All about the Gut Microbiome and Probiotics, with Raja Dhir

In this episode, we discuss:

• What “gut health” really means
• Individual differences in the gut microbiome
• The limits of gut microbiome testing
• How diet impacts the gut microbiome
• How probiotics affect gut health
• More about Seed
• What may cause probiotic intolerance

Show notes:

• Seed, Use promo KRESSER to receive 20% off.
• “The Neuroactive Potential of the Human Gut Microbiota in Quality of Life and Depression,” published in Nature
• “RHR: The Ocular Microbiome, with Dr. Harvey Fishman,” by Chris Kresser
• “American Gut: An Open Platform for Citizen Science Microbiome Research,” published in mSystems
• “RHR: Could ‘Eating Wild’ Be the Missing Link to Optimum Health?” by Chris Kresser
• “RHR: Why You Need to Eat More Vegetables—and How to Do It, with Dr. Tom Cowan,” by Chris Kresser
• “RHR: Is a Disrupted Gut Microbiome at the Root of Modern Disease?—with Dr. Justin Sonnenburg,” by Chris Kresser
• “RHR: You Are What Your Bacteria Eat: The Importance of Feeding Your Microbiome—with Jeff Leach,” by Chris Kresser
• “Sorry Low Carbers, Your Microbiome Is Just Not That into You,” by Jeff Leach
• “RHR: The Hygiene Hypothesis: Is Modern Disease Associated with Being Too Clean?” by Chris Kresser
• An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases, by Moises Velasquez-Manoff
• “Probiotics: Reiterating What They Are and What They Are Not,” published in Frontiers in Microbiology
• “RHR: What the Latest Research Says about Probiotics—with Lucy Mailing,” by Chris Kresser

Hey, everybody, it’s Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, I’m really excited about the interview with Raja Dhir. Raja is a life sciences entrepreneur and the cofounder of Seed, a venture-backed microbiome company pioneering the application of bacteria for both human and planetary health.

Raja serves on the editorial board for the scientific journal Microbiome . He is a member of the Microbiome Think Tank at Mass General Hospital and sits on the advisory committee for the International Scientific Association for Probiotics and Prebiotics. And he’s also a director and co-chair of the scientific advisory board for Micropia, a microbial ecology and education platform and the world’s first museum dedicated to microbes. I am really excited about this show because there’s been such an evolution of our understanding of probiotics and beneficial microorganisms in the G.I. tract and all over the body in general over the past couple of decades. And it’s proceeding at such a rapid pace that it’s really frankly hard to keep up with.

And Raja is one of my go-to people for helping me to stay abreast of the most recent developments in this space. He has, as you can tell from his bio, an incredible depth of experience and knowledge in this area. And Seed, which is the company that he co-founded, is one of my favorite probiotic products now that I use with my patients. I use it with myself and my family, and we’re going to be talking a lot about what has changed in our understanding of probiotics and that entire landscape over the past few years in this show.

Full disclosure, I am an advisor to Seed. I recently became an advisor because I believe so much in what they’re doing. I’ve have seen such incredible results with their products with my patients and also with my friends and family, and I think they have a really unusual approach to developing microbiome-based products. It’s evidence-based, very rigorous with the science, and the level of quality that they’re going for is far higher than most other probiotic products that I’ve seen in the marketplace. So I hope you enjoy this conversation as much as I did, and let’s dive in.

Chris Kresser:  Raja, thank you so much for being here. I’ve been looking forward to this.

Raja Dhir:  Thanks, Chris. It’s a pleasure to be here.

What “Gut Health” Really Means

Chris Kresser:  So let’s just dive right in and talk about a question that has been on my mind for a while and that I think is in some ways elusive. And certainly our understanding has changed quite a bit over the last 20 years. But we often hear this phrase “gut health,” that we should all maintain and promote gut health because we know from the research, a huge amount of research now, that the health of our gut and our microbiome is correlated with everything from Parkinson’s disease to cardiovascular health to skin conditions like eczema and psoriasis, to depression, to cognitive function. The list goes on and on. But what is gut health really? Like, what does gut health really mean for an individual?

Raja Dhir:  Yeah, it’s a really good place to start, and I think it’s so interesting because gut health is a term that’s been, I think in many ways, predates microbiome science. Ancient civilizations hypothesized that there’s a lot of activity in the gut, which has systemic effects.

Chris Kresser:  Yeah.

Raja Dhir:  And the microbiome as a concept really didn’t become popularized until 2006. And so, something that we always talk about here is how interesting it is where ancient kind of understandings that predate modern biology align very much so with a lot of these new understandings in a way that can confirm what intuitively or from a gut instinct perspective a lot of people have really felt.

But my approach at it is a little bit more, I’ll talk a little bit more on the post-microbiome side of things. So you’re absolutely right. The number of organ systems that are impacted by the collection of organisms in the gut, collectively called the microbiome, is vast, and it’s growing, more importantly, at a faster rate than any field in science that we see today.

So I can just point to, even in the examples that you presented in Parkinson’s and Alzheimer’s, we see that there is a different signature in the gut microbiome and in people that are affected compared to individuals that aren’t. And even so much that there is a, now a microbial theory of Alzheimer’s which is being positioned by blue-chip academic institutions. The largest depression study in a Flemish, Belgium, and Belgium looking at a Flemish cohort found that in over a thousand people, two organisms were deficient across the entire population in those that hide depression versus those that didn’t. That was published in Nature.

So we’re just at the surface, and these are just all very recent publications, but we are at the very beginning of seeing how far the reach of the gut really is. More localized, I would say that gut health is felt on a daily basis by individuals because it’s one of the few areas where there is a very tight feedback loop, so everything from stool consistency to intestinal transit time to bloating to indigestion or flatulence to acid reflux. I mean, a lot of these gut-mediated conditions or symptoms really have an impact,  and they punch out of their weight class in terms of affecting quality of life. So when people say that gut health is one of the most important areas to focus on, we can say scientifically, but also in terms of affecting day-to-day quality of life, I think it’s really deep too.

Chris Kresser:  Absolutely. I have shared many times on this show that IBS is the second-leading cause of people missing work behind the common cold. And it can be a very debilitating condition. Obviously, if the pain and discomfort’s enough to make somebody miss work, there’s a lot going on there. And when I first started blogging many years ago, first it was the gut–brain connection. Because there was some good early work on the inflammatory cytokine model of depression, which you just alluded to, and the connection between the microbiome and depression. And then it was the gut–skin connection and looking at actually that is like a triangle, the gut–brain–skin connection. You know the work of Stokes and Pillsbury from Duke back in the 1930s where they were looking at that?

Raja Dhir:  Yep.

Chris Kresser:  Which was pretty amazing. It took us 100 years to get back to that. But then of course, there’s the gut–gonad connection. There’s the gut, you could say the gut–muscle connection. There’s the gut–bone connection, and there’s really, you could just again, just go on down the list, and it’s kind of at this point, it seems to me that there’s no organ system that you can’t really draw a connection to the gut with.

Raja Dhir:  Yeah, now we’re starting to find even that there’s a connection and we’re even starting to find bacteria and microbes in places we never thought we’d find it.

Chris Kresser:  Right.

