Planting the Seed for a Stronger Microbiome, with Raja Dhir

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In this episode, we discuss:

• The relationship between the microbiome and COVID-19
• Probiotic interventions with COVID-19 and other inflammatory infections
• The gut–heart axis and cholesterol
• The gut–brain axis and depression
• Why Seed is different from other probiotics on the market
• New research on probiotics and IBS
• New research on probiotics and the pediatric population

Show notes:

Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, I’m excited to welcome back as my guest, Raja Dhir, who is the co-founder and co-CEO of Seed Health, a microbial sciences company pioneering applications of microbes to impact human and planetary health. Raja [has] a wealth of knowledge on all things microbiome. And today, I’m going to talk to him about the relationship between the microbiome and COVID[-19], because there’s some interesting new research out on that, as well as some updates on [the] microbiome, probiotics, IBS, the gut–brain axis, particularly with a specific focus on depression and the gut–heart axis. So let’s dive in.

Chris Kresser:  It’s a pleasure to have you back on the show.

Raja Dhir:  Great to be here, Chris.

Chris Kresser:  So I wanted to dive into some recent research that was published on the role of the microbiome or the proposed role, perhaps we should say, and in COVID-19, both in terms of how changes to the microbiome perhaps may make certain individuals more or less susceptible to COVID-19 and also the role that the SARS-CoV-2 virus has or the impact that it has on the microbiome. And according to one paper, the proposal is that SARS could adversely affect the microbiome in a way that may actually contribute to long COVID for the subset of patients that are developing long-term symptoms even after the virus has been cleared. This one paper at least proposed the idea that one potential cause of that is the disruption of the microbiome that’s caused by the virus itself. So it seems that there may be a bidirectional relationship here. And as someone who studies the microbiome pretty much on a daily basis, I’m sure that’s not a surprise to you, given what was already known about the relationship between viral infections and the microbiome.

Raja Dhir:  Yeah, I think it would be helpful to start a little bit with some background, which is the gastrointestinal tract and the lungs are both body compartments that host microbiota or microorganisms. The lung is much smaller and it’s much smaller in terms of absolute count when compared to that of the gut. The gut’s the largest reservoir of microbes in the body. And really, the evidence is accumulating, even before SARS-CoV-2 emergence, that there’s bidirectional communication between the gut and the lung. And this is referred to and called the gut–lung axis. And so this crosstalk is involved in immune homeostasis and inflammatory cascades. And it’s believed that gastrointestinal inflammation can result in lung inflammation through this connection. So the mechanism underlying this inflammatory shift from the gut to the lung is not completely clear yet. However, we think that dysbiosis of gut and lung microbiota is definitely one of the factors that play into this crosstalk. A lot of talk is going on back and forth, particularly in more academic circles, trying to pinpoint exactly what is the nature of this cascade? Is it that SARS-CoV-2 infects the host and that then changes the gut microbiome or is it that the gut microbiome increases the risk of severity when an individual gets SARS-CoV-2 and drives the severity of their outcomes? And I want to focus on this one part because this [is] what’s called like the chicken or the egg, or at Seed, we joke and call it the bacteria or the archaea, but it’s really not clear. And it also reveals one of the biggest limitations of the most recent study that came out, which we can jump into right now, which is we don’t have samples of these individuals prior to them getting SARS-CoV-2. And so that’s the critical little bit of information that you want to say, well, what’s really driving this outcome?

If you look at this study, [which] was published in BMJ a couple of weeks ago, it looked at stool samples from 27 hospitalized COVID[-19] patients. And the finding was that the bacteria in their gut seemed to influence the severity of the COVID[-19] cases. And this builds on two other studies that have come out over the past 12 months with a similar theme. One was in a clinical infectious diseases journal, and it found that the microbiome in people with COVID[-19] was different. Then another one, in about 15 or so people, saw a lot of changes in the gut bacteria during hospitalization compared to non-COVID[-19] controls. And this is just the gut microbiota, not anything else. So the small sample size, the fact that we don’t have information before they got the infection, and, importantly for me, the fact that none of these studies really excluded people who’d previously been on antibiotics or any other types of conditions, which we know play a really big [role] and have a long duration in the effect that they have on the diversity of your gut microbiome. So I do want to say at least that the associations are there and we know enough about the gut–lung axis at large to say that it’s certainly possible that [the] gut microbiome drives [the] severity of the outcomes. I believe it does for reasons for [the] very distinct mechanism, reasons we can get into afterward. But it’s not that these new studies that have come out are somehow a smoking gun in that they’ve identified something beyond just the same types of studies that we’ve seen over the past year.

