RHR: How to Protect Our Kids’ Microbiome, with Raja Dhir

In this episode, we discuss:

• The state of the pediatric microbiome
• Behavior and lifestyle factors that influence the microbiome
• The research behind Seed Health’s new pediatric synbiotic, PDS-08

Show notes:

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Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, I’m really excited to welcome back Raja Dhir as my guest. He is the co-founder and co-CEO of Seed Health, which is a microbial sciences company that [has] pioneered applications of microbes to impact human health.

Raja is extremely knowledgeable on the microbiome and [on] using probiotics and prebiotics to modulate the microbiome. He’s been a guest on the show a few times, and for this particular show, we’re going to talk about [the] pediatric microbiome. This is a really underserved area. It’s an area that I’m excited about as a clinician. I’ve worked with kids for my entire career, and there’s a growing number of challenges to gut health in general, of course, but [to] kids’ gut health in particular. We really need natural, safe products that we can use to modulate the pediatric microbiome, and there has, frankly, not been very much available in this area. So it’s a particular focus of mine and a place that I’ve been exploring for many, many years.

I’m really excited about this conversation because I think it’s going to be impactful for so many of you listeners who have kids who are struggling with gut issues, which is so common now in my experience as a clinician. I hope you enjoy this conversation as much as I did. Let’s dive in.

Chris Kresser:  Raja, [it’s] such a pleasure to have you back on the show.

Raja Dhir:  It’s great to be here, Chris. It’s always nice to combine minds, so thank you for having me.

Chris Kresser:  I want to just dive right in and talk about kids. Because in previous shows, we’ve touched on kids and specific questions around the pediatric microbiome and how we can intervene in ways that support the pediatric microbiome. I’ve treated [a lot of kids] over the years as a clinician. I’ve always accepted kids in my practice [who are] over two years old. I am really passionate about helping that audience for obvious reasons. And I know we have a ton of parents in our audience [who] have kids. I can say that, almost without exception, most of the kids I come across in any capacity, whether professionally as a clinician, as a parent, [or in] my extended family, it’s really uncommon for me to hear about a kid who has perfect digestion and is not experiencing any kind of digestive difficulties.

This is an area where you have expertise, and you spend a lot of time thinking about it. What can we say in general about the state of a kid’s microbiome versus the adult microbiome today? Are they in a similar challeng[ing] situation? What’s going on?

The State of the Pediatric Microbiome

Raja Dhir:  [Those in] the field of [the] microbiome got very excited when we started to learn about human milk oligosaccharides and how an infant’s exposure, including behaviors [of] the mother, are involved in the development of what we call a steady-state microbiome. At around age two is where we start to see breastfeeding, mode of delivery, [and] use or absence of use of antibiotics play really big roles. Then [we] fast forward [to] the post-adolescent microbiome, where a lot of people pick [up] those areas of inquiry. For a long time, we left behind that whole middle area where the microbiome is developing or emerging from its steady state. Where children are starting to expand into new dietary and behavioral patterns, [and] they’re starting, in certain periods, [to] have massive hormonal shifts as they go into puberty and become pickier and pickier eaters. And in westernized nations, we typically find this is the time where children have dietary patterns [that] are non-diverse. So they start to build behavioral patterns or dietary patterns, and they replicate those patterns. Parents think that this works, “I can get my kids to do this,” and they tend to just enable that rather than push it too hard or across the norm.

What we know is that, after a steady-state microbiome coming out of infancy, there’s actually a lot of diversity in the pediatric microbiome that is in response to, primarily, diet. We see that there [are] reproducible shifts within the microbiota based on behavioral patterns. If a child [goes] in a different dietary pattern, after about 30 days, you’ll see changes in that structure. This is where the science hasn’t fully fleshed itself out yet when we talk about the immune system. So when we talk about allergies or eczema, [when] we talk about engagements between the microbiome and child’s immune pattern, [and] even to some extent, behavioral patterns like the gut–brain axis, anxiety, depression, attention-deficit[/hyperactivity disorder], [and] autism-like behavioral symptoms. You know the microbiome is involved, but we don’t know if, “That ship has sailed,” if that early engagement with the immune system happens when the immune system is training, and we think that there [are] parts of the immune system that continue training, or at least are responsive to microbes, well into the pediatric lifecycle, or we don’t know if the bulk of that is still done while the immune calibration is ongoing. That part, still, I think I’ve seen a lot of back and forth in the literature and not something that’s super convincing.

But when it comes to the digestive system, to the microbiome, to the metabolites that are produced, namely secondary metabolites, including things like short-chain fatty acids and other organic acids, and gastrointestinal regularity, intestinal motility, the quality of bowel movements, the frequency of bowel movements, more of the quality of life and the lifestyle and behavioral impact of the gastrointestinal system on children, this is [what] we really focused on to say, “How can we support the development from age two to 18 of a pediatric microbiome primarily focused on, let’s say, the normalization and regularization of bowel movements?” Their frequency, [their] consistency, [their] resilience after acute events, like a course of antibiotics, a radical shift in diet or after travel, and during various periods of development, like puberty.

