The Microbiome’s Role in Sleep, Energy, and Longevity, with Dr. Zain Kassam

In this episode we discuss:

• The role of microbial diversity in sleep quality and overall resilience
• Emerging research linking the microbiome to eye health, sinus health, skin conditions, and autoimmune disease
• How modern life—diet, stress, medications, and environmental exposures—disrupts microbial balance
• The “4D framework” for evaluating probiotics
• Why melatonin dosing matters (and why more isn’t better)
• The emerging category of cobiotics– supplements designed to support both the host and the microbiome simultaneously
• The future of microbiome-directed healthcare and personalized interventions

Show notes:

• Use code CHRIS20 for 20% off your first order at Seed.com
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• If you’d like to ask a question for Chris to answer in a future episode, submit it here
• Follow Chris on Instagram or Facebook

Hey everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week I’m really excited to welcome Dr. Zain Kassam as my guest. He is an award winning physician-scientist, a gastroenterologist who has shaped the field of microbiome science for more than a decade, authored over 200 peer reviewed publications and abstracts, and co-authored international clinical practice guidelines. He is an expert in the microbiome and its relationship to all aspects of health and well-being. This is a fascinating topic that has evolved so much in my 20 years as a clinician, researcher, and educator. In the early days, we thought that the microbiome was mostly just about digestive health, and all you needed to do was maybe eat some fermented food and take a probiotic and you’re good to go. And we know now that it’s so much more than that. The microbiome is connected to everything from sleep to energy regulation, cognitive performance, stress resilience, vision, sinus and nasal health. I mean, you name it, the microbiome is connected to it, and we also have learned a lot about how to properly support the microbiome, and it goes far, far beyond just taking a probiotic. So that’s the subject of the conversation today. I really enjoyed it. I think you will too. Let’s dive in.

Chris Kresser:  Zain, such a pleasure to have you on the show, really looking forward to the conversation.

Zain Kassam:  Likewise, Chris. Thanks for the invitation, looking forward to the discussion.

Chris Kresser:  So I think pretty much everybody at this point has heard of the microbiome and understands that it plays an important role, not just in gut health, but in virtually every system of the body, from the endocrine system to the immune system to the brain and neurological system, energy regulation, nutrient absorption, etc. This is what you’ve more or less dedicated your life to studying. So I’d love to just hear you summarize where you think we’re at, like the State of the Union, in terms of microbiome research and our understanding of the role of the microbiome in contributing to overall health and longevity.

Zain Kassam:  Absolutely, I think this is an area of continuous development. But maybe this, I’ll start with a human story that frames the entire conversation, and I’ll tell you how I met the microbiome. I was a gastroenterology trainee, and it was winter, I had my coffee, and I saw a patient, let’s call her Mary, at two in the morning in the emergency department. She was British, she loved her grandkids, she loved gardening, and I saw her in tears in the hospital. She had taken an antibiotic for her bladder infection, and the antibiotics worked. It was wonderful. But a few days later, she had a terrible side effect, a gut infection called C. diff. She was tied to the toilet, terrible diarrhea. It was so awful she wanted her colon removed. We tried the most potent antibiotics, we tried everything, and nothing worked. So we turned to science that was first described in fifth century China then probably largely forgotten for the most part, something called a fecal transplant. We literally took the healthy poop from her nephew, screened it, and gave it to her. One very messy enema later, she was cured. She was gardening two days later. That was the closest thing to a miracle I’d seen in medicine. And that’s how I met the microbiome. And it unlocked a lot of questions, as you can imagine, as a trainee.

I realized very quickly that we’d really largely forgotten that humans are super organisms. As you said, it’s a huge thing now, but back a decade ago, a lot of people didn’t really know what that was; that we were only about 50 percent human, with the other half being microbial. Nearly 100 trillion microbes live on and in us. That’s kind of more stars than in a Milky Way galaxy. And what I realized in my journey is that, unlike our genome, our microbiome is dynamic. It’s always changing. It’s shaped by external factors: our diet, our environment. And 90 percent of our microbiome is influenced by external factors, right? Things that actually touch our day-to-day. But we’ve also had a modern living where we’ve totally disrupted that. The relationship between the humans and the microbes, it’s led to what we call the “climate change of our insides.” And this is where I think the power of the microbiome is.