Chris Kresser:  Yeah, it reminds me a little bit of the vitamin D and COVID[-19] connection, although there’s an advantage with the vitamin D research because researchers have been able to find data sets where people [had] a serum 25(OH)D measurement done prior to getting COVID[-19] often within the last three months. And then they can prospectively study what happens to those people based on their vitamin D level prior to getting COVID[-19], because there is some evidence that suggests that the SARS infection may actually suppress [vitamin] D levels. So it’s a similar question there of, is it a chicken or egg or bacteria or archaea. But the advantage with the vitamin D research is that they’re actually data sets where you can get that measurement prior to the patient becoming infected.

Raja Dhir:  And then the other thing is people latch on to community dynamics. In other words, which bacteria you can find because taxonomically, it’s very attractive. And all I mean by that is you can do co-aggregated, you can map through [permutational multivariate analysis of variance (PERMANOVA)] and see the way the microbiome changes, and you can get species and strain level resolution. And from a data perspective, it’s really attractive because you have so much data and when you have that much hay, you can make your own needles. So it’s very easy to find these types of taxonomic changes. But I want to give [the] same stump speech that I always give, which is the presence of a single or individual species is no indication of its function exclusively across the whole population, so different bacteria can do the same thing in different people. And so this kind of species-level obsession, I think, is more of a flaw of what drives good and novel paper publication rather than what drives for a real deep understanding of what’s happening now. That’s not to say that there aren’t biomarkers that we should use, and in the future, we’re not going to—we’re going to look back even as soon as two years and laugh that we looked at single species biomarkers as a way to understand what’s happening in the gut, right? Even in some of these more complex, major depressive disorder studies, they’re now starting to build more complex panels that include the presence or absence of a metabolite and the presence or absence of a bacteriophage. Then finally, when you stack on the presence or absence of one organism of a particular class, then you can start to get really, really high predictive power in things like cancer and depression. And you start to get a lot more resolution. But the problem is very few data sets have that integrated level of data that you can start to build those more complex panels with. So what I think is going to happen with SARS-CoV-2 is we’re going to see that a combination of blood, serum data, cytokine, and gut metabolome, and maybe a little bit [of] gut species are going to drive that some predictive value. But it’s not just going to be predictive for SARS-CoV-2. It’ll probably also be predictive of [the] severity of other viral infections.

Chris Kresser:  Absolutely. My take on this is [that] it’s not just related to the publication of scientific papers. It’s actually more of a philosophical bias that exists in the way that we approach health and disease and study it. It turns up in nutrition a lot, too. There’s a food philosopher named Gyorgy Scrinis who coined the term “nutritionism,” which refers to the reductive understanding of nutrients [as] the key indicators of healthy food. So this has been our obsessive focus on individual nutrients, whether you’re talking about macronutrients like saturated fat or cholesterol or whether you’re talking about micronutrients like vitamins and minerals. And his argument has been that this ideology has really narrowed and in many cases distorted our appreciation of food quality, which is a much more meta concept, right? We study and pay attention to nutrients in isolation without considering the context that they’re delivered in. Is saturated fat going to have—if two people are following a diet with identical levels of saturated fat, but one person is consuming that saturated fat in the context of French fries and donuts and lots of processed and refined food, and the other person’s consuming that saturated fat in the context of [a] healthy, whole-foods diet, I think most people would intuitively suspect that that’s not going to have the same impact. But the way that science has been done on this, on nutrition, does assume that it will have the same impact. And [now] I’m starting to see trials that are being designed with this in mind. In fact, I know there’s a [randomized controlled trial] that’s being designed now that’s explicitly going to look at the role of saturated fat in a Standard American Diet versus a whole-foods diet. So I’m curious if you think that’s playing a role, too, in how microbiome research has been done thus far.

Raja Dhir:  And it’s so challenging to get good, clean samples both in microbiome studies as well as diet studies. Most often, people rely on retrospective analysis. I think that really is what drives it. If you could recruit 100 people and get to that level of clustering and granularity in the type of saturated fat or the diet that corresponds to the presence of saturated fat, then I don’t think that there is some inherent desire to brush good research under the rug necessarily, but it’s just so hard that usually, what’s available is you look at everything that you can test for, you look at everything you can analyze, and you try to see what patterns emerge, and sometimes the patterns emerge with so many other factors being different. And then that starts to create a very skewed narrative. So I don’t think it’s malice per se, but it’s definitely a huge limitation in the ability to study the role of diet in any complex multifactorial system, whether it’s [the] intake of food or whether it’s the microbial composition within the gut. And you just see this in these complex communities. One thing that will really help is a focus on functionality and obsession on [the] mechanism, and I think that the ability to–getting a nature paper because you identified a species that’s present or absent in some areas, is at times also, even in microbiome, kind of coming to an end.

Chris Kresser:  Yeah, I agree. It’s multifactorial, as it often is. It’s usually not just one cause, but I think there are encouraging signs that we’re shifting that model and, hopefully, there’ll be more funding available for those kinds of studies, because, as you pointed out, they are more intensive to perform and require a level of effort and investigation that’’ not always easy or possible. So let’s move on.