So, it was fascinating putting together this research program. It took us about two years. We have strains with data on the gut–skin axis, on the allergic pathway, actually asthmatic, the airway response in children, ranging from toddlers all the way through to teenagers. And then, finally, [we] finished composition after we developed this and paired it with a preferential prebiotic to develop the symbiotic. Beautiful data show a bifidogenic effect. You’re changing or enriching for the organisms that we know are highly desirable within a pediatric gut microbiome and also [for] this improvement in bowel movement, consistency, and frequency in children [who] have less than four and less than five weekly bowel movements. I would consider [that] to be, and this is our hypothesis going to the trial, at a stage where that bowel movement irregularity will have the biggest impact on quality of life. It’s not a daily regular bowel movement, but it’s inconsistent, it’s variable, and it can start to push up against functional idiopathic constipation.

Chris Kresser:  That’s really, really common in my experience. I like the simplicity of tracking that as an outcome or as a marker because it’s something that even a parent with a relatively young child can track without having to rely on the child reporting gut symptoms, which can be really difficult to parse out for a lot of reasons, especially at younger ages.

Behavior and Lifestyle Factors That Influence the Microbiome

Chris Kresser: I want to zoom out a little bit and talk about some of the influences, [about] the things that drive the composition and health of the microbiome. And these are true not only in adults but also in kids. I just want to highlight them because what I see in terms of global patterns with food consumption is [a] similar direction in kids as in adults where [there is] this movement toward more processed and refined foods, acellular carbohydrates, as some have called them, refined flour and sugar, sugar-sweetened beverage[s], sweeteners of all types, snack foods, and things like that. Let’s talk a little bit about the impact that has on a developing microbiome and why we might be seeing an increase in these kinds of functional [gastrointestinal] disorders in kids.

Raja Dhir:  The first and foremost is antibiotics. And I am very careful to bring that up because I don’t want to discourage people from giving their children antibiotics in cases where it’s useful. But I’m more bringing it up to say that it’s very rare for a child to grow up in a modern westernized world and not have exposure to broad-spectrum antibiotics at least once during their pediatric development. And why this is so important is not so much the antibiotics themselves, but [that] the antibiotics can create a condition for radical shifts in the gut microbiome. One of our hypotheses is that this drives that cascade that starts and presents in gastrointestinal symptoms that can result in further long-term symptomatology that presents outside of the gut well into adulthood.

Why antibiotics are so important to focus on as a starting point is because they create a change in the ecology that was present during the steady-state development of the microbiome and actually allow for a very provocative finding. And so with you, I love that we can actually get into very frontier ideas. One of the things that we found in our clinical trial was [that] the best predictor with a P value of less than .0001, of whether someone would be responsive or nonresponsive to a probiotic treatment, was elevated hyper richness of the gut microbiome. What does that mean? That means that there [are] very low numbers of a lot of different organisms. And typically, in an ecology, you don’t really see that when it achieves [a] steady state. You’ll find there’s some convergence or there’s some dominance. And you see that in all ecologies. You see that with predators and prey, or if there’s too many small numbers of herbivores, then you start to mess up the grazing ecology, or you start to create [a] disadvantage for the stabilizers, in this case, it would be a predator. You see this in the relationship between many different organisms, that they actually operate more in an ecological framework than they do as individuals.

And why I’m so bullish about monitoring the effects of the gut microbiome after a course of antibiotics is because, with the right recovery or the right conditions for recovery, you’ll typically find, after sometimes up to two years, I think, in a pediatric population, it took two years to get back to a level of Bifidobacterium that you found before a single course of antibiotic[s]. I’ll have to find the source for that. But during that period of development, you’ve created kind of a scorched earth where you allow other inputs to have a disproportionate impact on that microbiome, which might never have even happened. Even if a trigger for dysbiosis was introduced, a steady-state microbiome that’s highly resilient probably wouldn’t be affected by it that much. But now, when you’re allowing new colonizers or the persistence of very low levels of a lot of different organisms, it’s our hypothesis that this is creating a condition where you don’t have the efficiency of a healthy and stable ecology.

That’s probably where you see most of the impact and why I think that we’re starting to find associational drivers in the use of over sanitization and antibiotics, or the whole range of other immunological outcomes in children. I think that this is why, because you’re now allowing a lot of other things that could come from food, they could come from fermented foods, they could come from the environment, they could come from, you name it. They could come from basic exposure [to] things that the body should be able to tolerate but wouldn’t be hospitable to colonization. So that’s the first one.

Chris Kresser:  To use an analogy for people who are gardeners, for example, if you use a lot of weed killer, you’re going to get rid of a lot of certain species. Is it the right analogy that in that scenario, there are certain species that will resist and act and proliferate? So you end up with fewer species overall, but a higher number of the remaining species, both good and bad. Is that a safe analogy to make?

