, you can basically Google and find a manufacturer that white labels a product for you. By that I mean, there are five or six places that in many cases spun out of the dairy industry. And so, they found actually, the reason why still some of the best fermentation facilities in the world are in Southern France and Northern Italy, I mean our whole supply chain is in Europe because they have the best fermentation facilities because they invested in that infrastructure because of the role that fermented cheeses and dairy products play in European culture. The big American contract manufacturers that produce probiotic strains here are–like Danisco and DuPont, they're these dairy manufacturers. It's very interesting to me that–
Ben: The big food corporations.
Raja: Well, yeah, these cultures that are used for dairy production, how whole side industry was born that said, “Well, we could just turn these into packaged products or we could turn these into supplements.” But it was really bad up until a couple of years ago when the microbiome field started. And then we have the whole new birth of organisms that are being discovered, that are being tested, that are going into trials, that are being properly designed trials, strains that are very specific and different and are catalogued. But to answer your question, so if you think about dogs as a species, they are all dogs, all domestic dogs are not the same, yet at the species level, they are. And so, each individual–
Ben: Like a Chihuahua is a dog and a Doberman is a dog.
Raja: Yeah. But they're very different strains of dog, so to speak, if you want to use the example, right? And so, their attributes are very different from one another, everything, from their physiology to the way they perform, to the metabolic output that they generate. And so, bacteria are actually, in some cases, way more different. Under the technical definition, a strain can be–some strains, the Lactobacillus reuteri are 70% genetically different from other strains of the same species.
So, if you just go look at a supermarket probiotic and it just says Lactobacillus reuteri, Lactobacillus is the genus, reuteri is the species, but that's it. That's where that story ends. And the question is if there can be 70% genetic difference between different strains of that Lactobacillus reuteri species. You need to look for a human trial. You need to look for a strain that has undergone a human efficacy study, and that is the minimum requirement. Otherwise, that product should call itself a microbial product and not a probiotic.
Ben: How do you even know if you're looking at the label of your probiotic?
Raja: Well, I mean, I think that there's a lot of confusion. I think that companies enjoy there being kind of a sense of consumer confusion in the category.
Ben: Yeah. Interesting. I want to talk later on about what is in some of these strains that you're helping to create. But what's the takeaway from the paper as far as the answer to these flaws in the research on probiotics? What's the answer? What's the conclusion there?
Raja: So, we lead with a really optimistic view. We have a table at the end which says, “These are all the physiological and metabolic processes in the body that can be changed or will be impacted by the human microbiome in the next five years.” I mean, a good–
Ben: I have a table now pulled up in front of me. It's enzyme pathways, energy metabolism, neurotransmitter production, which I think a lot of people kind of know about. The bacteria in your gut make things like serotonin, vitamin absorption, regulation of bile acid synthesis, it's an interesting one, endocrine and gut hormone regulation, protections, pathogens, cell proliferation, immunity, vascularization, bone mass appetite signaling, and metabolic transformation of xenobiotics. What's that last one? What's the metabolic transformation?
Raja: Those are, for instance, if you take drugs.
Raja: If you take an antidepressant drug.
Ben: And being able to metabolize drugs.
Raja: Yeah. Absolutely.
Raja: Or not even just drugs, I mean, even things like heavy metals; dioxins, PCBs. Bacteria provide you a line of defense against environmental contaminants. There are antibiotics. And those are just some of the more technical ones. For instance, we have a research track in our company where we're looking at activating a switch in the body which prevents and reverses food allergies. I mean, that's a huge indication to think that knowing that certain microbes can signal Th1, Th2 cells in a pattern that it promotes tolerance to foodborne antigens. That's the type of research around saying, “How are consumers going to take a probiotic which can reverse a life-threatening allergic sensitization seriously? How are they going to take that seriously when there are products that are marketing themselves as supplements or probiotic tortilla chips or–?”
Ben: That's huge.
Ben: That would allow me to eat green beans again.
Raja: Have green beans again.
Ben: I'm allergic to green beans. What are the other conclusions from this paper?
Raja: We go into the minimum strict requirements. Before anything should call itself a probiotic, you have to declare the genus, the species, and the strain. You have to undergo at least one human clinical trial, double-blind and randomized and controlled in the population that you're targeting. So, here's another trick a lot of companies use. They'll test that their probiotic is very effective at say antibiotic-associated diarrhea, right? But then market their probiotic as beneficial for a generally healthy population. But they haven't shown that it would have any benefit for a generally healthy population. They've just shown that it helps you–
Ben: Yeah. They've only shown if you drink bad water in Mexico, it could work.
Raja: Yeah. Bad water anywhere. But bad water in Mexico is [00:30:05] ______.
Ben: Yeah. Sorry, stereotype–
Raja: No. I mean, I know people that come back from Southeast Asia and they're shitting for weeks.
Ben: Oh, yeah. Raising my hand. It used to happen to me all the time when I go race triathlons over there in Thailand.
Raja: The field is really serious. The takeaway is that this is a serious field, and if people want microbiologists to stick around and continue using the term, then people need to start–then companies and the media and even other scientific researchers need to start taking it seriously and need to start respecting the scientific definition because you can't have it both ways. You can't market and sell products that have no science behind them at all. And then also have, for instance–I mean, one of our Seed fellows is a researcher in the Department of Genetics at Harvard. And he's now looking at using probiotics to deliver antivirals against HIV in Sub-Saharan Africa. How are these researchers going to continue using the term and shepherding the field if they're being compared with probiotic tortilla chips? I think the whole thing is just all wrong.
Ben: Yeah, yeah. It's interesting.
Raja: It's a serious field.
Ben: Hey, I want to interrupt today's show to sweat all over you. I was actually in the sauna this morning right before I killed that dang wasp in my office. I get my sauna. I do a whole bunch of different yoga moves, down dog. I do some Eldoa stretching. Google that if you don't know what Eldoa stretching is. And the whole time, my body is getting hotter and hotter and my tissues are becoming more and more pliable. I'm releasing a bunch of toxins through sweat because of the skin. It's the body's largest detoxification organ. Sweating out metals, sweating out toxins, and also stretching and doing breathwork and a whole bunch of other woo-woo crap.
I do all of this because I have this Clearlight Sauna that is big enough for four people to sit in. So, I have folks over and we just party in the sauna. We burn some incense and sit around and chat and then go jump with the cold pool. But one person in there can–I mean you could bring kettlebells or you can put a bike in there. And the cool thing about Clearlight is it has really good EMF and ELF shielding, which means that unlike most other saunas out there, you're not microwaving yourself while you're sitting in the sauna.
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I had an important question I wanted to ask you because I get this a lot, and I seem to have a hard time finding the answer for is about this whole colonization piece because I think it was the journal Cell that released a paper about how–yeah, probiotics kind of seem to work, like they're doing something, but we don't know why because it appears they don't actually even populate the gut. Is that true, like the probiotics just passed through you?