What do high cholesterol, depression, IBS, and COVID-19 have in common? They are all health conditions that are uniquely related to our microbiome. In this episode of RHR, we welcome Raja Dhir back onto the show to share new research in the world of probiotics. #chriskresser #probiotics #seedhealth

Raja Dhir:  But just quickly to close [the loop] on SARS-CoV-2. That one real example of how I think it can drive bad policy-making and drive bad medical outcomes is when let’s just take—everyone that follows SARS-CoV-2 has probably heard of this term “cytokine storm” by now. And it’s this idea that, partially driven through the gut microbiome, the inflammatory cascade or the way that your body responds by mounting an inflammatory response is determined by the gut microbiome, and inflammatory and cytokine storm or inflammatory cascade is really just this massive production of [tumor necrosis factor-alpha], interleukin 8 (IL-8), [and] interferon-gamma [IFN-gamma]. The whole cluster of what you’re looking for that then causes scorched earth cells and then a further cascade that causes a destruction of tissue and multiorgan system failure. But if you assume—if you go too quickly and run with this, then a lot of—a really nice article came out in JAMA that was titled, “Is a ‘Cytokine Storm’ Relevant to COVID-19?” And it’s not that there isn’t an elevation of cytokines, but when you look at SARS-CoV-2 patients that have elevated cytokines and compare it to the middle of the curve and people that have ARDS, which is the condition that SARS-CoV-2 leads to that actually results in 50 to 60 percent mortality, it’s acute respiratory distress syndrome, it’s still much lower. And in some instances, it’s like 1 percent to 10 percent of the cytokine levels that you would see in median cases in previous viral infections resulting in acute respiratory distress. So what that means is that, yes, cytokines are elevated compared to healthy controls or even compared to people that recover quickly. But is it too early to say that we should be using drugs that block healthy cytokine response in the treatment of it? Or is that just kicking the can down the road and increasing your risk of reinfection or blocking the ability of the system to effectively induce an inflammatory response?

And the immune system, and it’s what makes immunology so challenging, is so delicate and balanced that when you move too far on one side, you pull from the other. So it’s very hard to say. But as a cautionary tale, I want to say those approaches that except in very severe cases might be too extreme. But what makes microbiota intervention attractive is it has this element of homeostasis, where things like dendritic cells that play a very key role in immune homeostasis, by the way, in healthy intestines, they present antigens, and then they have a dependent response regulating proinflammatory or anti-inflammatory phenotypes. And so it’s that calibration, that regulation that the microbiome has, which makes it attractive compared to other typical pharmacological interventions where the stimulation can be responsive based on other factors that are occurring in the body. I think it’s definitely too soon to say, “well, is probiotic or prebiotic or dietary or targeting the gut microbiota modulation something [that] is going to reduce the severity of SARS-CoV-2 infection?” But we know that the gut microbiota drives dendritic cells to prime these cells. We know that it stimulates IFN-gamma production. We know that it can regulate proinflammatory Th1 cells. And with all that information in mind, especially with previous studies that show that respiratory tract infections can be mitigated through the type of whether it’s [immunoglobulin A] secretion or whether it’s boosting [inaudible] or neutrophils, or—there’s a number of different mechanisms that oral consumption of bacteria or modulating the gut microbiome can have very, very validated effects on regulating viral or respiratory infections. So I know that the connection, the link, is there. And people are going to be looking for a simple answer to this. But I think that the most I can say right now is consideration of the gut microbiome and the gut, kind of like the host microbe barrier is something [that] I wouldn’t discount. I think we’re going to find that it does play a big role in again, not just this infection, but other viral inflammatory infections.

Chris Kresser:  Yeah, I appreciate your clarity there. And I’ll reiterate that we don’t have any direct evidence yet with probiotic interventions and COVID[-19]. But there are quite a few lines of evidence from prior research with other viruses, for example, bifidobacteria and lactobacilli, studies have shown some beneficial effects against influenza. There [are] studies that have shown that probiotic consumption improves type 1 interferons, antigen presenting cells, natural killer cells, T and B cells in the lungs’ immune system. As you pointed out, probiotics have been shown to improve pro- and anti-inflammatory cytokine balance helping to clear viral infection from the lungs. We also have interesting research on the nasal microbiome, which is how you and I connected in the first place, right, geeking out about that and Susan Lynch’s work showing how re-inoculation of the nasal microbiome can help reduce chronic sinusitis. So there are a lot of interesting lines of research. And for me, I’m just curious. I think we should be exploring these because it seems to me that the benefits pretty far outweigh the consequences of this kind of exploration. You see lots of studies and stuff published in the media about drugs and interventions that are being explored for COVID[-19], rightfully so. Some of those have potential significant downsides. And they’re also very expensive and maybe not even accessible for a lot of people. And then you have an intervention here with probiotics that could be deployed on a pretty broad scale. As far as we know, they’re not significant. It seems less likely and we don’t know this for sure, but it seems less likely that there would be any adverse reactions or significant downside. But it’s a little bit frustrating that often, these nutritional interventions are typically seen as sort of second or third order and not worth exploring to the extent that some of the other interventions are being explored.