Raja Dhir:  It still needs to be confirmed in a larger cohort, but now even believe that they’re in the brain.

Chris Kresser:  Right, right.

Raja Dhir:  So it’s incredible. And then the one thing I would add to your comment just now is that in specific windows and periods of life, it’s even more important. So:

• Infancy;
• Birth;
• First six months of life.

There’s windows of opportunity when you’re shifting from weaning to solid foods. First exposure to airborne allergens. So a lot of these developmental processes are gut mediated.

Chris Kresser:  Yeah, another surprising one, for me, at least, was the ocular microbiome. We had Dr. Harvey Fishman from Stanford on the show talking about the ocular microbiome and the connection between the ocular microbiome and a bunch of different eye diseases, which is just fascinating to me to conceive of. Ocular probiotics at some point, as potentially being an intervention.

Raja Dhir:  And we can’t forget your idea, when you and I first met, of modulating the nasal microbiome.

Chris Kresser:  Absolutely.

Raja Dhir:  First inventorship of that.

Individual Differences in the Gut Microbiome

Chris Kresser:  Absolutely, that’s going to be here. So let’s talk a little bit about some other questions that have been on my mind for a while and I know that have been explored a lot recently, which is we have these population studies. We can detect patterns in the microbiome between populations. And we can kind of say this is a “normal microbiome” for this population. This appears to be a normal microbiome for that population. We see sometimes surprising things, like Bifidobacteria largely being protective in Western populations.

And then the Hadza hunter–gatherers seem to have much lower levels of Bifidobacteria that we would predict from what we know about the Western microbiome. But what do we know now about what a healthy individual microbiome is? Is it like a fingerprint? Or what are the general conclusions that we can draw versus where is the sort of individualization of like, well, this might not be good for this other person but it’s good for that person?

Raja Dhir:  Yeah, it’s a really good question. In fact, it’s one of my favorites because we assume, being an individualized society, that of course what is a microbiome for one person cannot be a healthy microbiome for another. And in some respects, population studies, it’s true. But I would encourage a lot of caution around the term “normal microbiome” because it implies that there’s kind of “this is a state of a microbiome that’s healthy versus one that isn’t.”

You’re absolutely correct that we find all types of interpersonal variations between different societies and also between individuals within a society when it comes to the organisms that are located in and on the human body. The Hadza not only have very little Bifidobacteria, but in some instances have none at all and are perfectly healthy. You couldn’t pay me to trade microbiomes with some of these indigenous cultures, because I’ve seen the pathogen load that those communities can carry which in their environment is advantageous. Because they have organisms that are protective against it but in built environments likely would not be healthy.

And so I think we have a bit of a romanticization with these … one side of it is that, “well, everybody’s microbiome is a little bit different.” But the other side of it is that we’ve lost our diversity from these hunter–gatherer tribes or ancestral tribes. And the truth of the matter is just because something’s more diverse doesn’t oftentimes mean it’s better. So there’s a really tight feedback loop between the built environment, between early-life exposure and one individual’s microbial diversity in the individual species and strains that are in there.

Now the flip side of that discussion is there’s a phenomenon called functional redundancy. Which means that over the course of the evolution of a lot of different bacteria, different species have evolved to perform the same function. So just because somebody on a metagenomic readout or a transcriptomic readout has a very different microbial community, you’ll find that a lot of the key functions are conserved amongst different people. So you and I invariably have very different microbial communities. But I can guarantee you that we have specific strains that are meant for the degradation of prebiotic fibers and short-chain fatty acid production.

No matter what the variation between our guts is, that part is going to be conserved. And so we’re just starting to see that conservation of function across a number of different roles that microbes could play. So that’s kind of at the introductory level. The take-home point there is that, yes, everybody’s microbiome is very different. But in a healthy individual, you should expect to see that the function of that part of the metabolic output of that microbiome is conserved, if that makes sense.

Chris Kresser:  It makes perfect sense, and I’m glad that you brought that up because to me that argues for a way of testing the microbiome that is including that information. So we’re not just looking at the presence or absence of certain species. We’re looking at what the transcriptomics, proteomics, and all of the other omics to see what’s actually happening functionally. So where do you see that going in terms of testing?

The Limits of Gut Microbiome Testing

Raja Dhir:  So the truth is that nobody offers metabolomics because any company that would try to do it would go bankrupt very quickly. Metabolomics is a very—

Chris Kresser:  Like AI.

Raja Dhir:  Well, it’s just the process of running this on a mass spectrometer. I mean, looking at the weight of those chemistries, and also the database is very immature. So you get a lot of unidentified metabolite, unidentified metabolite. And so it’s really hard and frustrating to work in these metabolite data sets. Because we know a lot more of the genomics of microbes than we do all the different metabolites that they could produce. But yes, in theory you’re absolutely right. I mean the furthest in line that somebody could do is all of the different metabolites that are produced, or what’s called the metabolic output of that entire community.

And here’s another really interesting thing. So you’ll find that some organisms, they are really good, let’s say, at … they have the pathway for propionate production. That’s an example of a short-chain fatty acid. But other organisms in that community through cross-feeding would gobble it up very quickly and turn it to butyrate. So you really want to see the end products that are being produced rather than a lot of these kind of encode-based or encoding transcriptomic sets. Because it’s not perfectly clear how that affects the final product.

Chris Kresser:  Yeah, yeah, I mean, this is, as a clinician, and of course we have many clinicians who are listening to this and practitioners of all types, it’s frustrating not to have a tool that gives us a more complete understanding of what’s happening in the microbiome. I mean, we can, I think qPCR certainly offers some benefits in terms of being able to detect pathogens. And even quantitatively assessing, “okay, so this person has H. pylori, but how much do they have?” And then looking of virulence factors and things like that to determine how aggressive we should be in treatment.

But I find that most of these tests are pretty limited in what they can tell me about the status of that person’s microbiome. And in some cases, we’ll get results back and they don’t have pathogens, but they still have significant G.I. issues going on. And I’m virtually certain that there’s some significant disruption in the microbiome. But it may not be showing up in any of these test results.

Raja Dhir:  So I think that qPCR for pathogens is actually, having definitive but limited data probably in the long run is better than having non-actionable broad data sets. And so I think that I share your frustration, but at the same time, I think that rightfully so, we need to be very cautious about introducing very large abstract data sets where it’s not clear how the interpretation or bioinformatics of that informs a treatment protocol or informs an intervention.

Chris Kresser:  Yeah.

Raja Dhir:  So I think we’re getting there. I think my estimation is in the next five years we’ll be fully, fully looking at metabolites.

Chris Kresser:  Cool. I look forward to it. In the meantime, of course there’s still a lot that we can do empirically.

Raja Dhir:  Yes.

Chris Kresser:  We know about the levers of diet and lifestyle and things like supplemental probiotics, which we’ll talk more about, that can impact gut health. Not necessarily regardless of what’s going on, but you could say in virtually every situation they’ll have, there’s certain choices that we could make that are very likely to confer a benefit regardless of what’s happening with the microbiome. And I know that you agree with that given your … it doesn’t necessarily have to be as personalized as we may think it does in order to have a benefit. But let’s come back to that.

