The Root Cause Of Disease: How To Fix Your Gut Health For Overall Health & Longevity | Raja Dhir

Fixing our gut is step one of any health program. It's linked to autoimmune disease, to allergic diseases, to asthma, Alzheimer's, Parkinson's. Just to kind of give people a little bit of background, your microbiome has as many, if not more cells than your own body. I've heard anywhere from the same amount to 10 times as much, but you have 37 trillion cells and there's probably at least that many bacteria in your gut. What's different though, is that there's a lot of variety in those bacteria, and each of those bacteria have different genes, and each of the genes of the bacteria produce unique metabolites or proteins. And those are biologically active compounds that we absorb that regulate our entire biology, our hormones, our brain chemistry, our immune system, our risk of a whole host of diseases, and are regulatory. In fact, there may be, I'd love to hear your opinion about this, but I've heard anywhere from a third to half of all the metabolites in our blood come from the metabolites that are produced in your gut by your gut microbiome that then are absorbed across your gut lining and end up in your blood and then regulate your biology. So, I mean, maybe you are just carrier pigeons for bacteria. I don't know who's in charge here, but it seems like they're in charge a lot. and each bacteria has these genes, and there's about 20,000 human genes, but there's maybe 2 million, 100 times as many genes in the microbiome as your own genetic code. And so the complexity is just enormous. I've heard it estimated that there's 100,000 petabytes of information data in your microbiome. I don't even know what a petabyte is, for Christ's sake. It's a big number. I know what a terabyte is, a gigabyte, a petabyte is, I don't know how many terabytes. It's a lot. And when you think about all that information, the body is essentially an information network. It's an information regulatory thing, process. It's an information superhighway. And part of that information superhighway is the bacterial compounds that are produced from this complex ecosystem. And when you have let's just for, you know, argument's sake, you have a bunch of ones in there that are not producing things that are good for you. You can get sick. And if you have ones that are producing things that are good for you, you can stay well or get well. And I think, you know, we think of probiotic, everything's, I'm going to take some lactobacillus or bifidobacteria. I mean, that's like so meaningless because there are hundreds and hundreds of strains just within those two categories, and there's many, many, many other species that are also relevant. We mentioned Akkermansia, there's many others. You mentioned the Fusobacteria that causes cancer. I mean, we're just sort of scratching the surface here. So the gut microbiome is this incredibly complex place where most of our health is regulated and determined. So learning how to understand how to create a healthy gut, how to tend your inner garden is essential if you want to be healthy. And I think we're learning literally more and more about this every day. I mean, I see papers come out every every single day. And the data on this has just skyrocketed. If you sort of probably searched microbiome in 1990, you wouldn't see anything. You'd be searching 2000, you might see a few papers. 2020, it's like a hockey stick. So the science on this is really exciting. There's microhuman microbiome projects. There's big efforts by governments all across the world to understand this. There's companies popping up all over that are testing stool, that are measuring what's in the microbiome, giving recommendations. It's a lot. And I think I'd love your kind of perspective on how do we take this incredible field that's so sort of promising and make it practical for us? I mean, how do we take home the news to use here? Because it can be overwhelming to think about the complexity here and what to do about it.

Absolutely. And, you know, I first came to the same realization that you just shared when I saw how remarkably successful fecal transplants were in treating patients and chronic infection. And so, that was kind of my first input.

I see C. Diff.

Where you get C. Diff infection.

Yeah.