Raja Dhir:  I don’t blame mainstream science for blocking nutritional and secondary interventions, or at least having a very high evidence threshold before it’s accepted, just because there [are] so many bad actors that take advantage of—you really have to watch—like, yes, I would love to have a nuanced discussion about why the AstraZeneca vaccine at a certain dose is only 60 percent effective, whereas at half a dose was 90% effective. But the problem is when you open up those gates, then it seeds the doubt for naysayers and conspiratorial theories to say, “Well, so you’re saying that vaccines could be dangerous?” And it’s like, “No, we’re saying that the dosage is very important in driving—more work needs to be done in establishing dose response to efficacy,” right? So I think that there’s this—and we could go as philosophical as you want on this, which is, I think, what got us here in such a polarized place, which is one side tries to over, kind of treat the other side, like withhold information that might allow for conspiracies to take hold. And in doing so, they actually seed and feed the very conspiratorial fire that drives the other side to believe that information is being withheld from them. And it’s because people don’t have attention spans and people don’t want to have a discussion and understand that the answer is often, it could be both. And that’s why these therapies aren’t looked at because the minute that—there was a report in [the] American Society for Microbiology titled, “Do an Altered Gut Microbiota and an Associated Leaky Gut Affect COVID-19 Severity”? And that is just a very, very interesting and deep scientific exploration of how intestinal permeability, which we know that diet, probiotics, and other interventions can definitely affect. We know that it can affect the severity of COVID-19 infection. And then another one that was in the NPJ Science of Food, which is a nature journal, which is a very nice review on “The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19”. And these are pretty balanced and high-impact journals and very clear and informative publications. But the minute that that then becomes a recommendation is the minute that you start to see companies taking ads out, positioning their product as immune-boosting. Just walking down the street here, I see juice shops talking about the antiviral activity of their juices. And so I think that both sides need to kind of—but both sides are to blame, actually. I think one side is a little bit less specific, to put it kindly, than the other. But yeah, both people need to just get their head out of their ass and say, “Are we going to have a discussion? Are we going to get into this and have a discussion about it? Or do we have to continue vacillating between these two extremes and shutting everything down that’s in the middle because of fear that someone’s going to take it and run with it and commercialize something fraudulently?” And I don’t really have a good answer for that.

Chris Kresser:  Unfortunately, that polarized dynamic is not just occurring in one field, science and medicine. It’s pretty much the nature of our reality at this moment in time. And that’s a whole other podcast. But let’s talk a little bit about the gut–heart axis, some research updates there, because that is relevant to COVID[-19]. And then we can use that as a bridge to talk about some of the IBS work and other exciting stuff that’s happening in probiotic research.

Raja Dhir:  Absolutely. So a new paper came out in Cell Host & Microbe, “Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level”. It was by a group at Mass General and Harvard. It was the senior author, I believe was Ramnik Xavier, and this was a really interesting paper because cholesterols—just to start a little bit on the story of cholesterol and what that really means. And a lot of your listeners are part of that saturated fat camp that says, “Well, it kind of matters. Dietary cholesterol, doesn’t it matter where it comes from, what are the other features of it, is it single-handedly an enemy or is it just an actor, is it the density of the cholesterol?” [There are] so many other factors to this that others before me have spoken about really well, like Peter Attia, for example. And cholesterol has kind of [risen] from this obscure component in gallstone to a main household word was really a defining story of the 20th century. And we first started with the fact that there were genes and this is a good, high-level analysis of how [the] microbiome and the human genome really play, right? We looked at genes in the host that were varied across the population and that drove both the synthesis and reabsorption of cholesterol. So cholesterol [is] synthesized by your body and then it goes luminal and then it’s reabsorbed back up by your intestines and goes back into circulation. And the biggest blockbuster drug in history works in modulating this human genome pathway and that’s statins, to keep cholesterol low. But cholesterol-lowering drugs explain how pharmacology can lower cholesterol, but not really how pharmacology can lower cholesterol to reduce death. And it’s that last part that’s really important because there’s so much human genetic variability. And today, it doesn’t really adequately explain these differences that are observed between people and complex processes like cholesterol metabolism.