Raja Dhir:  Well, just to quickly close the loop on that and to finish the kind of personalization on subject, that kind of brings me to, I think, one of my most important points, which is just because somebody has a different microbiota from the next, it has no basis for a different recommendation of what could be beneficial for that person. So in the gold standard is what we call efficacy in a heterogeneous population.

So if you can show that agnostic of an individual’s starting microbiome that an intervention has an effect, I mean, in science that’s really, that’s the gold standard. If something only works in a small subset of people and people have to be stratified into treatment groups based on their starting microbiome, that’s an inferior intervention then. One that works across a heterogeneous human population—

Chris Kresser:  Certainly.

Raja Dhir:  So I think that our research is fully focused on these microbes that work in a population regardless of where somebody’s starting microbiome is through a defined mechanism of action. So it’s a really interesting point.

Chris Kresser:  Yeah, I feel the same way about food in many cases.

Raja Dhir:  Yep.

How Diet Impacts the Gut Microbiome

Chris Kresser:  There is a lot of, I think, hype about personalized nutrition. And we’ll measure your microbiome and tell you that you should eat more carrots and red peppers and less broccoli and beans. And for me, there are certain choices that we can make like shifting to a more nutrient-dense, anti-inflammatory diet, eliminating processed and refined foods. Getting a certain number of hours of sleep each night. Reducing the amount of time that we spend sitting and getting a certain amount of exercise that, as you say, are consistent across all populations.

They’ve been shown to benefit you whether you’re living in Paris or somewhere in Botswana. And those are for me those are the most important things for us to be focusing on. And I think we can sometimes have a tendency to get a little bit too carried away with the kind of biohacking, hyper-personalized approach to health. And because it, especially when it distracts us from those more basic things.

Raja Dhir:  And the data, the data absolutely supports that. So in the late summer of last year, the results came back of the largest study ever to investigate the human microbiome. It was an extension of the American Gut Project. It is run by Jack Gilbert and Rob Knight. And they basically wanted to know the exact question that you answered, is across different countries and not concentrated in a single setting or a single age demographic, in a large population, what are the commonalities that you can find using every single testing method possible for increasing the alpha and beta diversity of the gut microbiome?

I mean, they looked at, I think they had over 15,000 samples that were given by more than 10,000 people. It was in the US, the UK, Australia, about 40 other countries. They used, they did shotgun metagenomics, they did metabolomics. So these types of large, comparative, diverse data sets are the ones that are really, really juicy. So you’ll find that the recommendation was that people that consume more than 30 different types of plant each week had a significantly more diverse microbiome than those that consumed 10 or fewer. And so not to say that that, there’s probably a lot of other factors that contributed to microbiome diversity that people that tended to have a higher plant-based diet would have.

So it’s not purely, it’s not causative. But the fact that the first most important one was the consumption of 30 more and the second factor was the consumption of 10 or less is really kind of leads us in the direction that, not that exclusively plant-based, but inclusively a plant-based diet with high diversity across the board had the biggest impact.

Chris Kresser:  Yeah, I saw that and it’s fascinating. I’ve had Jo Robinson from EatWild on the show and Dr. Tom Cowan and a number of others who have basically argued that if you look at the biggest difference between an ancestral diet and a modern diet, it’s the diversity of plant species consumed. Which is something that doesn’t often get discussed in the context of comparing ancestral versus modern diets.

Raja Dhir:  Yes.

Chris Kresser:  This research is another indication that that is crucial.

Raja Dhir:  Yeah.

Chris Kresser:  If you had the Standard American Diet, it’s basically lettuce and tomato on the burger, right?

Raja Dhir:  Yeah.

Chris Kresser:  Or the salad.

Raja Dhir:  No, but it’s, it’s—

Chris Kresser:  Maybe a couple broccoli and that’s it.

Raja Dhir:  And it’s just, I would encourage people that are still hooked on the personalization story to think through this case study. So people don’t read this and say, “Oh, well, let’s stratify and try to find subpopulations that had based on their microbiome responded better to a plant-based diet than other ones.” I mean, across a heterogeneous population, this was something that you could tease out. So I think that we should think about microbes very much in the same way, particularly when they’re intended to have gut-mediated effects.

Chris Kresser:  Yeah. Okay, so let’s talk a little bit about, we touched on diet a little bit and how this relationship between food; plants, we were just talking about there and microbiome. What about some other major drivers like sugar alcohol, fibers, of course, something that gets discussed a lot in the context of microbiome and fat?

Fiber

Raja Dhir:  Yeah, so I’ll start with fiber because there’s a really interesting study that’s on the top of my mind here. We used to think that there’s a number of phytonutrients which contributed to gut microbiome diversity. So researchers—and, have you had Justin Sonnenburg on yet?

Chris Kresser:  I have, I have, yeah.

Raja Dhir:  So, Justin’s lab did publish that study that was picked up as kind of the mass extinction inside of our guts that progressively looked at four generations of the high-fiber diet or a low-fiber diet in an animal model. And so they found that by the fourth, at the end of the third generation, even if you switch back to a high-fiber diet, species and strains are gone that are irreversible. And so you cannot bring back the diversity in as little as three generations. And so I think that’s a very, on a personal level, maybe it’s not so relevant. But if you start thinking at a population level, I mean, kind of the effects that we’re having as a species on microbial diversity on organisms that took a very long time to evolve that without a doubt, have very important functions, it’s going to be really, I think, it is an extinction of sorts. And so fiber is the first thing I would say is the most important. Fat’s an interesting one.

Chris Kresser:  And by fiber, just to clarify for folks, we mean not necessarily psyllium husk or supplemental fiber, but what Justin calls microbiota-accessible carbohydrates. So can you say—we don’t need to go into a lot of detail there, because I had a whole show with Justin about that—but can you say a little bit about which fibers and foods people should be thinking about?

Raja Dhir:  Yeah, so what you want are complex long-chain carbohydrates. And so these are often times found in root vegetables and the stocks of cruciferous vegetables. I mean if you follow the middle of the Venn diagram of every single nutrition recommendation, with the exception of some circles—

Chris Kresser:  The carnivore diet.

Raja Dhir:  Carnivore diet.

Chris Kresser:  Yeah.

Raja Dhir:  Which should give us all the information we need to assess the safety of the diet. It for the most part, leads you to the same place. It’s another point which is in some instances overthinking, this doesn’t have to be so complex where it’s a dark art that needs demystification. I think humans with much less excess information did it just fine for a very long period of time. And so I think intuitively a lot of the recommendations that are what people strive for that are listening already would give access. But, technically you want carbohydrates with a degree of polymerization greater than three. So everything from an oligosaccharide onwards.

Chris Kresser:  Yeah, great. So yeah, so you were going to go on to fat or sugar alcohol.