But, it begs a very interesting question, which is, so maybe you're transplanting someone's microbiome, you can cure an infection, but, as you just stated, the microbiome is connected to so many different outcomes. How do you know that you're not accidentally transplanting a microbiome that increases your risk for something else? And so I couldn't agree with you more. I think the microbiome is a huge field. The research has connected gut microbes to virtually every organ system, and we are in the halfway mark of making sense of this data. There's two things that I would draw people's attention to. So the first is only in the last few years has everyone kind of started speaking the same language. So the sequencing method started to become more standardized. People started going to minimum sequencing depth. So we're actually starting to all look at signals that are a little bit clearer now. And I think that's very, very important. People say microbiome, they cite a publication for microbiome, but you have to ask, How is this sequenced? What did you learn? What resolution are you getting? How are you even defining what is biome data sets in the scientific and academic literature? It'll give you an answer and it'll say it's this bacteria and it's statistically significant and this bacteria predicts obesity. This bacteria predicts leanness and it'll give you strong signals. Then you can ask that data set on a different cross section of 500 people the same question, and it'll give you a different bacteria. They'll say, this bacteria actually drives obesity, and this bacteria actually drives leanness, and they're all significant. P values of 0.001. And so this is what makes microbiome so confusing and why it seems that there's contradictory results all the time because small cross sections of microbiome data that are uncontrolled will give you significant findings. All the big journals we're publishing, This microbe predicts finds depression, this microbe finds this, but then, oh, but wait a second, does this also relate to this? Or this study actually says that it doesn't, or it doesn't in a Chinese population, or there ended up being so many caveats. And so what I look for in analyzing microbiome data is this, on any data set that you run it, is it going to give you the same answer? So turns out on this data set, when you ask the same question on a sample size of 3,500 people, It gives you the same microbe over and over and over and over again. And that's very exciting to me. This, I think, is the future of microbiome. And so when I say we're halfway through, I mean there's a lot of stuff that's here. There's going to be a lot of responders and non-responders, and I think there's still going to be some art and science interpreting the microbiome readouts that we get today. But I do see a future very soon where we're starting to get consistent population level readouts on microbes, their genes, their metabolites that drive all of these areas.

As a physician, I never learned this in medical school. I certainly didn't learn it in residency. And I began to understand the role of the gut early in my career when I got sick and I had severe gut issues. I developed severe diarrhea, SIBO, bacterial overgrowth, fungal overgrowth, stream abdominal pain. and it went on for years and years. It was a result of mercury poisoning, which totally destroyed my gut microbiome. And then I began to learn about functional medicine and understand the role of the gut in so many diseases that were chronic. And at the very early stages of functional medicine, we didn't really have a very deep understanding of the microbiome. It was just sort of like we understood this idea of dysbiosis or imbalance in the gut flora. We understood that if we helped repair the gut, that people would get better. And we had a methodology for doing it, which is to remove the bad stuff, replace what's missing, reinoculate with good bacteria, repair the gut lining, restore the nervous system and calm things down. That really worked. I would see, honestly, miracles when I would do this with patients. Their migraines would go away, their autoimmune disease would go away, their metabolic health would improve. I just was shocked. It was striking to me that I just never learned about this in medical school, and yet it was seemingly among the most important things I could do in treating almost any patient with almost anything. And now we're learning the microbiome plays a role not only in gut health, but in immune health. It's linked to autoimmune disease, to allergic diseases, to asthma, to neurodegenerative diseases like Alzheimer's, Parkinson's, to neurodevelopmental diseases like autism and learning disabilities and ADHD, to mood disorders like depression and anxiety and even schizophrenia and other diseases. And it's also connected to heart disease and diabetes and cancer. And the list goes on and on and on. It's all of a sudden, the very framework of medicine is sort of crumbling because when you go to your rheumatologist, they don't say, give me a poop sample. When you go to your cardiologist, they don't say, give me a poop sample. When you go to neurologist, they don't say, give me a poop sample. Or when you go to psychiatrist, they don't say, give me a poop sample, but probably they should. and so we're in this moment where I think this is the time in medicine that's the decade or the era or I don't know what of the microbiome. And I don't think we're all the way through figuring it out, but I think we've made such incredible advances and the knowledge base is accelerating at such a pace that most average physicians have no clue what to do with it. I think for me, it's still a very confusing field and there's different information science coming out every day that helps us to sort of navigate this complex territory. But I'd love to sort of get the chance to talk to you today because you're a scientist about your knowledge of the microbiome, the role it plays in our health, and the kinds of things that can be done to actually fix our gut. Because to me, fixing our gut is step one of any health program. And how does the microbiome plays such an incredible role in our overall health. I mean, how does it connect to all these different diseases? And how does it sort of blow up our paradigm of traditional medicine?