But we’re starting to see that in the human gut microbiome. We can explain some of these clinical observations with a lot more sophistication. We know that the gut microbiome metabolizes drugs. We know it tunes the immune system. We know that it influences nutritional imbalances. It produces neurotransmitters. The connection between heart disease and the human gut microbiota was a really early, big success story for the role of the gut microbiome in these organ systems across the body. And to this point, cholesterol has not yet been directly linked to specific microbes or enzymes or functionalities in the gut microbiome until this paper. So what this paper did was show that basically, gut microbes convert cholesterol into a secondary or tertiary metabolite called coprostanol. And coprostanol, interestingly enough, is uniquely made by human gut microbes. In fact, people actually developed an assay to look for coprostanol to see if there’s contamination in the environment from human sewer systems because if you find it, it means that human gut organism metabolism is present wherever you’re looking. And this step happens in soil a little bit differently than it happens in the human gut, and in the human gut, what happens is specific bacteria now convert cholesterol into coprostanol and, therefore, they lower the total circulating cholesterol load, in consequence, the amount that can get oxidized. And we believe, in consequence, the amount that can drive acute cardiovascular or vascular outcomes associated with oxidized cholesterol and [low-density lipoprotein] and [very-low-density lipoprotein].

What this paper really shows is a mechanism by which certain organisms convert that circulating luminal cholesterol that’s just floating through every time you eat food, it’s released and it’s floating through your digestive system and then it’s reabsorbed back up. But this is involved in the conversion of that. And I think that’s really important because the use of modulating the microbiome in the future for people that have a genetic predisposition to produce high cholesterol or get high dietary cholesterol, these things can help mitigate and keep those levels down because you’re siphoning some of it off through the production from cholesterol to coprostanol.

Chris Kresser:  That’s fascinating. And of course, it’s highly relevant because heart disease is still the number one killer in the [United States]. And now we have COVID-19, which affects the heart. And anything that makes the heart or the cardiovascular system more susceptible is something that we should definitely be paying attention to. I know there’s also been some new interesting work [about the gut–brain axis]. We talked about the gut–brain axis on the previous show. I’ve talked about it probably at least 15 or 20 times on the podcast with various guests. It’s one of my favorite topics. And I know that there’s been some new interesting research there, as well, particularly related to how the gut–brain axis may contribute to major depressive disorder.

Raja Dhir:  Yeah, absolutely. So I alluded to this earlier when [we were] talking about SARS-CoV-2, but this was a study that looked at over 200 people. And it builds on this—just to bring everyone up to speed. The study that we spoke about last time at the time had just come out in Nature Microbiology, and it was done with the Flemish cohort in Belgium. And Jeroen Raes was the senior author on the paper. In this paper, they found that first, it was the observation that hundreds of neuroactive metabolites are made by the gut microbiome. And this isn’t just like your hallmark GABA production, but a whole cluster of never before really characterized neuroactive metabolites that have systemic effects and that cross the blood–brain barrier. And so what was found is that in this cohort of people that had major depressive disorder and were unmedicated, two organisms that were responsible for driving a lot of this neuroactive metabolite production were consistently missing or were deficient in those patients compared to healthy controls or people that were not diagnosed with major depressive disorder. And I think it was because Coprococcus and Dialister, those were the two organisms.

This is really interesting because it’s actually one question that we get so much from customers, from patients, from investors is around this idea of personalization, and in answering this question, I want to weave in a little bit of a refresher or a response to this personalization story. And I’m sure everyone is getting hit up left and right with a two- or three-part story, which is act one is everyone’s microbiome is different. It’s as unique to you as your fingerprint, which is true. Second is we have a test that can find out exactly how unique and different and special your microbiome is. Okay, awesome. With you so far. The sleight of hand is that third little act where they then come in and say, therefore, you need personalized probiotics, or personalized dietary treatment, or recommendations to fix these problems that are personalized and distinct to you. And that’s the sleight of hand, right? The first two are fine, but it’s that third part where you have to ask a little bit closer and say, “Okay, so what are you basing your intervention on? But what about my microbiome are you basing your intervention on? Would someone who does not have my microbiome also benefit from the same intervention? And have you tested this with a control to see if this is effective?” And I haven’t found a single group that can answer that question for more than one out of those three other than the one group in Israel that’s doing it so responsibly because they’re looking at glucose metabolism, [and] they’re looking at insulin resistance. And so they have a very specific endpoint, right? It’s not like this is you and your microbiome and this is what you need to be healthy. It’s saying these are the foods that probably will spike your blood sugar more based on the organisms that you have in your gut. That, by the way, we validated in an 800-person trial [that] we published in Nature.