Raja: Yeah. So, probiotics, for the most part, are what you call transient microbes. They don't take up residence long term. Some ways of describing them have been they do their work on the road. But even that, I mean even to be respectful to what I just finished ranting about, we can't put all organisms that could have a benefit or could be probiotic in the future into one category. What we do know is that lactobacilli and Bifidobacterium tend to be non-colonizers and tend to be involved on their work through the production of metabolites, through signaling to toll-like receptors and activating their pathways in the body, which change the composition of the gut barrier, which produce mucin, which create specific metabolites that produce short-chain fatty acids. They swap genes. They deconjugate bile acids. I mean, these are all pathways that we have strains in our product, which have underwent double-blind, placebo-controlled, randomized trials to show these endpoints without having conversation–
Ben: You mean in the Seed probiotics?
Raja: Yeah. In our first product, we–
Ben: So, did your product actually seed to use the term? It's a good name, I'm telling you. Did it actually seed the gut?
Raja: The term seed actually comes from when in the earliest stages of life, when an infant's microbiome is first colonized by microbes, it's the biological process called seeding. And so, it's a little tip of the hat to the origin story of the microbiome. When a child gets it from her mother and then it's grown, I think that's a really nice story and it certainly was the basis for our name as a company. All the studies that have been done in our strains, the longest that we've shown persistence is about eight weeks afterwards. And at around eight weeks after ceasing consumption, you will get a sort of washout.
And that's why it's so important to take–if you want to experience benefits from organisms, certainly, these signaling and metabolic benefits that occur from the oral consumption of these probiotic strains, a daily consumption is very necessary. I mean, this isn't something like a drug where you can take it in a defined quantity and that's it, it's done.
Ben: It's kind of like coffee. Once you start drinking it, you just have to drink it for the rest of your life.
Raja: Yeah. You drink coffee on Monday morning and–
Ben: Probably, testosterone replacement therapy would be better. Once you start, you feel really good but you've got to keep doing it repeatedly.
Raja: You've got to keep doing it.
Ben: So, are you saying that's the same for probiotics?
Ben: Why wouldn't you just eat a wide variety of fermented foods for the rest of your life? I can just eat working kimchi and sauerkraut and some kefir and some yogurt and just go that route.
Raja: So, I'll give you an example. There's a study that was published on kimchi. And of the several hundred or so strains that could be found across kimchi products, only four or five of those strains have been shown to possibly have probiotic potential. That doesn't mean it's not good. That doesn't mean it's not delicious. That doesn't mean that–
Ben: By your definition of a probiotic that you laid out in that paper, you must have some kind of human clinical research behind it, be shown that to act on that [00:38:24] ______.
Raja: Yeah. I would love for Kombucha companies to do randomized control trials. I know it sounds crazy, but what is the benefit that their–I mean, you see these vague words like immunity or anti-inflammatory.
Ben: And ginger detox.
Raja: I hate to break it to you but there are many cases where you don't want to downregulate the inflammatory response in the human body. That is not a good thing to happen.
Ben: Well, what baffles me, even more, is that the anti-inflammatory one has like 120 out of calories of cane sugar in it.
Ben: Yeah. We could go off on Kombuchas for a while. By the way, your dog is absolutely enjoying that.
Raja: They're good [00:39:03] ______.
Ben: Yeah. If you guys hear the crunching in the background, that's this giant wolf laying on the floor, gnawing on this bone marrow bone. So, what you're saying with the fermented foods piece–because people are going to say, “Why can't I just eat like my ancestors who didn't take probiotics?”
Raja: I think that it's a beautiful story. I think that the idea that living like our ancestors–and certainly, the Paleolithic era has been really glorified in certain–even in modern-day health and wellness fitness communities, there are certainly very many good things about the level of activity, the resilience and exposure to environmental microbes and contaminants–
Ben: Being outside in the dirt with lots of animals getting covered in blood having natural burst. I don't know if you've seen the research. When you field dress an animal, like if you kill a deer, for example, while you're hunting, the act of field dressing exposes you to an enormous number of bacteria.
Raja: I believe it. I believe it. And it's the basis of a lot of books. One of our scientific advisors is the author of–was a professor at NYU in Microbiology, Martin Blaser, and now the star of the upcoming documentary called Missing Microbes. He's one of the big legends of the field and his whole thesis is around this idea that there are certain microbes in modern society that are missing from how we evolved or when we lived in the wild.
Justin Sonnenburg's group at Stanford has actually shown that when a low-fiber diet compounded over multiple generations actually results in irreversible damage and loss to diversity of the microbiome. After four generations, it doesn't matter if you return the animal to a high-fiber diet, those organisms have gone extinct. They have found that there's extinction in the microbiome and as little as four generations in their animal models from a low-fiber diet. And so, certainly, I think it's very intriguing. It's very interesting to think that we've departed so far from our natural state that our gut microbiome has evolved away from its normal state.
Ben: So, you could argue that maybe people who are working on farms, on the dirt, with animals all day, eating a wide variety of fermented foods, like that population might not even need to take a probiotic?
Raja: I would argue that if you are living like the Hadza, then–I mean, I actually think that's a very interesting study. I think that I would–let's design a trial and add a Hadza tribe arm to it and see the effect that it has.
Ben: But not living like a Hadza in a westernized society where you're also exposed to glyphosates and jet fuel and all these other things that influence the health of your microbiome. And part of it is that you're fighting an uphill battle, yeah?
Raja: They influence the health of your microbiome, but they also have a lot of functional effects. So, I'll give you one example. We've studied. Five of our strains that we acquired in our strain bank came out of a research partnership from the Department of Genetics at Harvard. There, they specialized in building these models, these predictive models, which look at really specific pathways in the body.
And so, one of the things that really bothers me is when people start talking about detoxification or detox this, detox that. I think the whole term means nothing because the body has very sophisticated detoxification pathways that are regulated by something called the Nrf2 transcription factor, which results in the production of glutathione. And we are very, very good at mitigating toxic and toxic stress in our body in oxidation. This is really well-established. But the problem is that there are a lot of things that are triggers for activations of those pathways, things like extended exercise which elevates your heart rate for a prolonged period of time, things like access to a wide variety of phytonutrients that are extremely diverse, that activate those receptors.
There are certain things that are bad for you–in a weird twist of events, things that are bad for you are good for you. Sulforaphane is a great example. Sulforaphane is the darling of the health community at the moment. It's found in raw broccoli and actually works the exact same way because of its defense mechanism that the plant produces to avoid against predation and it activates certain transcription factors in the body which catalyze or begin the detoxification response system, right?
And so, we looked in these models where you take these C elegans, you take these model organisms for looking at gene expression and you knock out some specific genes. And so, if you knock out genes that are response–or overexpressed certain genes, you can see how exposure to your microbe activates or inactivates very specific defined pathways in the human body, right? So, we thought that was a great target. We screened for strains, for probiotic strains which activate this Nrf2 transcription pathway in the human body, which begins the process of detoxification.