Sugar, Sugar Alcohols, and Fat

Raja Dhir:  Yeah, so, sugar is an interesting one. So the sugar is, we don’t know for sugar whether it’s a direct mediated effect. And by sugar, in this case I’m speaking of sucrose. We’ve seen studies that say that there’s a number of reasons why sucrose is very, in the quantities that’s being consumed, is pretty toxic for the body. New studies are now showing that it directly impacts and acts on tumor growth. That just came out last week. Of course, it’s the biggest risk factor for metabolic syndrome, which is one of those systemic effects which then goes and changes the entire physiology beyond the microbiome. So it’s unclear whether it’s a direct effect on the microbiome or it’s an indirect. But either way, it’s very, very destructive, particularly when it’s immediately accessible in the form of, or unbound, I should say from a fibrous or complex carbohydrate source. But there are pretty significant studies now showing a high correlation of simple sugars, glucose and fructose in particular, with low diversity that’s found in the microbiota. And so what we think is, it’s A, indicative of a diet which is, it comes at the replacement of complex carbohydrates, but B, operates directly on the microbiome.

Fat is an interesting one because the organisms in the gut that love fat are not the organisms that produce byproducts that we believe to be the most beneficial for the microbiome. These short-chain fatty acids, these deep, deep mucosally linked organisms that directly impact the immune response in humans, these aren’t traditionally fat-loving bacteria. And so while there have been dramatic physiological effects in terms of body composition on a ketogenic diet, the research is just getting started on what a high-fat diet that is devoid or absent of complex carbohydrates does to the gut microbiota. But early indications show that unless a complex carbohydrate intake is maintained in the presence, that the exclusive consumption of a high-fat diet is pretty destructive for diversity of the microbiome.

Chris Kresser:  Yeah, I know that’s bad news for some people. I’ve been writing about this for some time, and actually Jeff Leach and I talked about it several years ago when I had him on the show. And you probably saw this post he did a while back with a catchy title. It was something like, “Sorry Low-Carbers, Your Microbiome’s Just Not That into You,” which was very anecdotal data, but he was looking at people who’d submitted stool samples to American Gut who were doing a low-fat or low-carb keto-style diet versus people who were on just a more moderate-fat, moderate-carb, Paleo type of diet, and seeing some patterns there that didn’t look great. And I for several years have kind of cautioned people against a full-time ketogenic diet with low intake of microbiota-accessible carbs, unless they have a very compelling reason to do that, like if they have severe epilepsy, for example, and it’s the only way they can control it.

And more, if they want to get the benefits of ketosis, to do it in a more cyclical way where they have refeeds a couple days a week of refeeding, with higher intake of those carbohydrates just for that reason. Because I think if you look at ancestral populations, it’s pretty unlikely that there were really any populations that were in full-on high-fat ketosis for 24/7 all the time. And there’s probably a reason. Our physiology didn’t evolve in that context, and we need those microbiota-accessible carbohydrates.

Raja Dhir:  Yeah. And then one theory is, I think that for individuals that have … it’s almost like in short periods of time, ketogenic diet works also by modulating the microbiome.

Chris Kresser:  Right, right.

Raja Dhir:  So if somebody has a dysbiotic starting microbiome, that it almost functions the way that a bacteriostatic or antimicrobial would, by just starving everything like a wildfire just to allow more prime species to regrow. So I don’t want that criticism to discount the wealth of evidence that shows short-term benefits from a high-fat, low-carbohydrate ketogenic diet. I think that there’s more that we need to study the long-term effects of it on the microbiome. I just want to temper, I mean, offer the position that the long-term effects of it have not been positive for our current understandings of microbial diversity as we believe it relates to human health.

Chris Kresser:  Yeah. And it’s the difference in my mind between a therapeutic tool that can be really useful in the right context and something that we would do for long-term health. You can still benefit from ketosis without being in it 24/7. I mean, that’s the way that I look at it. And we absolutely use ketogenic diet as a gut reset for people who are dealing with SIBO and things like that. And it’s phenomenally effective in that context.

Raja Dhir:  And again, I think it also comes down to the specifics. I mean, if your ketogenic diet is exclusively a butter diet, I think that’s a lot different than a low-carbohydrate, your carbohydrate consumption is so low, but you still have sufficient, I mean, I’d have to go look at the macros, but I believe there may be a way to do a primarily … There’s some ways of doing even a plant-based diet where you’re in ketosis for a certain period of time.

Chris Kresser:  Yeah.

Raja Dhir:  So I think there’s nuance to a lot of these discussions. I think we know gut microbiota mediate polyphenolic compounds. We know that they mediate a lot of primary and secondary metabolites that are found in plant material that would not qualify or would not eliminate somebody from being in a state of ketosis.

Chris Kresser:  Absolutely. Yeah, you could.

Raja Dhir:  There’s a little bit.

Chris Kresser:  You can do an Atkins-style ketogenic diet, which I think is how it originally was done. And then you can do a much more diverse planned intake of non-starchy vegetables and still get a good amount of fiber that way.

So let’s talk a little bit about probiotics. Talk about a subject that has come a long way in terms of our understanding and where there is a lot of misconception out there. Where do probiotics fit in this? So we’re eating a nutrient-dense diet, we’re sleeping, we’re exercising, we’re doing all the other things I’ve talked about on other shows that we know benefit the microbiome. And then what about probiotics? Where does that fit into the whole strategy?

A healthy gut means a healthy body. But what makes a gut “healthy”? And should you take probiotics? Check out this episode of RHR to find out.

How Probiotics Affect Gut Health

Raja Dhir:  So, I think a lot of people start with the question that, well, it’s the assumption that because we’re living in modern built environments and our diet and our lifestyle has deviated from ancestral populations, that we’re deficient in these organisms or that they are missing or declined in modern populations. And so some people think of probiotics as necessary to replenish or add back in missing organisms. And in some ways, it’s such a nice story that I wish that’s how it worked. But it’s not the, I’ll tell you a better story. So a better story is that—

Chris Kresser:  I call that one the gas tank analogy.

Raja Dhir:  Yeah.

Chris Kresser:  The tank is empty, just fill it back up. It’s simple as that.

Raja Dhir:  Yeah. So a) that’s not how probiotics work. That’s how a fecal transplant works, which we’re not even going to go down that diversion—

Chris Kresser:  That’s a whole other discussion.

Raja Dhir:  At the moment. But here’s a better story. The story is that for the entirety of our known human existence, the only levers that we’ve had to modulate human health or tip health in favor of being healthier is diet, lifestyle modifications like exercise, cessation of factors that are bad for us, like being sedentary or smoking and drugs. And depending on where you put surgery, that might be a fifth one. So open intervention. And now it’s a really exciting time. It’s a time where we are learning more about the community of organisms inside of our body. But also what the ingestion or topical application of microbes do for various organ systems in the body. And so, we like to think of bacteria as this fifth or sixth lever to exert functional effects that would define activity in the human body to make us healthier.

So I’ll give you a couple examples. So, barrier disintegrity is one of those things that you would really need to, certainly a lot of people attribute their illnesses to what’s called intestinal permeability or barrier disintegrity, just leaky gut, if you will.

Chris Kresser:  Yeah.

Raja Dhir:  But the truth of the matter is, you’d have to do really onerous controlled 20-, 30-, 40-year studies to show causation instead of understand the mechanism. And so without going down that rabbit hole, we think that when membranes, or when barriers in the body break down … Or certainly one of the leading theories, whether it’s the blood–brain barrier, whether it’s vascular barriers, whether it’s gut barriers, poor barrier function, a unified theory of a cascade of health effects resulting in all-cause mortality is believed to be barrier disintegrity across different tissues in the body.