Raja Dhir:  That’s absolutely [the] right analogy. It’s a good analogy because there [are] also microbial communities within a garden itself. Think about if you brought a bunch of invasive plants onto an isolated ecosystem like Hawaii.  Then, when you introduce even one organism that might be good in California [to] there, it runs completely wild. We’re seeing this in Australia, as well. The ecology is very, very vulnerable right now to invasivity.

Chris Kresser:  I want to unpack this a little bit, too, because you and I are on the same page. We want to emphasize that sometimes antibiotics are necessary and even life-saving in the case of childhood infections. Neither of us is advocating for the elimination of antibiotics. There are times that they are needed, and absolutely, during those times, the last thing we want people to be doing is thinking, “Oh my God, we can’t take these because it’s going to affect the microbiome.” Having said that, we know from studies that the most common reasons for pediatric antibiotic prescriptions are upper respiratory infections and ear infections. And most estimates suggest that 60 to 75 percent of those infections are viral. So in those situations, antibiotics [being] prescribed are actually not anticipated to be beneficial. Because antibiotics, of course, don’t have an effect [on] a viral infection.

I’ve been, over the years, on a mission to educate parents about this. Because [with] things like upper respiratory infection[s] and ear infections, although they can be a little bit scary, there’s a tendency to want to do something. [If] you go to the doctor and you ask for an antibiotic, you’re probably going to get one. And it may not be the best thing in this situation. It’s led to a state where, I think the statistic I’ve seen is by age 20, the average American child has received 17 courses of antibiotics, and many of those it turned out were unnecessary and prescribed for viral infections for which antibiotics would not be expected to have an impact. That’s something I think all parents need to keep in mind, especially given this information that Raja just shared about the impact of antibiotics on the developing microbiome.

Raja Dhir:  And again, I don’t want to unnecessarily scare people because an antibiotic resistance gene doesn’t mean that you are resistant to antibiotics. But we found antibiotic resistance genes in the gut of every single child in our cohort. Every single one; 100 percent.

Chris Kresser:  Wow. That is very concerning. There’s a difference between being aware of something and acting appropriately on the basis of that awareness, and being scared and paralyzed. We’re going for the former, not the latter, and we’re trying to increase education and awareness so that you minimize the use of antibiotics to [only] when they’re absolutely necessary and they’re going to be beneficial. I think understanding what I just said about the upper respiratory infections and the ear infections being mostly viral, and maybe even asking your doctor if they can culture to see if it’s viral before deciding to use an antibiotic. I have an article on my website, which we’ll link to in the show notes, called “Why You Should Think Twice Before Giving Your Child Antibiotics.” That means thinking twice; it doesn’t mean not doing it. But it does mean at least having a second thought and evaluating whether it’s the best course of action. There are five suggestions at the end of that article on how we can minimize the use of antibiotics, or maybe another way to put it is [to] maximize their efficacy and reduce the possibility of downside risk. So, that’s the first factor that really drives the evolution of the microbiota in kids. What’s the next one?

Raja Dhir:  Next, I want to focus on diet. I think that 99 percent or greater of all beef consumed in the [United States] today is from grain-fed, factory-farmed cattle. So this, by definition, and again, I’m very careful [not] to demonize saturated fatty acids because saturated fat from the right sources is very beneficial, but we know that there’s a completely different fatty acid profile [in grain-fed, factory-farmed cattle] that is marked with the lower content of things like omega-3 fatty acids and monounsaturated fatty acids compared to grass-fed cattle. And that’s not even talking about the antibiotic use or residual pesticides found in the meat. I love when factory-farmed meats like Foster Farms write, “No antibiotics used ever.” I think to myself, “But if you don’t change the conditions or the infections that these chickens are now experiencing, [not giving] them antibiotics might even make this worse. You’re just permitting infections to ripple through this community and using this as a marketing stunt.” It’s just a symbol of everything that’s gone wrong. We never had this [before], right? In the early hominid diet, you would not have year-round consumption of saturated fatty acid-enriched meats. It just wouldn’t be present.

Other examples of this, just to stay on the macronutrient level, is the overrefinement of carbohydrates and ultra-processed refinements in processed sugars. I think that we’ve, historically, thought that you can just look at sugar content as a sum. But now we know that even sugar alternatives have an effect on the gut microbiome. So it’s not that simple. Some very interesting studies that I love to reference show that, even if you blunt the sweetness of the taste, in animal models, the body craves sugar. There’s an effect that’s induced from receptors within the gut as well as from the microbiome, even if it has nothing to do with the sensory perception. If you don’t “know” the sweetness feedback, [if] you eliminate that, you still get that craving. So these processed and ultra-processed foods, again, none of these things in isolation are bad. It’s not like eating one cracker is bad.