So, the biggest theory when people just refer to gut problems and they implicate everything from their autoimmune condition to brain fogginess is as follows. Their gut barrier is impaired. Compounds that are either produced by microbes or particles from your diet or contaminants from the environment enter into your bloodstream when they shouldn't. The body mounts an immune and inflammatory response to those foreign compounds which it rightfully should, and then that triggers and trips up the immunological response and it begins a cascade of events that some people results in arthritis, and other people they say could result in an autoimmune condition, other people they say it results in an allergic sensitization. I mean, there are a number of ways where people believe that their microbiome has been impaired.
And so, to the extent that that pathway is true, I can't say one way or another because I don't think those trials have been appropriately designed. But what I can say is specific bacteria do increase the expression of what's called tight junction proteins to tighten up the intracellular space in your gut. That's one cell thick and one cell deep. And so, I think we need to see exactly what functional effect that has. But certainly, one effect that we have tested our strains on are inducing expression of tight junction proteins in the gut barrier.
And to go back to your earlier point about how probiotics works, that's a pathway which has no effect on whether an organism, colonizers are not right because in passing through the long tube of your gut, it's signaling to your gut wall and it's tightening up gut barrier proteins.
Ben: So, when you're saying the different strains have different effects on more than just the microbiome, you talk about oxidative stress, I'm looking at the label right now of your women's blend, your women's probiotic blend, and you have a whole bunch of different strains in there like Bifidobacterium infantis and Lactobacillus rhamnosus.
Raja: So, those are species.
Ben: Okay. So, those are species.
Raja: And the strain designation is right after that. It's something like SD-
Ben: It's like, yeah, SD, GR-3, IT. Okay, got it. And then you also, in addition to that, have some things like Indian pomegranate, chaga mushroom, Scandinavian pine bark. Why are things like that mixed in with these different strains?
Raja: We were very curious about a specific end point that happens when gut bacteria that are already in your gut, it's called biotransformation of nutrients, they take food particles and they convert them into secondary metabolites that then enter into your body and unlock new nutrients or transform nutrients that you get from your food. So, bacteria, in some instances, can produce nutrients themselves, micronutrients themselves. So, one of the strains that we have in our product is actually a folate synthesizer. And so, it produces methyltetrahydrofolate as part of its metabolic process, which then passes through–
Ben: The bacteria does that. So, you're not taking methyltetrahydrofolate like you would in a multivitamin. Bacteria is making it for you.
Raja: Yup, yup. So, B vitamins and K vitamins, most people don't realize that if they're deficient in it, it's because they're very low in a normal diet, in a diet where you don't always have access to some seasons of the year, where you don't have access to meat or to fermented foods. I mean, most of our B12, for example, we get from meat, right? It's not really just floating around in plants, and that's why vegans and vegetarians are very deficient in vitamin B12. But originally, gut bacteria were who we outsource that responsibility to. They would produce these B vitamins and these K vitamins, which are then passed through receptors in the gut and entered into serum circulation.
And so, we have a folate producer and we think that's a really interesting way to think about. I mean, folate is involved in–every time I saw replicates, folate is used as a cofactor in cell replication. So, folate is an incredibly important micronutrient, and not just during times of pregnancy, its role in DNA methylation and methylation patterns and cell division is it's pretty remarkable. It is an essential micronutrient. And so, to think that bacteria can introduce a continuous supply over the course–I mean, it's a steady drip of these essential micronutrients to us was very–
Ben: It's like you're consuming little soldiers that make their own multivitamins.
Ben: But that Scandinavian bar, why is that–?
Raja: Yeah. So, our bark is standardized for these oligomeric proanthocyanidins. These are compounds which modulate microbial communities in the gut. Most important in that list is our–what we have listed–because from a taxonomy perspective, we have to identify the part of the fruit, but that pomegranate is standardized for a compound called punicalagin. And Punicalagins are really, really interesting polyphenol, which specifically is turned by bacteria that are already in your gut into a metabolite called Urolithin A. And Urolithin A was–a publication came out a couple of years ago in the scientific journal Nature and it made its big way around the press called the Fountain of Youth or the Golden Molecule or a molecule which doubles the lifespan of mice and reduces–
Ben: Really? Urolithin?
Raja: Urolithin A.
Ben: Nobody is talking about that. They're talking about metformin and rapamycin and NAD. Urolithin A.
Raja: Urolithin A.
Raja: Yeah. And so, the only way, it's only actually produced–there's no way to get it in nature, but you can use precursors from nature and couple it with the right bacteria in your gut to biotransform a nutrient into it. And so, this is really interesting. The way that that metabolite works is it induces a process called mitophagy, which clears out decayed or ineffective mitochondria and begins the cycle for mitochondrial regeneration.
And so, certainly, in C elegans, which is the model organism–and also in mice, we've now shown that Urolithin A has tremendous effects in the mouse study with Urolithin A. It was really interesting that older mice, older rodents that were exposed to an intervention of Urolithin A, they reverse sarcopenia, and so they regain their muscle function.
Ben: Very high, and things like a lot of these berries, like blackberries and boysenberries, pomegranate. Interesting. Urolithin A. But if you take a prebiotic like this along with the probiotic, you're making your own, you're getting your own.
Raja: Yup. So, you are–
Ben: So, there's almost like an anti-aging benefit, too.
Raja: To be determined. I mean, look, we're very cautious to say that's where you have to say that we know the mechanism. I don't know how many years or what functional effect that that's going to have, but that's very–
Ben: That's why I respect you because most people would say, “Yes. You live longer.”
Raja: No. We can't go there. I think the research is certainly interesting. I think it's very promising. And most importantly, it fits our thesis, right? Our thesis is how can we unlock the power of microbes or bacteria to confer benefits to their human hosts?
Ben: Yeah. Are males different than females in the–I mean, it seems that our biomes would be different, but because of that, it would seem the type of probiotic strains that we should have in our guts would be different.
Raja: I'll start with women have a slightly longer digestive tract than men. It's why women across the population suffer from digestive issues, cramping, bloating, indigestion significantly more than men. I don't know if that's because they have a slightly longer GI tract but that's one theory that's being proposed. In terms of the composition of the microbiome, it's unclear. It's easier to pick someone's microbiome or what their microbiome is based on what they eat rather than based on their gender. So, if there are differences, it's very weak. They're non-significant.
And it actually leads us into a really interesting point which is, look, there is no one healthy microbiome. So, this idea that this is the gold standard or this is what you need to move your microbiome towards is total horseshit. Scientifically, I can tell you why. It's because microbes have what's called scientifically a high degree of functional redundancy. And so, certain microbes within one genus or taxa might perform the same function as ones than another, but be very different on the phylogenetic tree.