And so it stands to reason that with the gut barrier being one of the primary and upstream areas where compounds can enter into systemic circulation, that that’s a very important barrier to protect. And so, without going into well, sure, a lot of people would say, “Well, this causes Alzheimer’s or this causes Parkinson’s,” I mean, the truth of the matter is we don’t know, but mechanistically, it’s very possible.

And so one thing that’s lacking in just having the right microbiome if you will, versus orally ingesting bacteria every day, are the effects that the oral ingestion of specific bacterial taxa exerts on epithelia-type junction proteins on your gut barrier. So we know that certain organisms stimulate that response, which overpower something as strong as even, like, bacterial endotoxin. Or a challenge where you just completely degraded that tissue as simple as applying the right organisms, or more importantly, protecting the tissue with the organisms before the aggressor maintains the integrity of that tissue. And so, as mechanistic scientists would find something like that very interesting, because without going into how everything that that can have an effect on, it is a new lever that diet itself will not exert to maintaining the integrity of that tissue system.

So we think things like that are very important. Even our strains we’ve tested consistently, and this is one of the primary endpoints that we like to look for, is both a response in repairing gut barrier after challenge, after an endotoxin-lipopolysaccharide challenge. But also protecting the tissue from a number of disruptions. And so, I was musing the other day, we know that there are a couple of different things that in the lab, you can use to simulate this barrier disintegrity. Believe it or not, alcohol is one of them. And so I wanted to design a test where we actually used tequila as the stressor and see if probiotics can mediate.

Chris Kresser:  Good one. I just got back from Mexico. I’d be curious to hear those results.

Raja Dhir:  Yeah, so I mean it’s funny in the way science works. Because I promise you that study would have the highest altmetric score of any study that we could publish.

Chris Kresser:  Yeah, it’s true.

Raja Dhir:  So it’s kind of in our back pocket.

Chris Kresser:  You could go on the Today Show and talk about it.

Raja Dhir:  Yeah.

Chris Kresser:  Yeah. So I’ve talked on the show and I’ve been fascinated personally with the hygiene hypothesis and the old friends hypothesis. I had Moises Velasquez-Manoff, who wrote Epidemic of Absence, on the show a while back. Many years ago, actually, to talk about that. Do you see probiotics as fitting into that category of old friends? Old friends are often more specifically thought of as organisms that could be potentially pathogenic or have been maybe categorized as pathogens.

Raja Dhir:  Yep.

Chris Kresser:  But how would you draw a parallel between that idea or hypothesis and what these microbes that we could now expose ourselves to in probiotics, but might have been exposed to in our natural environment?

Raja Dhir:  Yes. So two points. The first is, I think it’s worth just clarifying two things. First, obviously, not probiotic. The paper we just published is actually a pretty strong call to action for using the term very liberally. I think what people, we definitely can’t generalize that across all products, or even all discovered microbes today that are labeled as probiotic. By definition, I think that yes, the oral ingestion of microbes, either ones that have been discovered today or will be discovered in the next couple years or validated in the next couple years, absolutely will play into the hygiene hypothesis. I do not think that any of the Lactobacilli or Bifidobacterium, perhaps some Bifidobacterium when given to infants, but I do not think that those are mediated along the hygiene hypothesis.

So let me give you an example. So one of the core deficiencies that’s noted based on the hygiene hypothesis is that individuals will have a higher risk of allergic sensitization, whether it’s airway, whether it’s food allergies. whether it’s atopic in the form of eczema, psoriasis. You find that there are immune-mediated effects based off of a lack or insufficient exposure to microbes in these early-stage windows of life. So now we absolutely know, and in fact there is a very interesting paper that’s going to be coming out in Nature next month that was authored by somebody in our company, a postdoc at Harvard, showing that microbes, in particular specific microbes, they activate or inactivate the response that mediates food allergies. So there’s a switch in the body, a pathway which is based in a very defined window of time, is activated or inactivated based off of an infant’s microbiome, which sets that infant up for food allergies to food-borne antigens.

So that’s firmly within the idea of probiotics could prevent or treat very direct conditions that are believed to be the result of the hygiene hypothesis, which is that we aren’t exposed or get sufficient exposure to enough microbial diversity in the early stages of life. So I think yes, but I think that it would be premature to say that commercially available probiotics are activating pathways which are, these are really defined pathways. And usually they have very systemic effects. And so I don’t think we know enough to know whether commercial probiotics would work along that hygiene hypothesis.

Chris Kresser:  Fair enough. So there was a study that came out recently which you addressed in your paper, your recent paper, which I’ve read. And congratulations on an excellent paper—

Raja Dhir:  Thank you.

Chris Kresser:  Called “Probiotics: Reiterating What They Are and What They Are Not.” And I also discussed the results of the study with Lucy Mailing, who works in a microbiome lab at University of Illinois and has been a research assistant. And you have corresponded with Lucy a little bit about the results of this paper. And so essentially, this paper argues—I’m just going to paraphrase—so get more specific, claim to show that taking probiotics after a course of cipro, was it? If I remember correctly.

Raja Dhir:  It was metronidazole and ciprofloxacin, yep.

Chris Kresser:  Right. So Flagyl and cipro, two of the bad boys, delayed the recovery.

Raja Dhir:  The big guns.

Chris Kresser:  Yeah, the big gun, carpet bombers that people would be likely to take if they were exposed to a parasite or something like that. Or in many other situations. But delayed the recovery of the microbiome compared to people who did not take probiotics. Sorry, people who took probiotics after taking those drugs, had a delayed recovery of their microbiome compared to people who did not take probiotics after taking those drugs. So I know from witnessing your discussion with Lucy about this, I mean, we could get very, very deeply into the weeds here, but maybe a brief summary of what the questions you have are about this paper, what additional research is needed and what we should take away from that paper.

Raja Dhir:  Yeah. So it was, everyone’s probably, if they didn’t read the paper directly, they probably were part of that 24-hour press cycle or heard of this press cycle. I think the most impressive part of this paper was the PR campaign behind it. I think it made its way everywhere. I think that we take a very, our paper was a response that takes a very restrained approach to what probiotics are. It’s a call for specificity. I don’t think that you can generalize.

Certainly the first point is that you shouldn’t generalize one area or one mechanism of action to all possible microbes that could be ingested by humans. And so we kind of had a very strict definition for what a probiotic even is. And the very first definition—and this isn’t new, this is information in the definition from the original United Nations World Health Organization report—is that the strains must be shown to have a benefit in the human host for the indication that it’s being tested. So if the bacteria doesn’t show that it has a therapeutic or beneficial effect in the human body, by definition it’s not a probiotic. So that’s the first part, is that we want to make sure that people understand that unless it is a microbe which has already been proven in a randomized controlled trial to benefit human health, that consortia or that cocktail of species should not be called a probiotic.

But back to the Cell paper. So in this paper, they took a couple groups and they wanted to see if you gave a fecal transplant, if you could recover the microbiome quicker, when compared to doing nothing at all or giving somebody a probiotic. I think in your chat with Lucy she broke down what the paper was and how it worked in really elegant details. So people can go there if they want more of a primer on how the original trial was designed. But there is a lot of limitations to the study which I wish were part of the story to temper a little bit of the sensationalism that was around the outcomes.