It's a fascinating field and precisely for why you said, it's the relationship to the microbiome to distal organs and virtually all of them is profound. And what we know today is that this process starts very young. In the first weeks of life is when the first microbes colonize an infant and typically they're bifidobacterium. And these early organisms do something very have a very interesting effect that I believe is responsible for the lifelong effect of microbes and the microbiome to different organ systems, which is It begins the cross talk to the immune system. And so I remember sitting in a probiotic symposium at Harvard in 2016 and an immunologist came up and said, everybody, something very provocative, they said, everyone is born inflamed and the process of microbes and your early windows of development is to learn tolerance. And so microbes are the first tolerance promoting organisms to an inflamed host and to an inflamed and rightfully so human body. And so this crosstalk happens through many different ways. This happens directly. The dendritic cells come out and they sample microbes and differentiate and form immune responses and have it send inflammatory signals and initiate cascades. based on that information directly. Microbes affect different organs indirectly through other interacting with other microbes. So sometimes they colonize and prevent an opportunistic or a, quote, bad bug from colonizing or taking over that place, which is how some of these mucin degrading organisms work. Or, or sometimes they do so a little bit more indirectly through the metabolites they produce. So you talk a lot about acetate, butyric acid, but that's just those organic acids are just a tiny fraction of the entire metabolic repertoire that the microbiome works through. And then lastly, in some instances can drive pathogenesis directly. And so I'm fascinated, for example, by the story of Fusobacterium, which is in oral bacteria but is found at the center of cancers both in the colon, which is the primary site, but also metastasize and go elsewhere. And this is a oncogenic strain. We have similar, you know, we see in other organ systems that some viruses and bacteria can be oncogenic, but we actually have that in the gut microbiome as well. And, you know, Helicobacter pylori is one example. Sometimes it promotes stomach cancer and other times it's tolerable. And all of this is regulated by your microbiome that starts when you're born and achieves steady state in the first few years and then changes based on what you eat, the medications that you take, and your lifestyle. And those are the main drivers of this system. Yeah.

So basically what you said is that the whole ecology in your gut is not just sort of sitting in there. It's doing lots of things like protecting the barrier and making your gut immune system not get over activated. It's sampling what's in there and it can regulate what you should react to and what you should not react to. It's creating lots of metabolites that are absorbed and are having impact across all of your biology. And it may be producing certain toxins or other microbes that have a concerning effects like microbes that maybe get absorbed and that distributed in your body and maybe are in causing cancer. We've seen, for example, in biopsy specimens of Alzheimer's patients brains, microbes in there, which where are they coming from? How they get there, you know, it's like you got the blood-brain barrier, but there's actually something going on where these are entering into the overall host biology and are actually having a huge impact. So, good bugs essentially create health and bad bugs to simplify things actually make us sick. So, The real question is how do we keep the population of good bugs up and the bad ones down?

There are bugs that I would say that there's a spectrum. There's bugs that we know are good and mostly good for most people. There's bugs that we know are bad and they're mostly bad for most people. And then there's this entire mix in between which depending on your own microbiome and depending on the relationship between the other bugs that are there and the bugs that you're taking and your diet are either good or they're either bad. And so I would draw attention to an organism which I've been fascinated with for a very long time, an organism that a lot of people are talking about these days called Akkermansia muciniphila. And you know, this for those that aren't aware of this bug, It's very intimately related to the gut lining and so it colonizes actually where the mucin is produced. Generally you find positive features from having Akkermansia. You know, Patrice Cani was the first to really start talking about this and has isolated it and had a hypothesis that this is involved in metabolic regulation. and adiposity and weight gain and actually tested it both in its dead form and its live form in affecting those parameters. He didn't find efficacy in the sense that he was looking for it compared to placebo. And so I don't think anything came from that project in Belgium. But what's interesting about this idea of opportunistically good or opportunistically bad organisms is a paper which came out in November of 2023 and actually said that Akkermansia in the presence of a low fiber diet can exacerbate food allergies. And so it makes sense, right? If you're eating a lot of fiber and you're producing a ton of substrates for these organisms and others to degrade, they're generally healthy. If there's not enough positive dietary inputs for mucin degraders, then what are they going to eat? They're going to degrade your mucin and they're going to degrade it in ways that can be pro-inflammatory.

So, you've got to eat the fiber with the probiotic.