And so those are two very different studies, and that’s insulin. But to bring this back now to the gut–brain axis, this study that came out recently in Science Advances is going to start to give us that level of visibility for major depressive disorder when it comes to [the] gut–brain axis and not on the intervention side. Again, we’re very far from that, but at least act one and act two, we’re now going to get that visibility. And so they looked at all these people. They did the classic people that were depressed, had more Bacteroides and had less new bacterium. They did the species thing. That’s where everyone else leaves it. Then they went and said that disturbance of amino acid metabolism from the metabolome is a hallmark in the gut ecosystem of major depressive disorder. So now we have this whole panel of amino acid metabolism that leads us to say when this is dysregulated and it can be dysregulated in different ways in different people, but when there is a dysregulation of amino acid metabolism, there’s a very high predictive value that there’s going to be something that distinguishes people with major depressive disorder from healthy controls. And they put together a combinatorial marker panel that looks at the microbes, it looks at the metabolites, and it looks at a couple features on the host side, biomarkers circulating in blood. And they developed something that can actually predict major depressive disorder in 80 to 90 percent of cases just by looking at this composite panel together. And I always say, if you want a diagnostic or personalized company to be legitimate or technology to be legitimate, is, “can it be predictive,” right?

Another good example of it being predictive is a scientist that we collaborate with a lot, Chris Mason who’s at the Cornell School of Medicine, Weill Cornell School of Medicine. He published a big paper on IBS and found a gut-derived biomarker for IBS that has that final test. It is predicted. If you have this biomarker in this panel that they developed in a certain way, they can blindly send you 10 samples, five of them have IBS and probably [in] 4.8 of them, they’ll be able to predict someone has IBS just based on that sample. And until we get there, everyone else is just playing. And so this is really cool because it was nice to see that kind of evolution toward functionality, toward combinatorial biomarker panels that are put together toward predictive values, all the things that we really like to see in high-quality science that separates it from the rest of that noise, which is just another large, observational paper that [is] really like looking for tea leaves. And then they come up with something and they publish it and then they never talk about it again.

Chris Kresser:  Yeah. I’m encouraged by the quality of the research that’s being done in these areas. And speaking of that, let’s talk a little bit about some of the research that you have done and are doing. Let’s start with the simulator of [the] human intestinal microbiome ecosystem (SHIME). Or do you folks in the scientific community pronounce that [scheem?] or SHIME for a short time?

Raja Dhir:  SHIME.

Chris Kresser:  SHIME. Yeah. So tell us a little bit about what this is first and then how you’re employing it for the daily symbiotic and other probiotic interventions that you’re considering.

Raja Dhir:  Yeah, well as you know, we developed a symbiotic formulation, which is a broad spectrum symbiotic. It has 24 distinct strains of bacteria across 12 species. And very much by design, the purpose here was to say, what are these features that you’re really looking for or that are often dysregulated across a range of use cases that can have a rescue effect when you introduce a consortia like this into the gut or when you consume or administer orally this type of a microbial consortia or cocktail. And so, as part of that exploration, we’re pretty incessant about interrogating the effect of it in very different systems, in human systems, in simulator systems where there [are] limitations in human systems, you can get a little bit more immediacy, a little bit more granularity. You can actually look at it in response to different challenges. And then also kind of genomically, right? Mining the genomes of these organisms and others in our strain bank to say, well, what are these doing? Very similar to the Enzyte, the genes that are responsible for encoding the enzyme in the cardiovascular or the cholesterol study we spoke about earlier. And so we’re always interrogating this and other strands in our bank for these types of features. And some interesting new data just came back where we tested DS-01, which is this daily symbiotic consortia, the product that we’ve developed and we wanted to answer two questions: the first is everyone, when they talk about probiotics, talks about survivability. For the most part, you want the organisms to be alive and metabolically active to get the majority or to maximize the biological effect that these probiotic organisms can have. You don’t want dead bacteria. An entire industry has been spawned about soil organisms and spore-forming organisms and acid-resistant technologies that just try to speak to a lay consumer and say, “Well, just trust us. This survives really well.” But then when you ask them for the data or for the publication, they don’t have anything, right? They just rely on generic features of the nature of spore formers to make that claim.

What we wanted to do is very effectively validate. And why we wanted to validate it is because it took us two years to develop a two-capsule system with varying density polymers so that you have a precision release of the bacteria on the upper small intestines where most of the immune system is. And so you have the opportunity for these organisms to be biologically relevant and in engagement with most of the immune cells before they just dump into the colon. This kind of took a lot of time, a lot of R&D, a lot of effort to develop this. We screened and compared this against—I don’t want to get ourselves in trouble, so I’ll just say the number one in air quotes, gastroenterologist- or doctor-recommended probiotic today. It’s available at all of your supermarket stores and it’s a 100-plus million dollar franchise a year and makes a lot of these same claims. And we started to test against that. And by the way, if you want to see exactly what it is, you can go look. We do disclose all of the products we screened against in our patent filing. That’s a workaround to find out exactly all the products that we tested it against.