Chris Kresser:  Sorry, Raja, the media does not do nuance. You know this, I’m sure.

Raja Dhir:  Yeah, yeah.

Chris Kresser:  Nuance doesn’t generate clicks. So we know that very well.

Raja Dhir:  So I joked that the more appropriate title or a more nuanced title for the paper should have been “Delay of 10 to 12 species for 90 days in a population with lower starting microbial diversity.” But I think that that wouldn’t get the—

Chris Kresser:  Who took two specific drugs.

Raja Dhir:  Yeah.

Chris Kresser:  Because we wouldn’t necessarily extend that to all drugs either.

Raja Dhir:  Yeah. But the quick-note version of the, without going into a lot of weeds here, was the first is kind of at the end, at day 28, so this is 28 days, four weeks after, whether you got a fecal transplant or you did nothing at all, or you took a probiotic. The total species difference between those two groups, you’re looking at something like 10 or so, 15 maximum different species, without a deep understanding of what those species are or how they work.

And so what I wish that the paper did was if they had married that data set with a metabolite test and you show that the entire output of the system is impaired. Or that there’s more of an inflammatory metabolite or there is more of an aggressive metabolite that’s found. Or there’s a lack of an inhibition of a known pathogen that produces this metabolite.

Chris Kresser:  It’s a functional indicator.

Raja Dhir:  A functional indicator on what those organisms are performing. And the data is really mixed. So in some instances, Akkermansia was a lot higher in the probiotic group. Akkermansia is a really strong butyrate producer and it’s very beneficial. In other instances, Eubacterium is depressed. And so, I think it would be very wise in future studies to look at that type of functional data. And by the way, we know this dysfunctional data, again, if you’re going back to an earlier point in this discussion on redundancies in the microbiome, just because some organisms are deficient, perhaps there’s a higher concentration in specific organisms that work better with the microbial, with the probiotic “cocktail” that was consumed there.

Or maybe it was different in the lumen than it was in the mucosa. And so, I think there’s, that would be the first point, or the call to action, is that a lot of the functional analysis was missing from this. And more importantly, 10 species is a … everything lost statistical significance by day 90. So all of the error bars are overlapping by day 90. So again, these results show us that for the first 90 days, even if there’s a temporary delay of 10 or so species, all that disappears at around three months. And so the questions that a scientist would ask are what were the species, what were they doing, and could there be some beneficial activity that the oral microbes are imparting in that kind of impaired or low diversity environment that could be beneficial for the host? That justifies why there would be more of them or why the resources within that community, within that ecosystem, would be distributed more or less evenly, but in a more concentrated way. So those are all the questions that I think a scientist would ask.

Chris Kresser:  But also, maybe, what would happen with a different probiotic formulation? Does this effect also occur with other antibiotic drugs to the same degree? What happens if another group tries to replicate this finding? There’s so many questions, and that’s exactly how science is supposed to work.

Raja Dhir:  Yeah.

Chris Kresser:  You have a hypothesis, you test it, you see the results and then you want to replicate those results to have more confidence in that finding. You want to start exploring some of the mechanisms in other hypotheses that might be generated from that initial study. And so it’s fantastic that this work was done and published, and it does raise some interesting questions that I would really love to see explored. The unfortunate thing, as you pointed out, is just how carried away that the media can often get. And sometimes, I don’t know if this was the case in this study, so I’m certainly not suggesting that it is, but sometimes even researchers themselves understandably can get very excited about a finding and not remember to put it in context of other findings.

The unfortunate result of this is I’ve had patients coming into me saying, “Oh, I stopped taking probiotics because of that study.” And I said, “Wait, wait, wait, hang on a second.” We’ve got literally thousands of studies documenting the benefits of probiotics. And everything from metabolic to cardiovascular health, to women’s health, to dermatological health, to performance and muscle recovery, etc., and there was one study that showed what you just summarized. And that is not enough to suggest that all probiotics are useless. That’s a gross exaggeration.

Raja Dhir:  And it’s not even the most recent study to ask the same questions. So the funniest part is that within the same month, two other trials were published. The first was in a vulnerable antibiotic-treated infant population, infants that were born through C-section.

Chris Kresser:  One of the most important populations that you pointed out earlier in terms of thinking about this question, yeah.

Raja Dhir:  Yeah, and it showed a faster restoration to normal microbiotic composition in the probiotic group than doing nothing at all. So that’s conflicting data, and that was in a very vulnerable population. And then a second trial that actually had double the length of the intervention. So it was four more weeks of data and had a 700 percent higher dosage of probiotic. So in there, you’d expect to see that if that affect was reproducible, that it would be even more pronounced.

And finally, it was in even a more vulnerable population. It was for individuals that were given severe antibiotics after a Clostridium difficile infection. And the results showed that the probiotic group maintained and slightly increased both the richness and evenness of the starting microbiome when compared to placebo. So I mean it’s just much less interesting of a press cycle when three studies are discussed and one of them gives negative results.

Chris Kresser:  We’ve talked about this in so many contexts on this show about the nuance not, you know it’s just, yeah, it’s frustrating. What can we say?

Raja Dhir:  In many ways I’m having, I mean, I think that it just opened a whole new box of inquiry. I think that companies that can test their products on antibiotic trials will be very advantageous. It’s work that we’re doing. And so having the data in hand, the raw data, designing it as a double-blind trial, publishing the results, I think these are, as you mentioned earlier, that’s why science works.

Chris Kresser:  Right.

Raja Dhir:  And let’s hope that all of the initial journalists that wanted to cover the story find equal utility or value in enjoying the opposite results.

Chris Kresser:  Yes, let’s hope. So that’s a good transition to talking a little bit about Seed, your company.

Raja Dhir:  Yes.

More about Seed

Chris Kresser:  I mentioned this in the introduction, but I want to mention it again. Full disclosure, I’m an advisor to Seed. Raja asked me to come on board as an advisor and I happily agreed, because I believe so much in what they’re doing and how they’re doing it. I only really get involved with companies that I have either a personal experience with in terms of working with my patients or I use the products myself, or I just want to support their, I believe in their mission and I want to support what they’re doing.

That was definitely true in the case of Seed. And you’ll soon learn why when Raja explains a little bit more about what distinguishes their approach to probiotics from many other companies in the space. So why don’t you talk a little bit about that in the context of our whole discussion.

Raja Dhir:  Yeah. So, well, thank you for saying that. Of course, I’ve had so much fun interacting with you. I think that it’s rare to find somebody that goes as deep, particularly somebody who sees patients. And the first disconnect physicians or people who see and interact with people on a day-to-day basis notice is between kind of the theoretical or mechanistic science and what works in people. And so bringing those two worlds closer together, I think, is a noble task and it’s been really fun. So I think the road ahead is really nice.

But in terms of why our approach is different, I could sum it up in a couple ways. The first is we have a very … our DNA is, we’re not a traditional health company or a products company. We’re a life sciences company. Our entire approach to formulation, product development, discovery, validation of organisms is examining everything from mechanistic work all the way through, showing that the effect is present in a human population ideally and mostly in double-blind, randomized, placebo-controlled trials. So in our first product that we launched, it’s a cocktail of 24, depending on the variation, 20 or 24 strains.