Absolutely critical. In the case of Akkermansia or other mucin degrading organisms, this paper suggests what many in the field have talked about, but this paper was the first to prove that is not just mitigates the beneficial effects, but actually can turn that organism into something which is bad. So it goes back, Mark, to this idea that everything is connected. So you can't just take an Akkermansia, eat an ultra processed diet, and call it a day, right? So it's all part and parcel of the same circuit, the same network, how the bacteria relate to each other and how they relate to the host. It's kind of these two levels. That's what defines good or bad. Now, to answer your question, I think that we know when bad organisms are there. I'm sure you test for this all the time. There's fungal overgrowth, for example, or Klebsiella or Clostridium difficile. There's a list of about 10 or 20 organisms that I could definitively say in any person are suboptimal. You do not want them there. You should explore, in some cases, even antibiotics to reset your ecology and then reseed or repopulate depending on what you have, but these are your opportunistic or your known pathogens and that list is very clear. On the other hand, on these kind of good actors, I would paint a picture for the audience here of.

What.

Is the indication that you're looking for. And so what we worked on at SEED was to develop a very broad spectrum consortia of bacteria which are genomically rich. So many, many different strains, even from within the same species of these universal good organisms or these only demonstrated as positive and very specific at the strain level and put multiple strains of those same species so that all of the activity of that species or genus is captured within this consortia. And so this is kind of our approach to good bugs is for different people, it might be different genes of that species. And so you want to have as broad representation as complex of a microbial inoculation of these positive bacteria with whole body benefits. This is the kind of design principle that went into the good bacteria approach that we that we put forth.

Do you think that, Roger, that all these microbiome tests are legit? Should we be paying attention to them now? Is it all overselling? Is it premature? There's a lot of companies, some big companies, are actually doing this. And I always sort of feel like they're maybe getting a little ahead of their skis. Yeah.

If you're an academic microbiome researcher, you are going to be sequencing your samples. And if you want to get full readout at a depth, metagenomically of 20 million reads, 50 million. I mean, we're sequencing things at 100 million, but you want to be doing deep read metagenomic sequencing on the microbe side. On the host side, you want to be doing untargeted metabolomic sequencing without these two pieces of data stitched together for an individual and tracked over time you're not going to get anything useful that you can make recommendations on today.

So let me see if I can explain that in English. Basically, what I hear you saying is you have to map out first the genes of the microbes in your gut using very sophisticated gene analysis. And second, you need to look at all the metabolites of those bacteria that are produced by the genes. So you need to kind of map the metabolites with the genes to actually see what's happening in any individual person and make clear recommendations. Is that what you're saying?

That's right. So the genome, metagenomics at a very deep will tell you which bugs are there. That's important. Good to know. But you got to do it deep, otherwise you're not going to get strain level variation. So you've got to do it deep. The other side of it is actually comes from your blood. And so you want to say, okay, that's great that you have the microbiome, but remember when you said you have all these metabolites floating around, a third of you at any point in time is microbial. Well, you learned that from the blood. You learned that from your serum, and you learned that from looking at all those microbial metabolites. And, you know, in Italy, we actually did a very small, out of curiosity, just a very small pilot study When we gave people antibiotics, well, first we looked at their blood, then we had 10 people and we mapped their metabolome of their blood, then we gave everyone antibiotics, and then we did the same thing and we did it using NMR, and you couldn't, out of those 10 people, you could only remap three of them back to their original sample. That's how different the profile of their blood looked after just a single course of antibiotics. It's there. It's there and it's meaningful and it's rich in data.

So the take home that I'm hearing is that, you know, the average stool kid you get from some company selling you something, probably not ready for prime time yet. Is that what you're saying?

That's the gentle way of saying it. The less gentle way of saying it is, quite frankly, I think it's dangerous. I think it's dangerous to sell insights to a customer before those insights have been formed or to ask a customer to pay for you to generate insights before you've made sense of that data. And so I think it's very early for microbiome diagnostics. And lastly, I think any time you hear somebody say, oh, well, you don't have the best bacteria to metabolize pomegranate or broccoli, and so that's a food you should avoid. I just think that that flies in the face of all practical nutrition advice and I think that should be ignored.

Well, that's fascinating. That's not to say everybody that stool testing can't be useful. I've used it in my clinical practice to map out what's going on for people. I look at intestinal microbes for sure, but I look at also the metabolites of those microbes like short-chain fatty acids. I look for inflammatory markers for pancreatic enzyme function. so I'm looking for inflammatory markers. I see a lot of things that aren't just looking at the bacteria. So I agree with you. I think it's important to look at the whole ecosystem, but using this clinically as a doctor that are tests that I've used for decades that may not be commercially available for the average consumer, I think are very helpful for me.