But when you combine that with a lack of diversity of fruits, berries, diverse sources of fiber intake, and this opposite end of the seesaw, which would probably be supportive of a strong ecology, then you start to slowly compound what [are] called risk factors. None of these things in isolation are a smoking gun. But [if] you look at the additive and contributive effects of all these things together, and you start to paint a picture where the combination of pesticides and residual pesticides, refinement, ultra-refinement, mono diets, as well as totally disproportionate contributions within the foods that we eat because of industrialization create a completely different environment. Each and every one of these [has] studies to support that [they have] effects on the development of the immune system or the effect of the brain or the neurotic metabolites that are produced by the gut microbiome or by the amount of butyrate that’s produced, which feeds your colonocytes, or the alpha diversity and beta diversity of the gut microbiome itself, or its resiliency in response to antibiotics.

You stack all these things together and it paints a picture that is this mosaic of risk factors, which are very hard to pick apart, but in some are definitely speaking toward a trend, which actually is less about acute pathogenicity. We used to think before about infection or [about] one organism like Clostridium difficile or [about] Fusobacterium. Now it’s more about these chronic long-term, low-grade ecological disruptions that create an environment [for which] we haven’t fully teased out where and how it will break down for different people [and] at what stage in life.

There’s a growing number of challenges to gut health in kids, and we need natural, safe products that we can use to modulate the pediatric microbiome. Tune in to this episode of Revolution Health Radio as I talk with Raja Dhir from Seed Health. #chriskresser #microbiome #healthykids

Chris Kresser:  I think there’s another factor that is growing in relevance, which is the number of kids that have food intolerances, and then the impact of those food-restricted diets on food choices that are somewhat unintended. An example of that would be kids who have gluten intolerance end up eating a ton more rice-based products. There have been studies that have shown that, because rice is one of the most common foods in terms of arsenic exposure in the typical Western, at least in a gluten-free diet, you have kids [who] are eating a gluten-free diet [and] eating a ton of rice-based products who have higher levels of rice exposure. They’re fixing one problem, [and] maybe ending up causing another. But from the context of the microbiome, I also wonder about [things] like high soy milk consumption or high consumption of other foods that are driven by these food intolerances.

So it seems to me that there’s a chicken and egg situation there, where the gut issues are what caused the food intolerances in the first place, but then the limited food choices and excess consumption of certain foods actually further the development of food intolerances. [What] do you think about that?

Raja Dhir:  We see that with gluten and gliadin. We see that with amino acid metabolism, so [trimethylamine] (TMA) to [trimethylamine N-oxide] (TMAO), and [the] risk of long-term cardiovascular outcomes. The amount of elevated [low-density lipoprotein] (LDL) proteins that we’re seeing and [very-low-density lipoprotein] (VLDL) in children, even ones [who] don’t have hyper obesity, is also very staggering. I want to approach the subject very carefully because metabolic syndrome and obesity in children is something [for] which we don’t want to create the conditions for long-term body intolerance or for psychological imbalances [for] children [who] are developing. So I’m going to talk about the subject very, very scientifically and faraway. But we do know that the microbiome in pediatrics determines the accumulation [of] or the resistance toward adipose tissue accumulation and these hallmarks of metabolic syndrome. With elevated insulin resistance, elevated circulating free serum glucose levels, or what we call this early, early immunomodulatory inflammatory cascade that develops.

Again, it’s very complex. Some people think it’s related to gut permeability. Some people think it’s related to the gut microbiome. Some people think it’s purely based on the dietary impacts that come in, although I think some of that stuff is very limiting. I can’t tell you more than that without veering into [a] hardcore hypothesis. But we do see a predisposition of metabolic syndrome in children developing as early as a young age that is independent of [the] dietary impact that’s a consequence of the gut microbiome. I want to leave it right there because anything more than that would become too theoretical.

Chris Kresser:  That makes sense. I think we can talk about and recognize these general patterns that are pretty much not controversial in terms of the data. We’re seeing these increases, [and] we don’t fully know exactly why. But if we look at ancestral populations when those conditions are very rare, and we know that there’s something happening overall with the shift in our microbiome as a people and that kids are included in that, it goes without saying that the same dietary patterns that adults are experiencing, the same increase in antibiotic use, etc., is going to have an impact.

So we talked about antibiotics [and] we talked about diet. In the research you’ve done, are there any other significant behavior or lifestyle factors that are anywhere close to antibiotics and food in terms of their influence on the microbiome?