But I can’t explain how ridiculous it is that this product has 100 percent survivability, not 98 percent, but 100 percent survivability in triplicate that’s being tested that we’ve developed. And when you compare that against this product, which has less than 10 percent survivability and less than one billion organisms that even begin to start with it. And so I can say, based on this model, with a lot of confidence, that there’s very few, if any, organisms that are metabolically active when somebody buys this product and you just hate to see that because if you just said, we don’t know if this organism is surviving when a company sold their product, that would be one thing. But there’s this whole industry that overstates survivability. Voluntarily, they say survivability is a feature, and actually, it’s a bug. And so we then tested this out against 16 of the next largest, both medical and commercial probiotics that are available. And these are ones that you typically find prescribed by practitioners, including even the very big medical probiotics, like VSL#3. We went up and not a single probiotic in any of their current delivery systems or formats delivered absolutely more than 50 percent of the starting dose, not a single one. So look, maybe something comes out that actually, the organisms don’t have to be alive and full in the future to do it. But part of I think what you see this pissing contest of how big your [colony-forming unit] (CFU) count is is it really doesn’t matter because bacteria die logarithmically, right? So if you start with one trillion, but you have a two-log die-off, that’s kind of the same as a 10 billion CFU dose that has 100 percent. And so it’s really important. And look, I don’t want to overstate. Take that language, take that for what it is, because this assay that we tested was purely just survivability. So I don’t want to overstate and say, therefore, everything else is shit. But I can say with definition that the viability of active cells is not present in greater than 50 percent on any of the commercially or medically available probiotics that we tested. And we spent the money to test them because they wouldn’t do it themselves. So we just said, let’s just actually test everything head to head. And that part at least, if anything else, I just want this to be a call to action for people to start publishing their data if it is conflicting with the data that we’ve generated because we just took products off the shelf and did it at every single stage and tested these things.

What we can represent is that the delivery system that we have does actually deliver a precision small intestinal payload of 100 percent of the organisms by the middle of the small intestines in our product and we don’t see that [in] any other products that we’ve tested. [Those data were] really interesting. And by the way, we tested a ton. Again, I’m not going to mention anything by name, but a very, very popular, several popular spore-forming bacteria that are extremely big in the practitioner network. And that one actually had less than 5 percent survivability despite having spores. And so maybe they go dormant for a very long time before they become active. But at least in this model system, there was no activity that was detectable.

Chris Kresser:  Yeah, and [I] talked about this on our first show and I’ve written and spoken about this a lot as a clinician, that this has all been very obvious to me just in using the product. So many patients that I’ve had either had no response to other probiotics or they had a negative response. And with Seed and the daily synbiotic, it’s just number one, been so much more effective, and number two, so much better tolerated. So it’s not surprising to hear that. But it’s awesome that you have done that research. I do have a hard stop in about 13 minutes. So let’s definitely cover the [Investigational New Drug] (IND) status for the Daily Symbiotic for IBS. And then let’s talk a little bit about pediatric[s] and what your plans are there, because I’m, as you know, super, super interested in that. And this is maybe a good spot for full disclosure here. I mentioned this last time, but I am an advisory board member of Seed because I believe so much in what they’re doing and how they’re approaching the creation of these interventions with a very, very solid evidence base, as I’m sure you’ve gathered by listening to this show. But tell us a little bit more about IND for IBS and pediatric[s].

Raja Dhir:  And just to blaze through these last parts then. The SHIME system was also tested on the Daily Symbiotic after both ethanol, so alcohol consumption. We used vodka in the experiment, as well as a high dose of antibiotics, and that paper is going to be submitted next week. So maybe in the next few months, depending on reviewers, we saw a very, very nice recovery shift, a butyrate rescue that was higher than even the individuals before taking antibiotics, their naive microbiota when it was transplanted into the system. And so that’s something, which now that the paper is finished for submission, we can speak about.

Raja Dhir:  So regarding IBS, where to start on this one? The [U.S. Food and Drug Administration] (FDA) asks you to file an IND application, which is called an investigational new drug application, which is basically for anything to be FDA approved, you have to file that and then go through phase trials under the oversight of the agency. They ask for this if you ever want to test your product and even if it’s not intended to make prevention or treatment of disease claims, if you want to test this in a patient population that has a defined condition and if you want to assess recovery outcomes. And so that was almost a year[long] process of putting paperwork together, back-and-forth and communicating with them. This trial is being done at the teaching hospital, Beth Israel [Deaconess Medical Center], [a] teaching hospital at Harvard Medical School and in a patient population with IBS, type C and type M.