But I think you’re saying it right, and you alluded to this, is that the microbiome is not just about digestion. It’s a dynamic lever that allows us to really change many parts of our core biology, whether it’s in nutrition, as you said, where microbes are active partners to help us unlock and metabolize essential vitamins like vitamin B, or even produce vitamin D and K, whether it’s energy in the gut-brain axis shapes our cognition and our neurotransmitter production, or even our sleep, where microbes are central. In fact, 90 percent of our body’s serotonin, a precursor to melatonin, one of the key sleep regulators, actually is produced by the gut. So when we ignore the microbiome, we essentially leave half of our biological potential on the table. And I think we’ve come a long way in the field over the last decade, but I think we’re still starting to learn and grow about where the potential of the microbiome is.

Chris Kresser:  Yeah, it’s so fascinating. I think it’s hard for us to get our heads around the idea that we’re as much bacterial or microbial as we are human. I think it was Justin Sonnenburg from Stanford that said humans are more or less an elaborate mechanism for the propagation of microbes. Or something to that effect. I’m paraphrasing, but that was the general idea.

Zain Kassam:  Are we the puppetmaster or them?

Chris Kresser:  Exactly, right? It is kind of creepy to think about that, but it’s true. I mean, it’s consistent with what we know of what’s happening inside our bodies, on our bodies, in our skin, and our hair, our scalp, everywhere else. We know now that there’s not just a microbiome in the gut. There’s an ocular biome, there’s a vaginal biome, there are biomes in the skin. There’s biomes everywhere. And so I think as our understanding of this has grown, it’s really expanded from, let’s say, 20, 30 years ago, a real focus on the gut and digestion and most people would just associate problems in the microbiome with things that are more directly related to the gut and digestion. But as you said, we now know that it’s critical in so many other systems.

The Microbiome’s Role in Sleep Quality and Overall Resilience

Chris Kresser:   So let’s talk a little bit about how the microbiome influences things like circadian rhythm, cognitive performance, stress. Because on this show I’ve probably done 20 plus episodes on the gut and the gut microbiome, and quite a few on other relationships too. But I think this is more novel territory for most folks that are listening, these relationships.

Zain Kassam:  Yeah, I think it’s great to talk about the non-obvious stuff as well. And I think it’s the area of opportunity. When I first heard about these relationships over the last decade or so, it always made me scratch my head. Is everything related to the microbiome? And so let’s talk about the science, let’s talk about the research, and let’s talk about the biology a little bit. And maybe a couple key takeaways, specifically on circadian rhythm, and then we can unpack some of the latest research. So it kind of turns out your gut bacteria have their own rhythm. Just like you have a biological clock that tells you when to sleep and wake up, these bacteria, the trillions of them, follow a 24-hour cycle too. More than half the gut actually is influenced and changes and fluctuates throughout the day, and that’s largely based on when you eat and also when you sleep. And so these microbes actually help set your body clock. They help set your circadian rhythm. They produce these really important molecules, these super metabolites like butyrate, a short-chain fatty acid, or tryptophan, a metabolite that when you have a really large turkey meal, you have that heavy feeling, you need to go to bed. These actually come from microbes, and they signal your brain and other organs, and they help keep your internal clock running smoothly. Think of them like tiny time keepers who work alongside light exposure to regulate your daily rhythms.

And I think a couple of things that perhaps are important is, what you eat and when you eat actually matters pretty critically in that relationship. Plant-based, high fiber diets support a healthy microbial rhythm. We know, and you know this really well, that typically Western diets high in sugar and fat, they disrupt them. And when you have your gut bacteria, they respond better to food timing than almost anything else, so it makes you sensitive to scheduling. And so that’s kind of really another interesting point.  I think the science is actually really interesting here. And I think that’s maybe something that gets forgot about. This is like a hot space. There was a nice paper out of Florida a couple years back that showed that greater microbiome diversity was associated with sleep efficiency. They slept longer, those individuals did, and they reduced the number of times they woke up in the middle of the night. But what’s really exciting, a paper that just got published this year in one of the most prestigious journals, Nature Communications, it was a Dutch paper with about 7000 participants and they also demonstrated the same phenomena. They said that individuals that had low microbiome diversity, they had the poorest sleep quality, and they had more impacts on things like jet lag. And so to me, that’s a really powerful study to show this linkage to the microbiome. But it doesn’t stop there. I think that the key thing is those metabolites that really promote, and we see these in animal model studies and cross-sectional studies, where we’re starting to trigger important sleep molecules like orexin, which go right into your brain or lateral hypothalamus. And we also see that individuals that have sleep problems, a really nice study out of NIH, that are sleep deprived, or they have obstructive sleep apnea, they are associated with less beneficial microbes, which I think is really starting to see the, like, biology meets the cross-sectional data, and soon some of the interventional data.