Raja Dhir:  Yeah, the built environment is still a really big one. We live in an environment that doesn’t give us a lot of exposure to microbes that would be found in wild-type environments. Even [in] less wild-type [environments with] more domestication, like living around farm animals, this kind of “Amish hypothesis.” The Hutterites are another group of people that have remarkably low levels of allergic imbalance in response in a pediatric population as a consequence of being a little bit dirtier. [With] the removal of children from this type of environment and inclusion into a very built environment, [the data are] definitely there. We haven’t controlled those studies in a way that yields very clean data. So again, it’s still pulling things out of this epidemiological or this large data set. But it’s pretty evident when you look at these levels across many different populations that have exposure to a lot of different “tolerance-promoting organisms” that you might find out in the wild. [People] drink[ing] water that’s not 100 percent sanitized or chlorinated and clean, [and] the use of cleaning products in the home. One thing I learned recently is that the Amish don’t allow [the] cleaning of clothes within the house. They put all of it into one place, take it away, and they only use baking soda as [a] surfactant to lift and clean stains. Once it’s clean, they bring it back into the house. Small things like that. That’s just a fun fact; I wouldn’t read too much into that.

One of the collaborations [that] we’re working on right now is looking at the surfactants that we use in home cleaning products and trying to understand the effect that it has on the skin barrier, as well as the gut barrier when you ingest it. So, particularly, think about these heavy commercialized dishwashing systems. You’ll put a dish in there [for] a 60-second cycle, you flood it with surfactants, heavy high doses of it, [and] you have it at extraordinarily high heat. That’s what creates the conditions for you to clean this plate, and you need to turn it back around so you can put it back on the plate. But what you do when you expose it, after wetting, to very high heat for drying [is] you cake a layer of these surfactants on top of it that now crystallize on top of it. Of course, [then] you have ingestion of those. What does that do? A surfactant is a surfactant. The covalent bond that’s used to break the stain, whether it’s [on] a dish or whether it’s on a cloth, is very similar to the type of bond that you find in the intracellular space between skin cells. So don’t be surprised when these things cause temporary permeability either on the skin or on the gut because the nature of those proteins [is] very similar.

Now, we haven’t gotten the data back on exactly what the dose and the response and the effect is yet. But I think in the next six to 12 months, this is one of our more discovery stage research programs here at Seed, I think that we’ll be shocked when we find out the effect that it has on the intestinal microbiome as well as the skin microbiome and the structure of the tissue itself.

Chris Kresser:  Absolutely. That’s something I’ve encouraged people to do is reduce their exposure to these kinds of harsh home cleaning products and personal care products. Even though I think in some areas, we need more research and data, like you’re saying. To me, it’s a precautionary principle of the thing, personally.

Raja Dhir:  By the way, Chris, it’s not just that natural is better. A surfactant is a surfactant. Whether they isolate it from a coconut derivative and attach another molecule to it to make it active, or whether it’s a very engineered or more synthetic [one]. Actually, one could argue that some of the synthetic surfactants are used in dosages that are way lower. These natural cleaning products have been pushed as an alternative to something [that] is more industrial and not safe. But if you’re using 100 times the amount of the surfactant to get the same cleaning effect, then you have a much higher amount of residual compounds that are then found on it. I don’t want to comment more than that, but I’ll tell you that we’re actually developing [these] data head-to-head. We’re doing efficacy-to-toxicity ratios on over 200 surfactants right now with two of the top universities in the world. [Surfactants] that are found in everything from soaps to cosmetic products to dishwashing detergents to home cleaning products. We’re doing this work now. I’m very excited to see what comes out [of it] because this is something that the natural foods industry has gotten away [with] for a very long time. They say, “Well, it’s natural, so it’s better.” And it doesn’t make sense. Once you understand chemistry, that doesn’t make sense. The dose makes the poison.

Every surfactant, whether it’s natural or not, is designed to lift the bond between a stain and a surface, whether that surface is your skin or whether that surface is a cloth [or] a fiber. The dose really does determine the effect. I think some people are going to be very unhappy when we publish the results of that paper. We don’t intend to commercialize anything about this at this time. But, as you know, we’re super nerdy about basic science. I like to do these things and seek truth for the sake of academic research and [am] always protecting those discovery programs within our company.

Chris Kresser:  Absolutely. And that’s the imperative of science is to continually revise even our most cherished hypotheses when the research suggests that that revision is warranted and necessary.

What about stress? I want to explore a few other factors, and I don’t know if any of these were included in your research. But I know from other research into the adult microbiome that stress is a major factor and physical activity is a major factor in terms of the health of the microbiome. Are those things that you included in the study? Or are you aware of any other research that’s specific to the pediatric microbiome for those factors?

Raja Dhir:  It’s hard to define the direction of the arrow of causality in those. Typically, you find a lot of association in gastrointestinal disorders and stress. When the stress worsens, the symptomatology worsens, and vice versa. It makes sense when an organism, whether it’s a human or a [mouse], is under stress. You exacerbate intestinal inflammation, which alters intestinal motility, and then alters which microbes can be there or colonize and alters behavioral patterns. I just don’t know yet because it’s not studied so much in children, what really causes what. But you often find that children [who] have functional constipation or functional gastrointestinal disorders also tend to have higher levels of social stress.