So, you can't just say, “Well, you have this ratio of Bacteria titis or Firmicutes or you have this pathway that's being overexpressed or underexpressed. I mean, none of it means anything. I'll give you another example. To go back to your earlier point about, well, if we just lived like our ancestors did, would we need to take a probiotic or would we need to modulate our microbiome in some way? I mean, there's no amount of money that you could pay me to transplant a Hadza tribesman's microbiome. I've looked at the sequence data. There's so much junk in there. Yes, that's more diverse, but there's a ton of pathogens, there's a ton of uncharacterized metabolites that we have no clue what they're doing, what they're performing, which they probably, at some point, picked up living in the wild, but also probably kills–compounded across a population level.
Data set probably has harmful effects, too. It's not an easy answer that this is better than that or this is the right way to do this. What we, as a company, try to do is look at defining the characteristics of the microbes themselves to determine whether they would be beneficial for the human body or not.
Ben: So, what does that have to do with the males versus females thing?
Raja: For instance, females during pregnancy could benefit more from a folate producer in their gut. But that doesn't mean that it would be bad for a male to have that same–or it would be out of place in a male biome. And more importantly, a female Hadza microbiome is more different than a female in New York City's microbiome. And a female in New York City is probably very close to a male in New York City's microbiome. So, your environment matters more. Your diet matters more. Your antibiotic and drug use matters more than your gender, I think.
Raja: And the research does show that.
Ben: Okay. Got it. So, when you're talking about this idea of you, not necessarily being able to just toss any probiotic willy-nilly into your body to replace what you think might be missing, I'm curious what your opinion is of this idea that a lot of companies are now proposing where they'll test your microbiome, test ratios, like the ones you're just talking about, like bacteria to Firmicutes ratio and then spit out which probiotic strains that you should be consuming to fix your deficiencies or your imbalances. What's your take on that?
Raja: Without a doubt, I can tell you that there is no science–the field itself hasn't determined what a healthy microbiome is, or I mean, forget about looking through a pattern from an at-home sampling kit and then telling you that you're deficient or could benefit from a specific species or taxa. It just makes no sense. There's absolutely no evidence to support an intervention from an at-home diagnostic kit. Now, what I always say is at-home diagnostic kits are very interesting to the extent that one's curious about the organisms that are living in their colon. You're not getting the small intestinal microbiome from there.
It's interesting. Look, all these companies are using, for the most part, the same base technology. Everyone at a certain point is looking–Illumina changed the game. Illumina is a company that changed the sequencing game completely. And so, everyone's using iterations or applications of Illumina's underlying technology or related technology. I mean, some other groups or organizations, some are looking at RNA, some are looking at the 16S region. That's the least comprehensive. And then some are using whole genome metagenomic shotgun sequencing, which I think is still a very effective tool for understanding the gut at a population level than anything else.
But it's just that. It just tells you–it spits out–depending on how deep you go and depending on how wide you cast and set the parameters, it just looks at the DNA or the RNA and tells you which organisms are there, and ranks them in a phylogenetic tree and gives you a nice little distribution of the organisms in your gut. But knowing what those organisms are, do or mean, or even more so are deficient in, and the most egregious is if they then try to sell you a product or sell you a service based off of those findings, show me the paper. If people literally just said, “Show me the paper,” show me the study, show me the trial.
Ben: Yeah. Now, back to your analogy with dogs, how you have a strain, which is the dog, but then there are all these different species like the Chihuahua versus the Rhodesian Ridgeback versus the Doberman Pinscher or whatever. When a company like that is testing and then making recommendations on a probiotic, are they making species recommendations or strain recommendations?
Raja: Yeah. Well, they are making species level recommendations, and sometimes they're even just making genus level recommendations. They're saying you need more Lactobacilli. The whole thing just baffles me. It makes absolutely no sense. Forget mentioning that these companies look at what's called relative abundance. So, they look at the percentage of Lactobacilli compared against the rest of the organisms in the gut. Relative abundance means nothing. If you really want to start finding some information from these data sets, look at absolute abundance. You want to find the microbial load. You want to find the amount of organisms of that genus that are there in your gut, and then maybe you can start looking at enough data and saying, “Well, once Lactobacilli falls below a certain microbial payload, some issues begin.” But just comparing it relativistically amongst other communities in the gut, it's a very, what you call in science, an unclean data set.
Ben: So, are you saying a better approach would be to take the different strains and the species that have been identified in peer-reviewed, double-blinded clinical research to have specific effects on whatever, skin health, immune health, anti-inflammatory activity, and to simply say, “Okay. Well, regardless of what my gut test, whatever, my Viome test or Onegevity test or DayTwo or any of these other companies, regardless of what those numbers are telling me, which are interesting and may prove useful in the future to have that data, I should instead take the route of just taking a probiotic that has the strains and the species that actually have human [01:00:42] ______ behind”?
Raja: So, in our paper, we discuss personalization. It's really sexy in media and in the health and wellness community. But in science, there's nothing new about it. It's called stratification. If you can't show your intervention works in what's called the heterogeneous population so it works across a wide range of people not just on one individual, then that's generally a bad thing, right? That means that some depression medications were only working on stratified populations. Some IBS medications only work on a stratified population. But in general, the gold standard is always, can you find a microbe or an intervention that works across a human population and has reproducible effects?
I would go even further than say that. Most of these things work not just amongst all humans but they work amongst all mammals, too. So, even you'll find that they'll work in dogs and they'll work in horses and rodents, right? Now, I think for gut microbiome research, animal models are very poor approximations of the gut microbiome because I think that human immune system co-evolve in microbes much differently than other mammals. I think human studies do need to be conducted.
But the answer is if a personalization company publishes a paper that says, “Well, we placebo-controlled the study and we recommended that these strains work for people that have this condition and these are their findings and the results, but it only worked in people that had this starting gut microbiome, then I'd be the first to say, “Well, that sounds fantastic. So, as long as you test in the target population that you're marketing or selling to, there's nothing wrong with personalization. There's nothing wrong with stratification. It's just biologically not what you would expect from a microbe that has powerful modulatory effects. You'd expect it to modulate, have effects agnostic of an individual starting microbiome. In many ways, it's kind of settling for second if you have to find something that's customized or that only works with you or that only stratified to you.
Ben: Do you think there's any way that personalized microbiome testing is going to change in a way that would allow people to really target a probiotic species to their specific gut profile?
Raja: Yes, but it's not going to be anything like the probiotics that are available in the market today. It'll be like you don't have organisms that are butyrate producers that are within the Clostridium cluster XIVa. But you can't culture those. Trust me, my whole career has been in translational development including biofermentation, and I know what it takes to make faculty of anaerobes, which means organisms that sometimes are okay with oxygen grow. But to make strict anaerobes grow is one of the most magical feats in microbiology.