Several of these strains are also in the same species, which is a nuance that is, it’s first to market because at the strain level, they have very different effects than at the species level. And oftentimes in probiotic products you’ll see something like a Lactobacillus reuteri. But there’s hundreds and hundreds of different strains with very different biological effects. And so, one fun fact that I like to tell is that some strains within the same species can have up to 70 percent genetic difference between other strains of the same species. So if that were—

Chris Kresser:  Wow, that’s notable. And I don’t think many people know that.

Raja Dhir:  Yeah. So, irrespective of our work, I would just encourage if there’s one key takeaway, it’s the importance of strain-specific studies in a human population. But we do a lot of really interesting things. So a couple of our studies are, another thing that’s really interesting is our studies look at, in otherwise the range from unhealthy to healthy population. So we try not to only look for the treatment of antibiotic-associated diarrhea, for example, but rather what are markers that we can show at a large trial that affect a large, what would be beneficial across the population at large?

And so I’ll give you an example. One of our trials was published in the Journal of Clinical Gastroenterology. It’s on two strains that are in our formulation. It was a 300-person trial with very, very significant results on a number of digestive markers. Things like intestinal transit time, bloating, flatulence, stool consistency, hydration, ease of expulsion, barrier integrity, anal itching, believe it or not, was actually one of the markers. And so we validated a lot of different areas. And then aggregate have over 20 double-blind randomized controlled trials and strains in our very first product. And that’s just our very first product. We have research tracks that are looking at really specific indications that we’ll be making announcements about it in the next 12 to 18 months.

Chris Kresser:  Yeah, that was certainly something that impressed me right from the get-go about what you’re doing. It’s Seed being in the field that I’m in and seeing how many bad products there are out there. And I subscribe to ConsumerLab and other services that do independent third-party measurements of supplements and products. And what you often find is that they don’t contain what they say they contain or they’re just based on assumptions and ideas and there’s not really any peer-reviewed data to support them. And as a clinician, I’m constantly looking for products that have actual evidence behind them that can support their use. And I was really pleased to see that you guys are quite rigorous in your approach there.

Raja Dhir:  So, I think that’s a really important point. I think mechanistically one thing that’s lost is how, again, back to our original thesis, is how can the oral ingestion of bacteria improve health without somebody being diseased? And so another assay that we developed, which is really proprietary, is an emerge from the department of genetics at Harvard Medical School. And it looked at something called the Nrf2 pathway, which is a transcription factor that is involved with detoxification. And I’m very cautious to use the term because it’s been commoditized a lot. But true detoxification is the production of glutathione s-transferase and glutathione-related antioxidant molecules that the body uses to regulate post-detoxification, which I think is very different than, I don’t know—

Chris Kresser:  Coffee enemas.

Raja Dhir:  Celery juice, I think is the newest fad. So, in this case we found, we used a model that was very specific, only looking at that pathway, and screened strains for the activation of that pathway. So we do everything from deep mechanistic work to we look at epithelial grafts to look at tight junction protein expression. All the way to, of course, human clinical trials. We have a number of additional trials kicking off this year. So I think that, at the end of the day, there’s a lot of stuff that promises to use big data or technology or diagnostics or personalized interventions. But ultimately, we see all of those the stepping stones to getting those interventions into human population and validating the effects. And so we very much took a validation-first approach in our development pipeline.

Chris Kresser:  Let’s talk a little bit about delivery mechanism. The stomach, in many ways you could say, is designed to prevent delivery of bacteria from swallowed orally to any other part of the digestive tract. So how do you overcome that with Seed?

Raja Dhir:  And rightfully so. So you would think that with the benefit of eating 100 grams of fiber a day, like some ancestral populations did, you would be expected to acquire a lot of opportunistic or purely pathogenic organisms. And so, stomach acid is a first line of defense. There’s a couple responses.

So very select organisms, but only very few, are “acid resistant” or tolerate low-acid conditions. Depending on when you, for some people they say, “Oh, well, if I take a probiotic while I eat or on a fasted condition, that affects my outcome,” all these things change and alter the stomach acid and stomach pH, levels in pH. And so there’s a lot of variability. So what we actually do is employ a system, a couple things. We employ a system which emulates the gut, all five stages of digestion. Not just stomach acid, but including bile salts and enzymes, digestive enzymes and bile salts, which actually as a form of a secondary aggressor against microbes are pretty potent to validate transit of our cocktail through the G.I. system.

And we couple that with a couple of different approaches. The first is we use an algae-derived biopolymer, which acts as kind of an eggshell crate which engulfs strains that are more vulnerable. And it basically protects them that upon exposure to pH it constricts. And then upon a change in pH to around 6.8 or so, which is what you’ll find in the small intestines, the polymers degrade. And so it’s a really elegant targeted release system. And then for other strains, there’s nothing better than a good old-fashioned acid resistant protection tool which, if done correctly, does work for pH of as low as 1.2 for as long as 45 to 60 minutes.

So I think that’s one thing that’s really lost in this. Well, there’s a couple points. So the first is a lot of people are worried about the CFU or AFU counts, which they see on their products at the time of consumption or decay over time. But if you don’t have a proper delivery system, you can see three, four, sometimes five log cell deaths upon exposure, intestinal trends. So it drastically overpowers on any other quality metric that you want to look for in a probiotic. And so, yeah, people have been really creative, trying to find workarounds looking for spore formers, looking for soil organisms. But these are all kind of proxies for—

Chris Kresser:  Or just using the brute force approach, right? Just huge, huge CFU numbers so that you figure a certain small percent would get through. Then you use as many as possible to overcome that.

Raja Dhir:  Yep.

Chris Kresser:  We could go on forever. So, we always geek out when we talk to each other. I’ve got to wrap this up pretty soon here, but I have a question that has plagued me a bit as a clinician over the years and certainly lots of our patients who are extremely sensitive to probiotics. And I have to say that I found one of the things that I have really liked about Seed is that in many cases, patients who have not been able to tolerate other probiotics have been able to tolerate Seed. So that alone has really raised my interest in it initially in terms of using it with patients. Because people who were not able to benefit from probiotics before were able to.

And yet, there still are some patients who just, they’re extremely sensitive, even to Seed. And to me, my just kind of working hypothesis is that there’s some serious microbiome disruption and they may need to just move much more slowly and start with a lower dose and build up much more slowly than somebody else. But I’m just curious if you are exploring this in your research at all, like this kind of, we can characterize as probiotic intolerance and how to overcome that so that these people can benefit from the probiotics.

What May Cause Probiotic Intolerance

Raja Dhir:  So, certainly, one of the things that is commonly reported in high-dose probiotics is immediate, visceral indigestion or digestive discomfort upon initial exposure. Nobody’s looked at this mechanistically, and it’s not because there hasn’t been interest. But it’s because it’s very hard to do real-time in vivo studies that which part in the digestive tract, or what the mechanism is for inducing that response. And particularly because there’s genetic, your genetics play a role, your immune system development plays a role, and your microbiome plays a role. So in all these things that are what we call multifactorial, it’s really hard to pinpoint one exact area. I can tell you what my leading theory is.