Again, I’m very careful to make a caveat here, especially because things like autism are highly, highly polarizing. But one of the hypotheses in autism is that just by removing the effect that a poor diet has on the gut, you can get rid of a trigger or a stress, which intensifies or exacerbates other forms of symptomatology that are found in autism spectrum disorder because you remove one of the catalysts or you remove one of the triggers. This has been shown both in mice and in humans. So we definitely know that there’s a relationship. It’s been hard to study this outside of these extreme situations, like in functional gastrointestinal disorders or behavioral pattern disorders like in autism. So I’m hesitant to comment more than that. But we do find a lot of comorbidities in people [who] have functional constipation or other gastrointestinal disorders and forms of stress.

One very interesting finding in an adolescent to adult population was in extreme athletes. So it’s the people [who] are on both ends of the spectrum, but extreme physical activity is also seen by the border. It’s a positive form of stress, but it’s still treated as a stress. We know that athletes also have very, very high levels of gastrointestinal comorbidities. We see that across people [who] are involved in high levels, especially high-intensity interval training or very rigorous programs. Not so much in swimming, but definitely in other forms of intense activities. So it’s both ends of that spectrum. I think humans like to be in a little bit of this middle ground where you make sure that you expose the body to positive forms of exercise. But you also don’t want to experience a form of breakdown or stress.

I [am] going to give the caveat that this borders a little bit more on the side of science fiction, but my hypothesis was that after intense periods of physical stress, maybe the body would have increased permeability to try to sample and expose the immune system to what you just experienced or what you just ate. Imagine that you’re hunting or chasing down, in the Paleolithic era, some novel food or involved in some period of stress, and then you ingested something. It’s a way to actually temporarily increase the sampling of the immune system to get exposure to what you [ingested] to determine if there was a risk or if there wasn’t a risk. Again, I know that extreme athletes have high levels of intestinal permeability, but I have no clue why.

Chris Kresser:  I think there [are] certainly more factors that impact the development of the microbiome, but I think those are good starting places for understanding areas where people can really put attention toward and focus on improving. Let’s talk a little bit about Seed’s pediatric product, PDS-08. That’s the working [name], or the designator, for that product for now. Tell us a little bit about this product, what went into developing it, how it’s different [from] what’s available now, and when it’s going to be available for people who are interested in modulating their kids’ microbiome.

Raja Dhir:  Yes, let’s jump into that. Also, to close the loop on this first segment, [and] on the built environment specifically, studies do suggest that you don’t have to give up your urbanized life [and] go live in the wild to correct some of the impacts that the built environment have on stunting the gut microbiome. Temporary but frequent immersion into nature can satisfy this. I wouldn’t be able to say exactly how often or frequent that should be. But rest assured that just trying to make an effort to be involved more in non-built environments can be highly protective, especially during windows of development in a child.

Chris Kresser:  We’ve got some good resources on that on the website, [and] we’ll put some links in the show notes, as well. Let’s talk a little bit about the pediatric product, which is a synbiotic combined probiotic and prebiotic, and what you found in your research. That’s a good starting place. I want to remind people that very often, it’s pretty rare in the probiotic world, [and in the] supplement world in general but the probiotic world specifically, that any research is done, period. Then to do research at the level that Seed is doing is really exceptional. So tell us a little bit about the research that went into this.

The Research Behind Seed Health’s New Pediatric Synbiotic, PDS-08

Raja Dhir:  The formulation consists of nine distinct microbial strains that are paired with 6.2 grams of a multi-chain length prebiotic. This is the combination of medium- to long-chain oligosaccharides. We did that because our data suggest that different oligosaccharides can enrich different organisms. Again, it’s part of this broad-spectrum approach. When we started this discovery program, we looked at a lot of different mechanisms of action. But kind of how we started [out] this podcast, there’s a lot of research on the role that early nutrition and behaviors [of] the mother and microbial exposure plays in infants and then a lot more later in life with adults. Especially when things start to break down, but not so much in between. So all of our research and all of our initial strain analysis focused on data that [were] done in a pediatric population. And we did our trial, as well, exclusively on a pediatric population. So I think that part [is] really important and novel.

The other thing that out of the gate [we] were very passionate about [was] not just to focus on one outcome, one mechanism of action. Because, remember, everyone has a very different microbiome. So giving one strain to 10 different people might not work that well, or one different mechanism of action might not work that well, because the native microbiome might not be so permissive to that. But when you diversify the mechanisms of action, and when you diversify the strain contributions, you increase the chance that it works better and more reproducibly across as wide of a pediatric population as possible. And that’s always been something that’s been important to us and always been something that’s interesting.