Some organisms in your gut, in fact, won't–forget about oxygen, right? They won't even grow if other organisms that they like to hang out with are in the mixed community. If they're not in that same extracellular biofilm-like exopolysaccharide matrix that they like to be in that complex community, that's what people forget. Your gut is an ecosystem, and ecosystems theory comes into play.
And so, this idea that one organism or one bug–so my answer to your question is no, I never think that one organism from an at-home test were going to find that you're deficient and that you should take it, but there are some cool party tricks you can do. For example, if you have no Oxalobacter, then that means that you should probably avoid eating raw greens that are high in oxalates because your microbiome doesn't have an efficient means of converting those oxalates or detoxifying those oxalates so they don't accumulate in your kidney.
Ben: Okay. So, you could do useful things with the data that you get from one of these biome testing services. You just may want to avoid the part that says, “Take this probiotic because you're deficient in XYZ.”
Raja: Yeah. In fact, I can list on one hand all the useful things that you can find. So, Oxalobacter is one of them. You can find if someone has low or high butyrate production. The intervention is to eat more fiber.
Raja: Right? Or eat more —
Ben: Or butter in your coffee.
Raja: No. I think that the research is pretty clear that high-fat diet is modulated–I mean, a recent paper just came out [01:05:38] _______ showing the effect that high fat, in particular, has on modulating cancer stem cell is related to colon cancer. And so, the point is that no one in the keto community is looking at that type of mechanism stuff. All they're seeing is that if you have a high-fat diet over a six-week period of time, you lose a lot of weight.
We as a society need to decide if weight loss is sufficient as an endpoint, is the only endpoint, or if it's worth exploring other areas. Carnitine, high red meat consumption is in multiple mechanisms, whether it's TMAO, whether it's carnitine production that increases the risk of carcinogenesis in colon cell lines. There's a lot of mechanistic work that shows–again, a diet that is high in fiber is probably more important than red meat consumption.
So, my point is by having high fiber, you can mitigate or eliminate any of these risks that are found only in these mechanistic studies. But we do know that these mechanisms are clear. And I'd be very nervous for people on the carnivore diet because we don't have long-term data to show what eating that consumption of meat has. But to go back to your point, a gut microbiome test isn't going to tell you whether your gut is better for eating high fat or eating high meat. I mean, you can't tell that from [01:07:12] ______.
Ben: Okay. But you said there were five things. You said butyrate. What was the one before that?
Raja: So, Oxalobacter you can tell.
Ben: Uh-huh. And the trick for that would be if you're low in it.
Raja: If you don't have Oxalobacter, then you should cook your greens.
Ben: Okay. All right.
Raja: But again, I bring that up to say we don't know if there are other organisms in the gut which have that oxalate degradation pathway. I use Oxalobacter as an example. But that's an example of one functional endpoint, right? Another thing you can tell from an at-home gut testing kit, for example, is whether you have the pathways to break down certain drugs. But if you're not undergoing chemotherapy, you're not taking antidepressants, then that's kind of an irrelevant point for you. You can look at drug xenobiotic breakdown pathway if you have the metabolism for certain drugs.
Ben: Okay. And then what would the other one be?
Raja: Butyrate production. You can look to see if you have organisms in the particular cluster —
Ben: Yeah. We talked about butyrate production.
Raja: —that produce butyrate. Urolithin A. So, what we prime for in our community, in our product with the punicalagin, you can actually test for, and it's called the dominant species which produces and converts punicalagin to Urolithin A as Gordonibacter. And so, that's an organism that you'd want to look for that could be very beneficial. And the last one is we are now starting to–none of the at-home testing companies are offering this because it's very new research, but in the future, you would be able to also add on your predisposition for type 2 diabetes.
Raja: We now know that there's certain —
Ben: So, that's some actionable data.
Raja: It's not actionable because the action, it'll tell you whether you have a higher risk of type 2 diabetes or not, but the action is the same. The action is don't have high quantities of simple sugars in your diet.
Ben: Yeah. That's what I mean. That's actionable. Yeah.
Raja: That is not. The point I'm making is regardless of whether you took the test or not, the prescription of what you should eat or how you should live your life is the exact same, right?
Raja: Eat more than 30–a diversity of 30 fruits and vegetables in any given week. That was implicated with the highest diversity microbiome across an 8,000-person cohort in the HMP Part 2. Second was people that had less than eight different fruits and vegetables per week had an inverse relationship with diversity. So, the two most dominant dietary-related factors were actually causative and inverse causation. That's so powerful when you see that in a study. That means that you're onto something. It's a smoking gun.
So, diversity of phytonutrients and fibrous foods. And if you're a creature of habit and every morning you just eat blueberries, switch it up, have blackberries, have raspberries, try different types. There's a bunch of nutrients you're getting from a wide variety of different fruits and vegetables. If you only like one different type of vegetable, if you meal prep, just try to switch it up. Diversity is good.
Ben: Diversity and seasonality, yeah. That will as market.
Raja: And seasonality is good.
Ben: Yeah. Okay. So, I have a few other important questions. I want to make sure I get the time to ask you. There's one probiotic strain I know a lot of doctors talk about, VSL 3. And one of the things they say about it's got like 10 times the number of bacteria in it. And I think they call it CFU, colony forming units.
Raja: Forming units, yeah.
Ben: Yeah. How important is that to have a really, really high CFU? Because that's like a breaking point for a lot of probiotics.
Raja: Well, it depends on the indication. It depends on the study and the trial. So, we have two of our strains were tested in a 300-person randomized double-blind controlled trial at a potency as low as 12 billion CFU in aggregate and had–
Ben: So, 12 billion would be considered low?
Raja: It would be considered low.
Ben: What would be considered high?
Raja: You'll see products that are in the hundred billion–VSL 3 is about 120–their consumer dose is 125 to 150 billion CFU, and their therapeutic dose goes up to 400 or 450.
Raja: We call that, and microbiome researchers call that the shotgun approach, where you just barrel the gut with high density of organisms, hoping that it works, but not without having established the mechanism. So, VSL 3 actually doesn't disclose their strains. They are an eight species blend that has a very high dose, and they have a lot of clinical data which is effective on conditions like pouchitis. I don't think they have anything on colitis or IBD, but pouchitis was the original condition that they looked and studied.
The answer is I know the organization, the pharma company in Northern Italy that makes it, and there's nothing particularly special about their strains. They weren't isolated or derived from a special microbiome. They weren't screened or identified on any interesting technology. They're probably pre-selected, if I were to guess, because they are very–what, in the biofermentation industry, we call Hardy growers. And so, you can get a high yield reproducibly and very limited amount of nutrients. So, they're very good commercial strains. And then you put a really high quantity in there. And for some people it works, and if you have pouchitis–
Ben: So, what you're saying is you got to return to human studies. The best dose, the best strain is what's been shown for whatever you're going after in actual clinical human studies?