Chris Kresser:  Yeah, it’s really fascinating. Particularly the circadian connection. We went on a trip to the Azores in Portugal last summer, and I’ve found that as I have gotten older, I’m much more susceptible to jet lag than I used to be. And so I wanted to pull out all the stops to prevent it. I was using melatonin strategically. I was also using glasses, I forget the name of this company, but they have glasses that emit pulses of blue light. So you can wear them when you’re supposed to be waking up in the new time zone to, like, trick your body into thinking that it’s light, that the sun is rising, you get the cortisol. But another big piece of it was meal timing. Shifting your meal timing to when you would eat in the new time zone is one way of helping to prevent jet lag and adapt to the new time zone. So I just thought it was fascinating that something like meal timing and gut would affect how you can fall asleep. And the study you just mentioned highlights that, but there are a lot of other examples as well.

Zain Kassam:  No, you’re totally right. There’s a nice paper in Frontiers in Microbiology and they talked about this timing window. Eating with a consistent timing window, like an eight to 10 hour period, totally helps you realign your gut bacteria with your natural rhythm, and that helps your overall sleep. And so your lived experience with the Azores is totally right. By the way, a beautiful place. I love the Azores.

Chris Kresser:  Yeah it is amazing.

Zain Kassam:  Gorgeous. The hiking there is incredible, and the scenery is like nowhere else. But well, I’ll ask you, did it work? Did it help?

Chris Kresser:  It did.

Zain Kassam:  You were able to beat jet lag?

Chris Kresser:  Yeah, I wouldn’t say I beat it completely, but it was certainly better than the last trip that I took where I didn’t do much at all. And I think it really shortened the adjustment time and made it easier, for sure.

Why Melatonin Dosing Matters

Zain Kassam:  And you mentioned melatonin, which I think is an interesting thing. As a clinician, I like melatonin, but I think that everything has its pros and cons. And one of the things that I’ve noticed with melatonin is that it’s rare to get the right what we call “bioidentical dose.” A lot of these doses are just extremely high, like 10 milligrams or higher. And there’s a really nice paper out of Australia. They did a meta-analysis. They took 79 studies across about 4000 people, and they showed high dose melatonin leads to pretty significant drowsiness, headaches, and dizziness. I think melatonin, and we can talk more about it, at the right dose, it’s a very powerful and effective tool. But often people take too much.

Chris Kresser:  I completely agree.

Zain Kassam:  Very, very high doses and it snows you. And I think that’s the thing that we have to watch out for. As you know, the dose matters. I think there’s a term in pharmacology where everything can be a benefit or a poison.

Chris Kresser:  Depending on the dose. Yeah. Including water.

Zain Kassam:  Yeah, exactly, exactly.

Chris Kresser:  Yeah. I would agree with that. I would even say in most cases I don’t generally recommend melatonin on an ongoing basis. It’s good for the scenarios that I just mentioned, like where you’re trying to adapt to a new time zone or shift the circadian rhythm in some way, but I don’t love it for just ongoing use, for a variety of reasons. Especially at the higher doses, like you said. Maybe in the microgram, three, 400 micrograms, which is more like a physiologic dose, it could make sense. But yeah, I think it’s overused. And we’re getting a little sideways here, but it’s worth talking about, especially for kids, because it’s a hormone, right? And kids are still developing, and we don’t know what the long-term effects of, particularly higher dose– three, five milligrams– of melatonin are for kids. So I definitely caution people about that.