Then, lastly, we like to move outside of just one [thing], [to] try to think about this general prophylactic preventive nutrition type of approach, rather than waiting for one thing to break down. “Okay, my child has [irritable bowel syndrome], so I give them this,” or, “My child has constipation, so I give them this.” We have data to support the gut–lung–airway axis here and very large well-powered trials, interventional trials, [with] about 400-plus children on asthmatic and airway response and acute respiratory events. We have data on the gut–skin axis, data that [were] published in very high-impact journals like JAMA Dermatology, [on] psoriatic and eczematic populations and reductions in the gold standard for that, which is the SCORAD score. Data on metabolic syndrome and some of these lipidology parameters that you’d find also within a pediatric population, predispositions for obesity, as well as in normalization of the response to gluten and gliadin. There [are] other triggers I’m sure we could have looked at. But the data that we have today focus on these two. Some of it’s in animals, but some of it’s in humans, as well.

Lastly, we took this composition and we looked to make sure that all the organisms would coexist together in a single ecology and a [consortium], and actually that they would enrich preferentially to the prebiotic that we designed. We looked at many different chain length substrates in designing this prebiotic. We optimized and picked the prebiotic, and, by the way, at a dose [that] I think is higher than any other prebiotic product to my knowledge. Don’t quote me on that, but 6.2 grams is a very, very high dose of a prebiotic. Most prebiotics are found in less than a gram and a half to two. And that’s just, from our research, too low to have a very strong bifidogenic effect or to overpower the effects of a bad diet. So all these different things came together, and then we looked to say, “Okay, let’s make sure we’re also not producing the wrong type of lactate or making too many histamines or things that typically have been ignored or under-studied.” We took this composition and we followed the same approach that we did with DS-01 for adults, and said, “Well, because children generally, especially the younger they [are], can’t tolerate or take capsules, how do we reconcile that? How do we make sure that we get a high level of microbial survivability without a loss?”

So whereas in DS-01, we recommend feeding on an empty stomach because we found that there’s a much higher microbial survival rate in fasted versus fed states—100 percent, actually—we found that in this pediatric population, you actually want to give it in a fed state. Because although there’s a longer incubation time in the gastric chamber, there’s a pH buffering effect. So instead of exposing it to [a] pH [of] 1.8, it jumps up to about 3.5 to 4. And that’s actually permissive. These organisms are much better [off] being there for two hours instead of 40 minutes, which is the difference in incubation time generally in a gastric chamber in response to food. We looked at all these different in vitro and development parameters. And again, it’s not like we have to do this, but it’s just important. It would be such a shame to not optimize your product. And this precision release and this basic microbiology and these pharmacokinetics, [and] these release profiles are such a big part [of] how we think about the probiotics category.

Chris Kresser:  It’s such an attention to detail there that I appreciate, and it’s so rare in the industry in general and this specifically. Since we’re getting short on time, you mentioned before that frequency and consistency of bowel movement improvements was one of the main outcomes of the trial. What were some of the other outcomes? Any side effects or adverse effects, etc.?

Raja Dhir:  We took this composition and we scaled it up. We generated stability data both in a high heat stress environment, so we know what it can handle in terms of stability for product quality. Just basic product quality, as well as for when we’re shipping or transporting these to customers. Then we did a gold standard, placebo-controlled, double-blinded trial in a pediatric population. Most of these children had weekly bowel movements [of] less than four, and another subsection had weekly bowel movements [of] less than five bowel movements per week. And then a small percentage of that cohort were kids [who] were all over the map. So some were having up to 14 bowel movements, 15 bowel movements per week, and others were a little bit more normalized. And that’s important, because though we really initially set out to study the effects of this composition on increasing weekly bowel movements, you have to design clinical trials [in] a certain way to make sure that you can answer with the right statistics the questions that you’re asking. You do want to show tolerability and safety, and also that you don’t elevate bowel movements in children [who] already have a healthy state.

You want to show this homeostatic effect. If the child already has a normalization of bowel movements, you don’t want to now make them have excess. So we got all [these] data back. Most striking is that we found a significant improvement in weekly bowel movements of greater than two, and greater than three even, in both children [who] had less than four and children [who] had less than five starting weekly bowel movements, compared to a placebo. This is very important because, in interventional trials, [and] especially when it comes to these multifactorial conditions like bowel movement response and frequency where you can’t control for diet, you can’t control for stress, you can’t control for their starting microbiome, you can’t control for genetics, typically, you find such a high placebo response because of psychosomatic effects of hope. “Okay, I’m trying something, my child’s suffering, [and] I really want them to get better.” So to be [a] placebo is very hard. A lot of trials show that children report feeling better. We could argue whether that’s still in and of itself good enough, but I think that doesn’t answer the scientific side of if the product actually works versus if it doesn’t. And I think that’s really important.