And I think for many people in this space. In a controlled clinical practice, I agree with you.

Yeah. Now I want to get into the next phase of this, which is, okay, so we're not quite yet at the place where we can go get a poop test and figure out what probiotic we need. But we are understanding the probiotic use in medicine as a valid interventional tool to treat various serious diseases, to optimize health, except there's so many probiotics out there. You go to the grocery store, you go to the health food store, there's ones in the fridge, there's ones not in the fridge, there's this strain, there was that strain, nobody knows what's going on. Even most doctors have no clue what's going on. Can you define like what's a probiotic and whether we should actually be taking probiotic supplements? Because we've been taught, for example, that when you take probiotics, they don't really take up residence there. They just kind of pass through and do little things and they go on. Do they colonize? Do they not? Does it matter? And should we be thinking about probiotics from a basic health maintenance perspective? Should we all be taking them? how do we pick the right probiotic? And, you know, should we just be eating sauerkraut and kimchi and forget about probiotics? Can you help us unpack some of that?

I think probiotics are fascinating in the sense that anytime a piece of news or press comes out that says probiotics are don't work or they don't do this, it seems that probiotic usage goes up. And so I can't explain it, but It's people love them, people use them, but the science and the understanding and the development of them is very confusing and varied. And so just to start with some definitions, probiotics are defined as live organisms that confer a health benefit to their host. It's a very simple definition. Gregor Reid chaired the panel at the UN that wrote it in 2001. At its core, probiotics are not a new discovery or not a new hypothesis. Typically, they were in the early 1900s organisms that were isolated that were found to be beneficial. And benefit has changed over the years dramatically. I mean, back then it was just keeping your food sterile or safe from pathogens that could be considered a benefit. preventing you from getting sick from what you eat could be considered a benefit today. People look for a lot more complex things. So what is it intended to do? And what is the health benefit? That's the question that you have to ask. Anytime you hear the word probiotic, that's what you have to say right back. Say, okay, so it's a live organism, yes or no? You'd be surprised. Many times they're not live or they're not guaranteed to be live or they don't make it to your colon alive. And so there's a whole spectrum of even that live part. And part two is, okay, so beneficial. What are they beneficial for? What are they going to do? What is the basis for if they are beneficial or not? I think people confuse probiotics sometimes with fermented foods, which have a very different definition. Fermented foods are microbially metabolized food matter that carry a microbial load. And so that actually was just defined by in a nature review this year for the first time. And they're both good. They both can be good or they both could do nothing. It really depends on what you're looking at. So fermented foods are different from probiotics, but sometimes fermented foods can be probiotic and sometimes probiotics can be fermented foods. But it depends on what they are and what you're trying to accomplish.

Yeah.