Zain Kassam:  I think you’re totally right. I think you and I are aligned on that. I think a low dose, or a bioidentical dose, makes sense. The reason I say that is because some studies have been conducted on individuals that have poor sleep quality. There’s a scoring system called the RSQ-W, less than 50, and turns out those individuals have low melatonin baselines. It’s one of their underlying biology things. So if you can, not give them 10 milligrams, but give them a little bit. A little bit of bioidentical I think, over time, that actually will help. But I agree with you on not giving ultra-high dose melatonin and not to be on, regularly, ultra-high dose melatonin.

The Surprising Connection to Eyes, Sinuses, Skin, and Beyond

Chris Kresser:  Absolutely. So let’s talk just a little bit more about some of the other interesting connections, the most maybe novel or unique ones that stand out for you. I mean, I’ve had so many clinicians and researchers on the show to talk about ones that are interesting to me, like the ocular microbiome, I think is fascinating. And we know that that contributes to a bunch of different degenerative eye diseases and conditions, inflammatory issues. The vaginal microbiome, I know that Seed has had a product for that recently. But what are some of the most interesting connections that you have come across?

Zain Kassam:  Yeah, absolutely. We’ll talk about the two that you mentioned to start, and we can, of course, expand the conversation. But I think the ocular microbiome is really interesting, and also the gut-eye connection. Actually, my brother’s an ophthalmologist, and I worked on a project with him many moons ago which looked at the gut and microbiome’s impact in individuals that have inflammatory bowel disease like Crohn’s and colitis. It turns out some people with Crohn’s and colitis have inflammation in their eye and some don’t. And we don’t know who gets it and who doesn’t get it. So we looked at individuals that had inflammatory bowel disease, [and] looked at if they had inflammation in their eye, [if] they didn’t, or [if] they were healthy. And it turned out their gut microbiome told the story. Individuals that had protective microbes that produced short-chain fatty acids, they were the highest in the healthy, lower in those that had inflammatory bowel disease, and lowest in those that had inflammatory bowel disease with eye inflammation. Which is kind of interesting, actually. And then the reverse is in those that have pro-inflammatory microbes like Fusobacterium. They were the highest in those that had inflammation in their eye and in their gut, lower in those that had inflammation and IBD alone, and then basically non-existent in those that are healthy. And so you’re totally right in the eye areas being really interesting and emerging and how the gut and the eyes connect directly. In addition to what you’re probably also referring to, which is the microbes in and on the eye directly, which is interesting. But it was Hippocrates that said all disease begins in the gut.

Chris Kresser:  That’s right, 2500 years ago.

Zain Kassam:  Certainly seems that way. Exactly.

Chris Kresser:  He knew something, somehow. He didn’t have the modern research we have, but he understood it already.

Zain Kassam:  That’s right.

Chris Kresser:  Yeah, I mean, since we’re up in the head area, the nasal microbiome is pretty fascinating, too. And all of Susan Lynch’s work out of UCSF showing that it’s not actually the presence of pathogenic species like fungi and bacteria that drive chronic sinusitis, but the lack of diversity. I mean, that’s a really interesting finding in light of some of the other things you’ve already mentioned. And it makes sense, right, if you understand that it’s an ecosystem. Like, all ecosystems have pathogens in them. The question is balance and the ability of that ecosystem to keep those pathogens in check. And that seems to largely be related to diversity and presence of beneficial organisms that can hold those in check.

Zain Kassam:  You’re absolutely right. I think you were mentioning the head and neck area, the one that always got me a little bit. A couple of colleagues of mine are ear, nose, and throat physicians, and I was mentioning this to him, and it was the ear wax microbiome. And children that have recurrent otitis media, or otitis externas, they have a lot of ear infections, and there is, like, it’s only a case series, so we don’t want to get over our skis, but some really interesting reports where, if you take the microbes from the other ear and put it into the ear that had this recurrent infections, the infections kind of go away. Which I thought was incredible. So fitting the sinusitis, but also the ear microbiome, it’s really, really interesting. And another one is around the skin microbiome, where I’ve seen some pretty incredible stories. Maybe this was gut and skin, but the condition alopecia areata, where they have no hair, right? Super challenging condition, an autoimmune condition, and a colleague of mine at Harvard Med school now, Colleen Kelly, she was seeing patients that happened to have alopecia, but she focused actually on Clostridium difficile, that infection I was mentioning earlier. And she was giving a fecal transplant for the C. diff infection this individual had. And she gave this, the C. diffinfection went away, perfect, as you would expect, it worked really well, amazing. But there was an interesting observation that happened six months later. An individual with alopecia areata, didn’t have any hair. Six months later, the hair came back, which is wild. And so we published it in a journal which is really interesting. And so, fantastic kind of outcome for that individual.