Raja: Before you take any probiotic, ask the company, “Show me the studies on your strains.” Have your strains, Ben, studied in a human population and for what endpoints, because another trick that a lot of people use is–so for instance, VSL 3 is very good at pouchitis, but that doesn't mean that you would expect it to have any effect on having any immune modulating properties or having any effect on your cholesterol, right? But these are all areas that we've shown that different microbes can have an effect on you. I wouldn't use VSL 3 for barrier integrity because they've never published a study that shows that it has this effect on LPS-binding protein that's found on serum.
Ben: Okay. It makes sense.
Raja: It sounds technical if someone has non-scientific background trying to sort their way through the biomarkers and the words and the company messaging. But at the end of the day, if a company can't explain to you clearly and simply what their strains are and what they were tested in and for what endpoints and why that matters, that responsibility falls on a company to do it, right, to clearly articulate what their strains are and what they've been tested in.
Ben: Got it. Another question. Delivery mechanism. That's another thing. People say, “Oh, probiotics don't survive the acidic nature of the human stomach. They never wind up in your large intestine.” Is that true? Like when you take a probiotic, is it actually just useless because you get beat up by your acid?
Raja: We do see that microbes die off in prolonged exposure to pH below 2.5 and the gut ranges from 1.8 to 2–sorry, your stomach acid ranges from 1.8 to 2. The less exciting answer is that that problem has been solved for like 10 years with delayed-release capsules or acid resistant capsules, which don't release organisms until they've entered into your small intestines.
Ben: You were talking to me about algae, how you somehow wrap a bacteria, algae.
Raja: Yeah. Well, so we took three strains of ours that were notorious for the highest die-off rates, and we wrapped them. We basically embedded them inside of a matrix using biopolymers that are derived from microalgae. In this case, we wanted to have a polymer which was very dense and was very tight but also had these pockets inside of it that microbes could nest.
And so, we did it. We did it on three strains. All of our other strains are in the acid resistant and we've tested this in a technology, which is the simulator of the human gut. So, we can tell you exactly what die off there is, at what stage in the gut for every organism, right? And an acid-resistant capsule solves the majority of viability concerns.
Ben: So, it's acid resistant because it's actually been enveloped in microalgae?
Raja: So, you embed it inside of a polymer which constricts, which constricts upon exposure to low pH conditions. And then as a counter-expansion to that restriction, it opens up in the gut. I don't want to sit here and say that that's the most radical or revolutionary breakthrough thing. In fact, I'm trying to say the opposite, which is everyone solved–I mean, acid-resistant capsules and acid-resistant technologies, as long as something has one of many acid-resistant technologies for the most part, and a company has data that shows that those organisms could survive prolonged exposure to low pH, that's sufficient to check that box.
But it brings up a very important point, two important points. The first is some organisms don't actually die off in low acid conditions because they're acid producers themselves. And so, they're very tolerant of low acidic conditions. Only some strains are very vulnerable. Bifidobacterium species and strains within Bifidobacterium genus are very sensitive to it. And the second is that's why there's such high die-off of microbes in foods because there is no protection system. It's not an acid-resistant capsule. It's not processed in some biopolymer matrix. You don't have any technology or any delivery system that makes it more viable.
And oftentimes, you'll find in freeform microbes. You find a high amount of die off. And remember, at the end of the day, that's a good thing. I mean, stomach acid is your first line of defense against environmental microbes. Not all of them would be good for you, right? You would think that the human body would evolve a defense system to protect ingested microbes from just entering into your microbial community willy-nilly. Overall, that's a good thing. It's spoken about a lot like it's a bad thing, but it's actually a highly protective mechanism. Very few strains that co-evolved with us have the ability to withstand those conditions.
Ben: Got it. What are the most exciting things you guys are doing right now at Seed? What's the company up to right now? Because I know you've produced some of these probiotic strains that people can go buy them. They're actually available as a supplement now, right?
Raja: Yeah. Well, we launched our first product, which is a very interesting concept. It's an aggregate of powerhouse strains that we found with academic collaborations. We either developed them with an academic collaboration or we identified an academic partner that met our requirements for double-blind randomized controlled trials, or we conducted that work ourselves.
And so, our thesis was let's just raise the bar with strains that have human clinical efficacy data, most importantly, for a wide range of indications. And so, we have folate producers. We have strains which downregulate the inflammatory response in the gut. We have strains which mitigate oxidative stress. We have strains which deconjugate bile acids to increase cholesterol reabsorption. We have strains which work on the gut barrier integrity, which strengthen the epithelial barrier. So, this aggregate of strains. And then, of course, we have our functional strains on multiple markers of digestive health, things like stool consistency, regularity, bloating, ease of expulsion, anal itching. I know that's a funny one but it happens. And we built a strain bank.
Ben: So, you basically got this bank of different strains. You've got all the academic research behind and you can simply draw on each of these, mix them with the stuff like the pomegranate and the pine bark and the chaga, the things that improve their ability to be able to grow, and then you simply package those. And if I'm not mistaken, you've got one for males and one for females with the female one being more focused on like the folate production?
Raja: Yeah. We have two products. The female product is different, and that it has a consortium of strains which downregulated the inflammatory response in the skin. And so, it decreased inflammatory expressions in atopic dermatitis and eczema, which is a shared inflammatory response for a lot of skin conditions and pathologies. And the strains in the female formulation also are folate–we included our folate producer because of its role in fertility and pregnancy. Our first product was meant to say for anybody that is currently taking a probiotic, there's no better combination of strains with human clinical support than what we developed in our first product.
Ben: When do you take it? Empty stomach with food, does it matter?
Raja: Ideally, an hour before a meal that contains some fat.
Ben: Yeah. Okay. I think on your label it says empty stomach, space before a meal, something like that. But I've been using it for about a month. I quit using other probiotics. Just switched to the Seed male formula. Yeah. So, I'm four weeks into regular use. Meaning, I'm taking three capsules a day. So, it sounds to me like I need to wait like eight weeks to really notice differences in terms of either dermatological health or gut health or anti-inflammation or things like.
Raja: Wait eight weeks. If not eight, take 12 and pay very close attention to stool consistency, ease of expulsion, elimination, the color. Most people don't realize that stool is brown because the microbial communities are responsible for that pigmentation. If you have inactive microbial communities, your stool will be discolored and it'll be resembled closer to color of the food that you ate.
So, stool, in many respects, is a very interesting biomarker. But let me give you a peek preview of some stuff that's coming out this year. We're actually going to do a trial where we're using a very new technology that was published in nature, which is a gas sensing capsule, which actually goes through the gut and picks up metabolites and gases that are produced by organisms through the entire gastrointestinal tract. And so, we're going to get a closer look at the effect that our consortium of strains has on metabolite production and modulation of the microbiome. That's a trial that we're doing now.
Ben: That would be something useful like SIBO?