And we announced a couple of months ago that we got that authorization, the acceptance of that authorization, and are halfway through recruiting for this trial. So a small plug if you have IBS and you’re in the greater Boston or Cambridge area and you’d love to participate in this trial, we’re still recruiting. Please reach out to the team at Beth Israel hospital. We’d love to have you in this trial. And we’re really excited, partially because how compelling—the thing with IBS is that there’s such a psychosomatic component to it. And I don’t mean that in a way [of] saying that it’s contrived, but just that there is such a bidirectional relationship between stress, the gut–brain axis, and all these other factors and the severity of these conditions that are also broadly defined, like IBS and response rates, and particularly when people are really excited about a new intervention and they can get it and feel temporary improvement. The problem with IBS trials is that the placebo responder rate is so high. In some instances, it’s over 40 percent or 50 percent, which is higher than what you would find in many pharmacological interventions for IBS or for IBD. And so it’s made studying these really, really challenging. So this is a really, really nice trial where we hope to beat that placebo responder rate and with an efficacy rate that’s even a lot higher and have some screening techniques that allow us to get much cleaner data. And so that trial is underway. And IBS affects a lot of people in the United States. And even if it’s not for resolution of the disease, but small things like symptomatic improvements in quality of life that we hope to obtain from this, at the very least, we just hope to say this is when things like the reports, like those from the American Gastroenterological Association come out and say that you need to test your products in a patient population to make sure that it’s well tolerated before even recommending them as nutritional inputs. We just hope to follow suit in those types of calls to action and engage with the regulatory bodies instead of hide from them and hope to set an example and encourage other companies to do the same, which is if you want to make claims on IBS, which you should never do it as another probiotic company or you have to go through the process and you have to study it and you have to have data to be able to provide it to physicians and practitioners and clinicians to say that this is well tolerated and the microbiota remain stable. And maybe if there are improvements in symptoms, then you can report those are secondary endpoints. But at least to just back up that this is going to be something that’s safe to go into that targeted population. So that’s what’s going on with IBS. We hope that we’ll get that publication out this year.

Raja Dhir:  And kind of a sneak preview on our next big launch. Right now, it’s just open to insiders and current users only is our pediatric product. And this was very much driven by the same methodology that we had in the development of DS-01, which is the cultivation of a strain bank and the development of strains that had really strong mechanistic and clinical data that drove them and improvements in the delivery technology and the ability to deliver that payload where it needs to go with the use of delivery technologies or microencapsulation systems, which is what we’re using in this product. And lastly, is just a very clear evidence base that is applicable across a wide range of indications in a pediatric population. And so here we’re looking already at established strain-specific, pediatric-specific outcomes, and in the gut–skin axis and particularly dermatitis and eczema symptoms in children. And this just patchiness and the modulation of the gut–skin axis in that. [There is also] a new study, which is under review and, hopefully, will be published soon and in Frontiers in Pediatrics, which were two strains that are in our strain bank and this product that were in a 400-person plus trial looking at airway allergy and asthmatic response and severity of asthmatic response in a pediatric population and a significant reduction in asthmatic events in the intervention group, the group that got the probiotic, compared to a control, which just got the placebo. And so this is everything you want to see. It’s a very large-scale trial. It’s an interventional study. It’s randomized and controlled. It’s multicentered insight. And it’s going out for peer review. It’s going to be published prior to the launch of this product.

And so really kind of starting to piece together these other areas, or these very interesting use cases of probiotics in a specific and defined population. And the last is that we have our own trial on the formulation—a new trial, I should say, on constipation in children and modulation of the gut microbiome in children, particularly in children that [take] a long time in the bathroom, slow intestinal transit time, less than four bowel movements per week, poor stool consistency, and a whole panel of digestive and gastrointestinal mediated outcomes in children. So far, that trial is going really well, too. So [it’s] very, very exciting to bring that same level of rigor to a pediatric population with pediatric-specific studies. And I think it’s really important, particularly when parents look to make decisions for their children. I think that having that evidence base and having that established beforehand is something [that] is really important to parents. And so I hope it’s very effective and it’s able to be helpful for a lot of parents and their children.

Chris Kresser:  I agree 100 percent. Raja, thanks so much for joining us again. If you’d like to try Seed, you can go to Kresser.co/seed to check it out. And Raja, just kudos for all the phenomenal work you all are doing. It’s really exciting to see the rigor with which you’re approaching the research and refreshing as a clinician who’s been in this space for some time and seen so many of the claims that are made that are really just unsubstantiated. So it’s really refreshing to have a company that we can depend on that’s doing this really rigorous research to ensure the quality and reliability of their products. [It’s] always fun to just geek out with you and talk about the science. And I know we have a lot of listeners that appreciate that, as well. We’ll definitely have you back on again in the future to talk about what’s new. Thanks again for joining us.

Raja Dhir:  Always a pleasure. Thanks so much, Chris.

Chris Kresser:  All right, everybody, thanks for listening. Keep sending your questions to ChrisKresser.com/podcastquestion. Take care, everybody.

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