Chris Kresser:  Absolutely.

Zain Kassam:  But it goes to show how everything’s connected, right? And similarly, had a colleague in the Netherlands who, the patient had celiac disease. And then when you scope patients with celiac disease, you can see that their villi, those little, they’re like finger-like projections, are flat. And it did that, and they were treating this patient for C. diff again, and they gave them the microbes, the healthy microbes, back. And six months to 12 months later, the villi came back, which was incredible. And so, I think, you talk about the microbiomes, I think the gut is definitely dominant, because we have the most microbes there, but all these other areas are connected, which I think is fantastic and very, very fascinating and then the area that I think we’re going to continue to see more and more research on.

In this episode, Dr. Zain Kassam joins Chris Kresser to explain how the microbiome influences circadian rhythm, brain chemistry, immune function, and whole-body health—and why supporting it takes more than just a probiotic. #ChrisKresser #microbiome

Chris Kresser:  I mean, I tested pretty much every patient that came to see me for 15 years, I tested their gut and their microbiome. And I rarely saw test results that indicated a very robust, healthy microbiome, which is disappointing. It’s like, I don’t even know, outside of really isolated populations like the Hadza in Africa, if we even know what a normal microbiome is at this point. I’m curious to hear your take on that. But it seems to me there’s just so many modern threats to the microbiome. Everything from the obvious ones like antibiotics, which, of course, are necessary in some cases, to poor diet, to disrupted sleep, to stress, to other chemicals and compounds in the environment. We know that certain medications beyond antibiotics adversely affect the microbiome. It’s very difficult without intention, like conscious intention, and probably supplementation, and reversing as many of those risk factors as I just said as possible, to get us back to something that’s still probably not historically normal, but as close to that as we can get.

Zain Kassam:  I think you’re totally right. I’m an 80/20 guy. I try to live my life fully, but I’m also a realist. I think it starts with our diet and having a high fiber diet. We know that over the last centuries, the amount of fiber in our diet has gone down dramatically. That’s kind of one of my gold pillars. I try to get my fiber in, and we’ve seen that dramatic reduction. Because they’re the fuel that makes our microbes go. They help produce those special molecules. But yeah, supplementation is just that. It’s a supplement. It needs to be added to a daily regimen which should be optimizing their microbiome. But I consider it like an insurance policy on my microbiome, right? We know that there are things that are going to be untoward if we live our lives fully, and if we can have an insurance policy, that’s certainly something that makes a lot of sense from our day-to-day.

Chris Kresser:  Yeah, absolutely. So let’s talk a little bit about that. I mean, there’s the world of probiotics, prebiotics, postbiotics, polyphenols. There’s been so much evolution in the field. When I first started practicing, it was pretty much just probiotics, and even then, it was mostly like, a few Lactobacillus strains and Bifidobacterium strains and that’s about it. There was not much beyond that. And now we have this huge plethora of options, including cobiotics, which is a term that you’ve used. So I’d love to hear how you think about this in terms of the highest ROI kind of activities beyond the basics that people can take. And you can include the basics too, because there’s so many things people could do. I’m an 80/20 guy myself, and I think it always makes sense to look at, how do we get the most from our efforts?

The “4D Framework” for Probiotics

Zain Kassam:  Yeah, I think there’s maybe two pieces I’ll offer. So maybe we’ll talk about, as a gastroenterologist and with gastroenterologist’s focus on the microbiome, how do I think about supplementation in this sector, in a probiotic kind of place? What I call the “4D framework.” And then let’s talk a little bit about cobiotics. I think this is a new and exciting area that’s branching beyond the gut which I think could be also very interesting. So we’ll break it into two pieces.