Raja: Yeah. That's exact right. Right now, people are looking at breath tests or these proxy markers, but we want to get a closer look at every step of the way how are the oral consumption of our strains is modulating microbial communities through the entire gastrointestinal tract. We are announcing this shortly, but we'll be the first group that ever uses this in a clinical trial. We're doing it with Harvard. We're running our trial there. We have a paper and a draft that's going to be coming out on a two-strain combination that was a 560-person trial, and it looked at allergic response, allergic sensitization including seasonal allergies. And so, this would be data that shows that the consumption of two specific strains of bacteria systemically modulates the response resulting in allergic sensitization. And we're going to work and publish a paper on that.
Ben: Wow. Well, what I'm going to do is link to–you'll send me this other paper, reiterating what they are and what they are not, probiotics?
Raja: Yeah. We have a couple of weeks.
Ben: Okay. So, I'm going to put that in the show notes over at BenGreenfieldFitness.com/seedpodcast. I'll link to that documentary too that you mentioned, “Missing Microbes,” because I think that's going to be very interesting for folks. And then also, you've got the male probiotic formula, the female probiotic formula. I'm sure that at the time that this podcast gets released, this other formula that you're talking about might not have come out yet, but I'll link to your website.
We also have a discount code for those of you listening in. I'll put links to all this stuff at BenGreenfieldFitness.com/seedpodcast. But if you go to BenGreenfieldFitness.com/seed, there's a 15% discount code BEN15 that you can use over there at BenGreenfieldFitness.com/seed, if you want to try this out. And again, I see a lot of probiotics companies. I talked to a lot of people in this sector. Raja and what they're doing as you can tell, they're basically in all clinical research. It's very interesting. It's very unique. And your website is actually pretty cool. It's a very cool design. It's fun to explore, like there's a lot of really cool information in there. Like we only scratch the surface of what you guys have on your website in terms of really cool probiotic information.
Raja: I appreciate you saying that. I mean, education is really a big deal for us. So, we think that if someone learned–if you can teach somebody the fundamentals, people are a lot smarter than companies treat them. Educated consumers move the market, so we're really big on that. And the last thing is that–well, I'd be remiss if I didn't say as a company, we're not as–I mean, we have a lot of research tracks that are looking at every single ecosystem on the body. We have a whole women's health track that's looking at modulating the vaginal microbiome for applications and fertility and preventing urinary tract infections. We have a skin research track where we're looking to modulate the skin microbiome to dampen the inflammatory response.
On the next time we talk, I can give you more details on this breakthrough research that we're in the process of acquiring from UCLA, where actually, they look at the methylation patterns of any individual cell and they can predict your age of that tissue within 2.4 years. And so, it becomes this really interesting way if some people are–they are 10 years older than what your methylation patterns predict. And some people are aging 10 years quicker. And most people are somewhere in between. But the idea that–the choices that you make and the products that you use and the interventions you have, you can actually look at the epigenetic level. It's something that–it's very attractive. And certainly, microbes and microbial communities have a big effect on that. There's just never been a system like this ever of quantifying it. This is really deep science.
So, we're researching a lot of the oral microbiome. We have several research tracks in our company. All of which over the next couple years, we're going to be making some really big announcements. And the last thing is for people that–since your community probably is outdoors, fitness-oriented, environmentally leaning, I think that they'd enjoy–we have a division of our company called Seed Labs where we look at environmental projects. And our first one that we announced that Fast Company covered last year was probiotic for honeybees, which increases their resilience to neonicotinoid pesticides, which are commonly used by farmers in conventional farming. It's a huge problem. The EU just banned them. American farmers still, of course, use them. And it's the leading predictor or cause that people believe for honeybee colony collapse disorder, the decline of the honeybee population. I'm sure you know living where you do, if the honeybee goes, a lot of the crops that we are used to, a lot of the pollination goes.
Ben: It's a huge problem. Yeah.
Raja: And so, we found that actually, by isolating microbes from the hindgut of the honeybee, characterizing them and reintroducing them back into young bees, we increase their resiliency to those pesticides, but also, we protect them from a very nasty pathogen called Paenibacillus larvae, which kills off baby bees.
Raja: I mean, the field is incredibly exciting. I don't want to get too bogged down into what a particular–as a whole, microbiology is going to impact every decision that we make in the coming years from the choices we make for our food, from what types of medications we take to how we cleanse ourselves, to how we treat and prevent and treat diseases, child care, fertility, how you brush your teeth, hygiene, you name it, there's a microbial component to all these different categories. And microbes are going to fundamentally disrupt all these different categories.
Ben: I'm glad I know you, man, because I can text you anytime I have a question about bacteria.
Raja: Yeah, you can.
Ben: Or saving the bees. You got the answer. You live this shit, I can tell. Okay, folks. So, I'm going to put a link to all this stuff over at BenGreenfieldFitness.com/seedpodcast where you can also jump in. If you have comments or questions, you can ask them. Either Raja or I will jump in and reply to any questions that you have. The probiotic we talked about, that's the Seed probiotic. That's at BenGreenfieldFitness.com/seed. You get a 15% discount on that with BEN15. If anything, check out their website. Like I said, it's pretty cool. And Raja, thanks for coming on the show, man.
Raja: Thanks, Ben.
Ben: Thanks for keeping your giant wolves quiet with bone marrow to make podcasting magic. Alright, folks, until next time on Ben Greenfield along with Raja Dhir of Seed signing out from BenGreenfieldFitness.com. Have an amazing week.
Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at BenGreenfieldFitness.com, along with plenty of other goodies from me, including the highly helpful “Ben Recommends” page, which is a list of pretty much everything that I've ever recommended for hormone, sleep, digestion, fat loss, performance, and plenty more. Please, also, know that all the links, all the promo codes, that I mentioned during this and every episode, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.
Do probiotics really seed or populate your gut?
How do you decide which strain or species of probiotic to take?
Do certain compounds enhance the efficacy of probiotics?
Should probiotics be personalized?
I tackle all these probiotic questions and many more in today's episode with Raja Dhir.
Raja is Co-Founder and Co-CEO of Seed, an ecosystem of kindred scientists, doctors, innovators, entrepreneurs, and translational storytellers from around the world. Seed's members collectively believe in the potential of the microbiome to improve human and planetary health.
Raja leads Seed’s research strategy and academic collaborations, clinical trial design, product development, and intellectual property strategy. He is the architect of the Seed Platform and has unique expertise in translating scientific research for product development – including patented inventions to stabilize sensitive compounds to improve human microbiome diversity and inflammatory biomarkers. He’s also the co-chair of Seed’s Scientific Advisory Board where Seed focuses on solving complex ecological problems including honeybee colony collapse, plastic degradation, and soil fertility through bacteria.