So improvements [in] bowel movement frequency was the primary endpoint of the study. We met that endpoint. Another really interesting thing that we found in this trial was a bifidogenic effect. We saw an enrichment of all the species that were found within the probiotic composition within the interventional cohort, but not in the placebo. That’s important because you want to say, “Okay, is what you’re actually giving enriched? Even if it’s not long-term colonization, are you actually seeing the presence of these microbial genes in the gut and it’s not just something that happens because the child is engaged in a clinical trial or something that might already exist in their own microbiome and you’re just picking up on strains that already exist there?” So that was really interesting to find. And then thirdly, we saw what’s called bifidogenicity, where we saw an elevation of Bifidobacterium at the species level in the intervention group compared to the control. And again, I don’t want to over-sensationalize this because Bifidobacterium is, of course, a very protective species. It’s one of the first that are found in the gut. It’s organisms that are uniquely able to utilize the human milk oligosaccharides found in breast milk. It’s species that are uniquely elevated in people [who] live to 100 [years old] compared to ones [who] don’t, and a lot more emerging research shows that many different strains and subspecies of Bifidobacterium predict response and immune response to a whole range of conditions. But this study wasn’t the subject to go into any one or more of those particular mechanisms. I think that’s a much broader discussion and the subject of future work. But it’s still very nice to show that the combination of the prebiotic with the strains does result in this effective bifidogenicity. It starts to point toward this idea that you’re getting enrichment. Or you’re getting these improvements, or you’re getting these microbiota level shifts that are generally believed to be safe and even arguably protective. So that was the bulk of it. It’s fascinating stuff.

Lastly, we did deep, deep bioinformatics using cutting-edge computational techniques on the starting microbiome of these children to say, “Can we actually go beyond the product and the intervention and start to understand a little bit more broadly what determines whether somebody is effective versus not?” And also, by the way, the response rate was equal to what was found in laxatives of the intervention. So you’re starting to see not just something [that] is mild to modest, but something [that] is equal to many of the [over-the-counter] and arguably disruptive. I don’t know; I haven’t looked at the laxative data in great detail. But arguably disruptive long-term to the microbiome. And you’re starting to see this with microbial intervention.

Chris Kresser:  But even short-term, a lot of those interventions like fiber-based supplements, laxatives, or even high-dose other probiotics and prebiotics can cause a lot of side effects in kids. I’ve seen that firsthand because I work with kids in the clinic. But in your trial, I think there were no observed side effects or [gastrointestinal] distress unlike a lot of these other interventions.

Raja Dhir:  That’s right. For us, we hope that would be a given. But you do bring up a good point where you do see a lot of side effects, or a lot of these trials achieve statistical significance because the placebo group gets worse. Or the symptomatology gets worse for some unexplained reason, and then the intervention just keeps it how it is. But it’s very important [that] we designed this trial to actually show changes between the two groups that we believe would have clinical relevance. Not [it’s] just that you’re data hacking it, so to speak.

Chris Kresser:  So when will this product be available? This podcast is going to be published on April 19.

Raja Dhir:  Imminently. So around the time that people are hearing this, it will be live. Again, we haven’t launched another product as a company since our inception, because hopefully, it’s evident from this conversation that we take the responsibility very seriously to develop things. Even if it’s a given for most people or they don’t care, [or] there might be desperation to try anything. At least we try to make [the] data available so people can make informed decisions on what they want to put in their children. This product will launch in April, and we’re very, very excited to share it with people.

Chris Kresser:  I’m excited about it, too, as a clinician, as a parent, and as someone who appreciates rigorous science and products that are developed on the basis of that. If you who are listening want to try this for your kids, you can go to Kresser.co/Seed and use the promo code ChrisKresser to receive 15 percent off your purchase, and that would include the PDS-08, which is [the] pediatric daily synbiotic, or the DS-01, which is the daily symbiotic for adults, which is a product I’ve been using myself for many years and recommend to basically almost every patient [who] I work with and people [who] I come in contact with because it’s been such a game changer.

I was an early beta tester of earlier versions of the pediatric product, as well, in our clinic, and it’s just something I really believe in and think is going to make a big impact on pediatric health, and I’m excited to be a part of that. Raja, thank you again for joining us and for continuing to blaze a trail in terms of the research that you’re doing in this area and the products you’re developing based on that rigorous research.

Raja Dhir:  Thanks, Chris. Thank you. I really appreciate your enthusiasm and overall commitment to follow the literature, and overall acknowledgment that science isn’t this static, hierarchical thing, but rather it’s a process and it’s a methodology and [about] bringing people along in that journey and educating people as you go along the way. So I really enjoy our conversations. Thank you for the conversation, the platform, and I hope we get the opportunity to spend some more time together.

Chris Kresser:  Absolutely. All right, everybody. Thanks for listening. Keep sending your questions to ChrisKresser.com/podcastquestion. Again, go to Kresser.co/Seed and use the promo code ChrisKresser, all one word, to save 15 percent. I highly recommend you give this a shot if your kids are experiencing not just digestive issues, as we discussed. There are respiratory issues, skin issues, the gut–lung-skin axis, and I think brain health is also pretty impacted often by [the] gut microbiome. So thanks again, everybody. We’ll see you next time.