So, chapter one. The thing that I think is really, really helpful when I think about selecting gut probiotics is looking for four things. I look for the first D– diversity. And you talked about that. Diversity is a really good thing, right? We know that you want to have a broad spectrum approach. A wide diversity of beneficial bacteria is a good thing. Just like in a forest, you want lots of different types of trees. You want that as well in a probiotic. But most probiotics don’t have a lot of strains and don’t have a lot of biology that goes behind that. The second is delivery. Just like in a forest, you need to have sunlight to get to the trees. Most probiotics die in the stomach. The stomach is really harsh. If you can’t get the sunlight to the trees, then obviously they don’t grow. And so, one of the things that we really look for is a targeted delivery to make sure it gets into the actual colon. That’s where the microbes live. And then the third D, I like to call it do-gooders, which are prebiotics. You want to have probiotics that include prebiotics. Kind of an all-in-one, because those are the things that require the microbes to grow. Look for that as well. And the last D for me is data. Not all probiotics are created the same. I think you and I know this. The word “probiotic,” to me, is like saying the word “medicine.” Aspirin and Viagra are pretty different, right? And so it depends on what you’re trying to solve for. They all have very important niches, and different probiotics do different things. So you have to look for the data. And we’re really proud [that] we just published a large randomized control trial on DSO on our GI symbiotic, which we can talk about if that’s interesting. And I think for us, that’s the last D. So a couple of product things. Look for diversity, look for delivery, look for those do-gooders or prebiotics, and look for data. I think are some of the key components, and we could talk about cobiotics as well.

Chris Kresser:  Yeah, let’s talk about cobiotics. That’s probably a term that many people are not familiar with.

The Emerging Category of Cobiotics

Zain Kassam:  Yeah, I think you kind of hit the nail on the nail on the head when you said things have really been focused in the gut. And nearly a decade ago, microbiome science was really just focused there. But we know that science has evolved really quite rapidly beyond digestion, and, as you said, touches almost every part of the body. And that understanding kind of inspired us to reimagine daily supplementation. We know that products are not really designed for the full ecosystem in the body, for the human and the microbe. And that’s really important, we think, for daily health on a day-to-day basis.

And so we launched what we call cobiotics, which is a new category of supplementation designed to support both the human body and the microbiome. Kind of together, the essentials for fundamental functions like nutritional absorption, energy, and sleep. And so we’re debuting our formulas, DM-02, which is a daily multivitamin, AM-02, which is an energy and focus supplement, and PM-02, a sleep and restore, which target those functions that are co-regulated by those pathways. It’s kind of our first expansion beyond probiotics into the microbiome-centered approach for everyday health. And we’re really excited about what’s to come from that entire new sector for you and your microbiome.

Chris Kresser:  How do they do that, Zain? For someone who’s new to this, how do they affect those systems differently than just a standard probiotic, for example?

Zain Kassam:  Yeah, absolutely. So these are not probiotics. They’re different than probiotics. They don’t have any live microbes. They have a collection of two components. So the first component is on the outer capsule. So we have an outer capsule that has ingredients for the host. So for example, in the PM-02 product, the outer capsule contains an ashwagandha extract, which has been very well evaluated. A beautiful study in sleep medicine, a 150-person randomized control trial, where our patients received either the ashwagandha extract or placebo for six weeks and saw a 72 percent increase in the quality of sleep in the ashwagandha arm versus the placebo, which I think was 29 percent in the placebo. So a really strong effect, and that’s affecting the host, there. That’s not affecting your microbes, that’s affecting the host. And then, for example, on the inner capsule, the inner capsule has a set of ingredients that are designed to optimize the microbes in your gut. They’re kind of prebiotic compounds that are designed to be microbially-accessible nutrients to the colon, where all our microbes live, and those microbes then support the microbial activity downstream, like we talked about, all those powerful molecules.

So you can kind of think of it as the outer capsule for the host, the inner capsule for the microbes that help the function. And all using our proprietary capsule-in-cap, the ViaCap technology, for that targeted delivery. And we think that’s a kind of a unique approach and introducing a new type of biotic.

Chris Kresser:  Yeah, that’s fascinating. And so what are the mechanisms specifically that are at play here? How does the magic work, so to speak?