Raja is an entrepreneur-in-residence at the Church Lab in the Department of Genetics at Harvard Medical School and is a director and co-chair of the Scientific Advisory Board for Micropia, a $20MM microbial ecology/education platform and the world’s first museum dedicated exclusively to microbes. He also serves on the Editorial Board for the scientific journal, Microbiome, on the Industry Advisory Committee for the International Scientific Association for Probiotics and Prebiotics (ISAPP), and is a member of the New York Academy of Sciences (NYAS), the American Society for Microbiology (ASM), and the American Association for the Advancement of Science (AAAS), among others.
During our discussion, you'll learn:
-Why we misunderstand probiotics and especially probiotic research…8:30
- Raja's research paper: Probiotics: What they are and what they are not
- We're understanding more and more about the gut and microbiome every day
- An organism must show that it has a specific effect on the body before the term “probiotic” can be used
- The term “probiotic” is unregulated in the United States
- Consumers are way ahead of the science
- Proper definition of a probiotic: live microorganisms, which when administered in adequate amounts confer a health benefit on the host
- Unscientific research on probiotics has led to damage in credibility in the field
- Taking one single data set that's not causative and applying the results to the entire field is an unscientific practice
-The recent studies on probiotics that Raja mentions, and sometimes criticizes, in his work…13:45
- Conducted by the Weizmann Institute
- Got subjects to consent to invasive small intestinal biopsies, versus just the colon
- Ordinarily, you test the large intestine only
- An overemphasis on testing stool samples
- Fallacy: Collecting large amounts of data will give you an accurate answer
- How classical biologists are different:
- Have a hypothesis,
- Narrow down an intervention,
- Test (in a large enough sample size) and look for biomarkers that change in the host
- How the test worked:
- Gave 3 groups of people large amounts of antibiotics
- Gave one group probiotics, one group allowed to recover spontaneously (watchful waiting), third group FMT; their own stool injected back in rectally
- Hypothesis: What's the fastest way of recovering to your normal baseline?
- After 90 days, everything lost statistical significance; all 3 groups indistinguishable from one another
- 3 things you can do to improve an infant's health
- Vaginal birth
- Not having antibiotics during birth (if you have a c-section)
- Do at least 2 of the 3 correctly, you dramatically increase the chances that the infant's microbiome will develop normally
- Science should not be a sensationalistic field
- Temptation to exploit research for short-term PR gains
-What regulations or standardizations exist when it comes to the microbiome and probiotics…23:25
- Contract manufacturers: used by big dairy companies, big business, probiotics found in local grocery stores
- European facilities are better equipped due to dietary differences
- Species vs Strains:
- Ex: Chihuahuas and Dobermans are different strains of the same species
- Some strains are up to 70% different from strains of the same species
- Must be tested on humans, otherwise should be called a microbial product vs. a probiotic product
- Some less disciplined companies benefit from the existing ambiguities in the probiotic field
-Raja's answer to the flaws in probiotic research he discusses in his paper and in his work…27:15
- The paper concludes with an optimistic view; possible changes in the next 5 years
- Click here for a table of physiological and metabolic processes influenced by the human microbiome according to Raja's research paper.
- Activating a switch in the body that prevents and reverses food allergies
- Minimum requirements before anything should call itself a probiotic
- Declare the genus, the species, and the strain
- Undergo minimum one human clinical trial
- If you didn't get all that, get this: While there is tremendous potential and reason for optimism in the field of probiotics, overuse of the term in the media and commercial use “cheapens” it and could discourage serious scientists from pursuing it to its full potential.
-Whether or not probiotics interact with the microbiome…34:30
- Article: Human gut study questions probiotic health benefits
- Probiotics are “transient microbes”; they don't take up permanent residence in any part of the body
- “Seeding” is the process by which an infants microbiome is first colonized by microbes
- Typical time a probiotic stays in the microbiome is ~8 weeks
- Daily consumption is necessary (kind of like coffee)
- Why not just eat fermented foods all the time?
- Only 4-5 out of several hundred bacterial strains in kimchi had probiotic potential (by the standards laid out in Raja's paper)
- Kombucha companies should do randomized controlled trials
- Terms like “immunity” and “anti-inflammatory” are misleading
- Certain bacteria can become “extinct” in as little as 4 generations when fiber is removed or reduced
- Certain populations do not need to take a probiotic because of their lifestyle and diet (ex. the Hadza people)
- “Detoxification” is oftentimes a misnomer;
- The body has its own detoxification pathways that are regulated by the nrf2 transcription factor
- Triggers for activation of the pathways: extended exercise, access to a wide variety of phytonutrients,
- Things that are bad for you are good for you
-The varying effects from different species and strains of probiotics…46:35
- Biotransformational nutrients: take existing food particles and convert into secondary metabolites and unlock new nutrients
- Probiotics supplement the existing micronutrients and gut bacteria
- “Consuming little soldiers that make their own multi-vitamins”
- Pomegranate is standardized for punicalagin: turned by already existing bacteria in the gut into Urolithin A
- Article: Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents
- Potential anti-aging benefits
- Thesis: How can we unlock the power of microbes or bacteria to confer benefits to their human hosts
-How probiotics affect males and females differently…52:35
- Women have a longer digestive tract than men, which leads to more issues with the digestive system
- Females could benefit from a folate producer in their gut during pregnancy; would be out of place in a male
- Environment & diet are of far more significance than gender
-Raja's take on companies who recommend particular probiotic strains to consume based on tests of the gut and microbiome…56:10
- Still no consensus on what determines a healthy microbiome
- Recommending a particular product based on test results is problematic
- Genus vs. species vs. strain recommendations; the more specific the better results
- “Relative abundance” vs. “absolute abundance”
- Better approach: take specific strains identified to treat specific issues
- Stratification, personalized approach, is not the optimal goal
- The gold standard is a microbe that is applicable to the entire human (or mammal) population and has reproducible effects
- To conclude: There are some good things about microbiome tests; however, use caution when they recommend certain products based on the test results
-Whether personalized microbiome testing will allow people to target a probiotic species for their specific gut profile…1:03:00
- Yes, but it will not look anything like the probiotics that are on the market today
- Some organisms won't grow if other like organisms are not in the mixed community
- The gut is an ecosystem; ecosystem theory comes into play
- Diversity and seasonality of plants rich in phytonutrients and high fiber foods
-The importance of the CFU (colony forming unit) of a probiotic…1:10:24
- Depends on the study and the trial
- Shotgun approach: inject high density of organisms into the gut and hope for the best
- Before you take any probiotic…
- Ask the company to show the studies on their strains
- Have they been studied in a human population
- And for what endpoints
-What Raja is most excited about with his work…1:18:10
- Get 15% off your first order from SEED when you use discount code: BENGREENFIELD
-And much more…
Resources from this episode:
-SEED Male Probiotic formula. Click here and use discount code: BEN15
-SEED Female Probiotic formula. Click here and use discount code: BEN15
-Documentary: “Missing Microbes”
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