Chris Kresser:  Please.

Raja Dhir:  Which is that some individuals have, so microbes also work by activating, there are these microbial-associated molecular patterns or these toll-like receptors or these MAMPs, which are basically the body’s detection system. Dendritic cells go out and sample what’s passing through the lumen and come and present it to the immune system.

And so my thesis is that some individuals immunologically have a stronger response to microbial cell walls when they’re presented in the body, just as an early detection system. Or what I would call a nonspecific immune response. And so it doesn’t, it hasn’t acquired or learned that these are beneficial or tolerated organisms.

Chris Kresser:  Right.

Raja Dhir:  It would present them to a way of at least alerting the host on that whatever this food source was or whatever this environment that they’re in carries a higher microbial load. So again, it’s really hard to, there is no test that one can design to really prove that in vivo, I would say. But that’s the leading hypothesis.

Chris Kresser:  What do you think of the idea that if there are, for example, preponderance of opportunistic bacteria present and there is, the microbiome’s out of balance, that introducing healthy bacteria, which one of their functions is antibacterial, they’re competing for adhesion sites with these other bacteria. And then you get some of those unhealthy organisms, which then releases toxins. Do you think that’s a part of what’s going on here possibly?

Raja Dhir:  Yeah, it’s a very, I mean, it’s an extremely competitive environment. And the closer an organism is to a binding site or to the human body, the more pronounced you would expect the effect to be. So certainly I think bacterized productions or competitive exclusion or direct inhibition in some cases can have a microbial shift, which you can imagine that they’re likely to induce or use whatever toolkits they have to ensure their survival.

And so I would imagine in that environment, it’s not an unrealistic hypothesis to think changes or removals of pathogens could get be at play there. And the last point I’d make is just because something, we just don’t, just because something feels like it’s not tolerable doesn’t mean that it’s not good for you or doesn’t mean that it’s bad for you. So it’s kind of along the lines of what you’re saying, is some people might have early skin disruptions or systemic effects that they feel. The initial instinct would be to say, “Oh, well, this doesn’t work for me,” or “This is bad for my body because it’s resulting in a negative effect.”

But those are just all negative or bad quotes by looking through a very specific lens. I mean, in this period of flux biologically could be having a very different positive effect. And so I think that that’s a really interesting point too.

Chris Kresser:  Yeah, I look at it and sometimes explain it to patients. It’s like when you switch from a super-high-refined carb, Standard American type of diet to a whole-foods diet, there is usually an adjustment period. You hear about the low-carb flu and this kind of malaise that you experience maybe as your metabolic machinery shifts a bit. And that’s often, certainly very often the case with starting probiotics, in my experience with patients. And sometimes we’ll just have them start … We’ll have them do one every other three days on an empty stomach and experiment with taking them at different times and then just gradually build up to the recommended dose, which is three a day for maintenance for Seed.

But you and I recently had a communication where I reached out and said, “Hey, the maintenance dose for Seed is three per day. But what about my patients, some of whom are very sick and have a severely disrupted microbiome? What’s a therapeutic approach in that case?” And you had responded that certainly taking more than three a day, maybe as many as 12 a day or more in some cases, could be beneficial in those situations.

Raja Dhir:  So, the range of products that have shown therapeutic utility, product dosages range from 2 billion—actually, I should say even dead strains tyndallize your heat-killed strains all the way to 2 billion, all the way to 3.6 trillion in some high doses of VSL-3. So I heard recently of a Japanese product which had 20 trillion—

Chris Kresser:  Oh, boy.

Raja Dhir:  Which is basically more than 50 percent of the microbial load of the whole gut.

Chris Kresser:  Right.

Raja Dhir:  So again, the thesis is—

Chris Kresser:  I would be scared to give that to some of my patients, that’s for sure.

Raja Dhir:  Yeah. More does not mean better, and in a world of confusion, the simplest path to follow is follow the studies, follow the trail. Look at the dose that had therapeutic utility in a randomized controlled trial and that is the dosage that must be maintained.

Chris Kresser:  Great. Well, this has been fascinating. Like I said, I could keep going. We’ve got to wrap this up, but where could people find more about Seed and about your work. I think you’re on Twitter, if they want to follow your scientific endeavors.

Raja Dhir:  Yeah, so Seed.com. We have a wealth of information, research papers, new data. It’s kind of our, where we have art. It’s a really fun place. So I would encourage everybody to check out Seed.com first. On Instagram, we try to trojan horse science into daily life. And so our handle is just @Seed there. But we think that if people understood their biology a little bit more, that they would make more informed decisions for their health.

Chris Kresser:  Yeah.

Raja Dhir:  And so our approach is really to invest in people’s education up front and try to do it in a fun way. Not a cute way, but a fun way. And it’s really resonating, I think. Our audience is, we’ve attracted a really nice audience so far. You can find me @WildRaja. And I’m not on Twitter at the moment, but I encourage you to follow our chief scientist Dr. Gregor Reid, who actually was the chair of the UN World Health Organization panel that authored the definition of probiotics at Reid Probiotics. And also @seedhealth, you can find us on Twitter as well.

Chris Kresser:  Cool. So last question is more practical, logistical. I know you’ve been transitioning, I think, to a new encapsulation method, and there’s been some availability issues with Seed. My patients keep emailing me and asking me when they’re going to be able to get it. So what’s the latest on that? And this podcast, we’re recording here on March 25th, and it’s probably going to be a few weeks before it comes out. So probably late April is when people will actually be listening to this.

Raja Dhir:  So “current me” talking on behalf of “future me” should say at some point either today or in the next week from the dates that you just described. And indeed, we are really excited. We adopted a capsule-inside-of-a-capsule technology, which is particularly important for high-heat, and more importantly, high-humidity conditions. Most people don’t realize that oftentimes more than heat, water activity and moisture is worse for stability of probiotics than heat, in some instances. And so, we’ve suspended our probiotics-inside-of-a-liquid suspension, which wards off environmental and ambient moisture. So, revamped everything all around and very soon either, if not today from the day people are listening to this, then within the next week.

Chris Kresser:  Cool. Well, thank you, Raja. It’s been a pleasure speaking with you, as usual. And I’m really excited about what you’re doing, and we didn’t get a chance to go into some of the products that you have in the pipeline, but we’ll have you back to discuss those. Because many of those are really exciting to me as a clinician. And I’m sure a lot of our listeners are going to be interested to hear more about them.

Raja Dhir:  Absolutely. Of course, thanks for having me. Skin microbiome, vaginal microbiome, oral microbiome, all good days ahead.

Chris Kresser:  And one specifically for constipation, which has been my bugaboo as a clinician for so long. Because so many probiotics work really well for loose stool and diarrhea but in some cases can actually have the opposite effect for people who are constipated. So I can’t wait for that one to use with my patients.

Raja Dhir:  Great.

Chris Kresser:  All right.

Raja Dhir:  Thanks so much, Chris.

Chris Kresser:  Yes, take care.

Raja Dhir:  It’s a blast.

Chris Kresser:  Have a great week.

Raja Dhir:  All right, see you.

Chris Kresser:  Bye.