Zain Kassam:  Yeah, sure, let’s get into the magic a little bit. Can’t give you the entire playbook, but I can give you a little bit of the magic. So we talked about the outer capsule. Another one that we talked briefly about in passing was, in addition to the ashwagandha, we have very low dose melatonin, right? So this, again, we talked about that being very, very small, and it’s a little bit of rapid and a little bit of sustained. So you have a blend of these two components, and it’s spread over time. And we think individuals that are really suffering, particularly on sleep quality, have a reduced amount of melatonin, and we think that little gentle supplementation, not a lot, is really important. Kind of bioidentical, mimicking what your body does. Similarly with the Ashwagandha, it’s another tool that we know from a botanical perspective affects from a sleep perspective.

But let me tell you a little bit about the inner capsule and where that magic could be. So components like PQQ, which is a vitamin-like compound in kiwis and spinach, and this compound has essentially been shown in studies to improve sleep quality as well. And how does it do that? I think it’s some of the mechanisms you and I talked about earlier. The microbes release special compounds, things like butyrate, things like tryptophan. It’s designed to increase these super molecules that affect your circadian rhythm, which I think is a key component for supporting your microbiome in general, but also kind of supporting microbes that are produced, these powerful molecules that we know are good not just in the gut, but also good in changing your circadian rhythm, adapting your circadian rhythm.

Chris Kresser:  Nice, yeah. It’s really great for me as a clinician and someone who’s been in this space for a long time to see how this landscape has evolved and become much more directed and targeted and precise in terms of the formulations and the delivery, the sequencing, and even targeting specific outcomes. Again, it used to be, “Okay, you want to help your gut health, take a probiotic.” That was basically the discussion. And now it’s, “We’ve got cobiotics, prebiotics, postbiotics, polyphenols.” And then we have specific organisms and species that we think about, maybe for metabolic benefits. And then we have other compounds, like inner and outer capsule, like you mentioned, that we think about for sleep or stress or energy or nutrient absorption, and it’s just exciting to see where we already are now and what the trajectory of this is.

Zain Kassam:  I always love it when you’re on the bleeding edge of innovation. Because, like I said, when I talk to clinicians like GI doctors who’ve spent their entire career treating GI patients and I ask them about probiotics, they kind of blink at me a little bit, right? And they’re like, “Yeah, I give a good probiotic.” And I’m like, “Well, which one?” And they’re like, “Oh no, I just give a probiotic.” And I’m like, “Well, that’s like me going to you and saying, ‘I’m going to give you an antibiotic,’” but one’s an antibiotic and one’s aspirin. They’re totally different things, right? And even our researchers are doing meta-analyzes of probiotics, which I think can be helpful, but have to be done really elegantly, because that’s like putting an antibiotic and aspirin in the same study. They’re totally different. And so it’s on us to help to educate communities that a prebiotic, or which prebiotic, they do different things. A probiotic, they do different things. A postbiotic, they do different things. A cobiotic, they do different things. And getting to precision, which takes time, and we know that, and unlocking that these are different types. Just like you would go to your pharmacist and there’s like hundreds of medicines. It’s kind of the same thing with the biotic sector. And so we have to know what we’re using it for.

The Future of Microbiome-Directed Healthcare

Chris Kresser:  Yeah, absolutely. Let’s talk a little bit about the things you’re excited about looking forward, because this field is changing so rapidly. There’s been so many interesting developments recently. But as you look out on the horizon, what do you think, if I was to have you on the show in three to five years, what are we going to be talking about?

Zain Kassam:  I think we’ll probably be talking about a lot of microbial things, but I think we’re starting to move away from just biohacking necessarily, and we’re focusing on isolated, high-dose interventions that have biological coherence. Things that are working together in harmony. I think this harmony is really important for internal systems. I think the future of daily health is microbiome directed models of care, where we think about the microbiome in totality. We think about the gut microbiome. We think about not just your gut, but also beyond your gut, on where that’s coming from. And I think there’ll be products for vaginal health, for skin health, for ear, nose, and throat health, right? I think being very precise about that. Some will work through the gut, but some will not work through the gut. And we have to be mindful of what we’re trying to actually manage and support. And I think that’s going to be where we’re going. At Seed, we view the microbiome as a really powerful tool to restore balance in the world. And we know that world often disrupts it, and so our mission is to translate that science into innovation that allows people to manage their health through the lens of interconnectedness. The systems biology approach. It’s not just about living longer, although I think that’s really important, it’s about healthy lifespan over time. And I think that’s something we’re very excited about, about nourishing the super organisms that we truly are, not just the human parts, but our microbial parts as well.

Chris Kresser:  Personal question, which of the cobiotics do you like the best? I’m assuming you’ve experimented with all of them. Just curious.

Zain Kassam:  Of course I’ve experimented with all of them. I like all of them, so I’ll start with that. I think they all do different things. My sleep is not the best in the universe. I used to be an exceptionally good sleeper, and I still have some pretty good moments of sleep. I think it’s the medicine in me, the 42 hours. But I really like PM-02. I think that is the one that I feel the biggest pep. The daily multivitamin I actually also really like. 80/20, right? So I think that’s a key piece.

I have a ton of energy, I’m always going, I’m always really focused, so AM-02 is great, but does it map what I need directly? So everyone has their own collection of things. For me, sleep and the daily multivitamin fit best for me. But I know colleagues of mine who literally swear by AM-02, and they’re like, “This is the only one I’ll use, this is the supplement of choice for me.” The PM-02 one, they didn’t really need. They sleep fine. And so I think it depends on what you’re looking for. And I think if you’re looking for optimizing your nutrition, I think DM-02 is a great multivitamin for everyday health, and I think differentiated compared to your general over-the-counter multivitamin to help support those microbes. And then, of course, if you’re looking to optimize for a little bit more focus, then that energy product is really quite good.

Chris Kresser:  Yeah, there’s some really good stuff in there. I’m just looking at it now. Shoden ashwagandha is a great, branded form of ashwagandha, high with analyte content, and then PQQ, as you mentioned, and then pterostilbene and spermidine for longevity and cellular regeneration. And then the 500mcgs of melatonin, yeah, what a great formula. I can see how that would be helpful in terms of just putting the brakes on, like a nice mellowing out. And this is the difference between really good supplements like this and medication. It’s not like a sledgehammer knocking you over the head. It’s just working with the endogenous mechanisms that are already there to promote the normal cortisol curve. I see you have a nice graphic of that on the website. I know ashwagandha, in particular, has been shown to reduce evening cortisol levels by up to 30 percent and that’s, I think, a big problem for most people in this culture. With exposure to artificial light and screens and our work schedules, it can be very easy to keep that cortisol pumping all the way through the evening, instead of the natural curve reduction that we would expect to see.

Zain Kassam:  You’re totally right. I mean, quality of sleep is essential for long-term health. It’s one of the biggest drivers that we know one in three people don’t get enough [of]. And I think you’re totally right, it’s that cortisol, that disruption, just our lifestyles. And we then compensate with sleep aids, or sleep medicines, I should be specific, and you’ve got to be careful with those, I think. And I think we have a gentle approach, trying to harness some of these ingredients that hit the core biology. We know that sleep has many different elements. There’s falling asleep, staying asleep, quality of sleep, right? They’re all different elements. What’s beautiful about and what we’re proud about for this formulation is that we try to hit different elements along the way. That’s why there’s a diversity of ingredients, right? Which we think is important to help kind of allow for an optimal sleep experience and optimal restore experience.

Chris Kresser:  Cool. everyone who’s listening, you can check these out at Seed.com.

DM-02 is the multi, AM-02 is the energy and focus, PM-02 is the sleep and restore. There’s one more, right? Am I missing one? Or are those the three?

Zain Kassam:  It’s the three.

Chris Kresser:  Yeah, that’s like the big three.

Zain Kassam:  It’s the big three for now, for now.

Chris Kresser:  Yeah, for now, of course. Yeah, you guys have been exciting to watch your trajectory and all the fantastic products you’ve provided over the years. As you know, I’ve been one of your biggest fans, so it’s been really cool. And for folks who want to save a little bit of money, you can get 20 percent off your first order with the code CHRIS20.

Dr. Kassam, such a pleasure to have you on the show. I really enjoyed the conversation, and look forward to having you back in three to five years to see if your prediction was accurate.

Zain Kassam:  Let’s do it, Chris. I look forward, too. I’ll put it in my calendar now. Thank you for being such an advocate for Seed and we’re really appreciative. And I think your education for so many is so powerful.

Chris Kresser:  Thank you. Thanks everyone for listening. Keep sending your questions to ChrisKresser.com/podcastquestion. We’ll talk to you next time.