Classically, Probiotics have been Lactobacillus and Bifidobacterium. Two years ago, the scientific community convened and said, okay, this is way too generic. And so, Lactobacillus actually was broken into about 200 subclasses and was completely renamed. And so, we don't really use Lactobacillus anymore, but there's way more genus and species variation now from what was originally called Lactobacillus. Bifidobacterium, at least Lactobacillus and Bifidobacterium and Streptococcus, I would add is the third, are the three class of probiotics that have been used in food in Japan, in Europe, and predominantly in North America. And so almost every probiotic product that is a microbial product that's standardized will contain or derive some version of these or it's going to come from soil. So that's kind of the landscape, right, when you hear probiotics. And we'll get to the cases at the edge a little bit after. I do not think that most people in the absence of any gastrointestinal or gut microbiome related, you know, people that I call like your super healthy individuals that that exercise well, but not too much. They're not elite athletes because that carries its own risk or not over endurance athletes. People that eat virtually no processed foods and that have no environmental toxins in their environment. You've talked before where you can even find that in ways that you wouldn't expect, which you can talk about later. So if you're kind of living in the wild, if you're growing all of your own food, if you're regulating contaminants in your water supply, and in the soil of the food that you're eating and you're eating a very diverse plant and animal based diet, I think that that's that you're in more or less peak performance. And lastly is you didn't have heavy antibiotic usage either early in life or at any period throughout your life or periods of disruption and recolonization from the built environment, which means you didn't move to a big city or an urban dwelling place and change your microbiome away from what you would get in the countryside or in a more agrarian or a more kind of wilded environment. So these people that meet those conditions, I would say you probably are doing just fine. You don't need to do too much. And a simple microbiome test will tell you, you know, what you need, what you don't need. the converse of all of those are people that live in kind of more of the modern world. And so you're getting, you know, yeah, you know, you're bathing using modern and eating modern foods or packaged or foods or foods bought from a grocery store. You're drinking beverages which are contained in some container. you're generally using urban infrastructure and you may or may not have gastrointestinal or related to gut microbiome maladies. This is kind of that area that I want to focus on where I say probiotic usage is the most impactful, it could be the strongest, and it could be the most helpful. My hypothesis why is that people that are in this environment actually have a very low microbial inoculation. So I don't know if when you're in medical school you heard this theory that actually they were giving people with IBS or IBD helmets. They were giving them known worms basically. And they found that actually it was very effective. And I don't know if it was an urban tale or not, but the idea is that Remember what I said about being born inflamed, right? That an active immune system has to be active or has to be inactive, and that's very context dependent. So, I've actually even heard many in the field and on this podcast talk about the indigenous microbiome or the hunter-gather microbiome and kind of define it as this optimal state. But optimal for who? If you took this microbiome and you transplanted it to an urban an urbanite living in New York City, that person would probably get very sick. I remember when the AmeriIndian project was happening, it was Maria Gloria Dominguez-Bello, Marty Blaser, a lot of the missing microbes people that were involved in characterizing the northern Amazonian microbiome. And actually they went for six weeks to go live like them and see how their microbiome shifted. This was an experiment from from the mid to late 2000s. And I remember Gloria telling me that she could do everything. She could follow all of their practices except for she snuck a little toothbrush with her and snuck away to brush her teeth every night because that's the one thing she couldn't give up. But that's what it means. That's what it means to live like that. It means that you're taking it all.

So with probiotics, I mean, There's a lot out there and what's important to think about, if people are trying to choose a probiotic, how do they evaluate it? For example, when people are choosing a vitamin, I'm very clear with them. They need to make sure that the product is in the right form. So in other words, the right version of that nutrient. For example, if you're taking folic acid, maybe you need five methyl folate as opposed to just folic acid. Or if you need magnesium, maybe you need magnesium glycinate or magnesium threonate instead of magnesium oxide, which isn't well absorbed. Second, you need to make sure that what it says on the label is actually what's in the bottle. That things are third party tested to be there for both purity and potency. In other words, there's no contaminants or toxins and it actually is what it says on the bottle. that there's no weird stuff in it, like allergens, fillers, excipients, colors, dyes, sugar, lactose, gluten, all that stuff can be in vitamins. And I, and I think, you know, it has to be bioavailable in terms of the form. It also has to be absorbable. So if it's in a crushed tablet that's under tons of pressure, it might be the right everything, but you may not digest it. So tell us about. How do we think about probiotics? Should we be taking hundreds of different strains? Do we just take one? How do we know what's good? How do we know? I mean, if you buy something in the store, it says 50 billion units on the bottle, is it actually that? How do we know? What should we be thinking about?

It's a very simple rule of thumb for people is there's two major classes of probiotics. One is targeted for a specific indication. I want to lose weight. I want to improve my mood, I want to signal to improve my skin. You know, they're very different microbes that work on these different axes, and they're usually very specific. So it's not necessarily a bunch of bugs that will do that, but you could find ones that are very targeted, that have that targeted effect. And so I think that this is bucket one, bucket two, or you is.

Your, I just wanna stop there for a sec. That's an incredible statement you just said was that there are different strains of probiotics that have different effects for different diseases and conditions. And some may be good for your skin, some may be good for your brain, some may be good for your immune system, some might be good for your heart, some might be good for your metabolism, regulating your blood sugar. I mean, it's quite interesting, you know, the differential ability to determine which probiotic is good for which thing. And that is something that's pretty new. I mean, it's almost like personalized probiotics?

Well, you're not gonna get that from one or two bacteria. And so you have to either only take one benefit you're looking for or you have to take a more complex consortia. And so it's not that you need a hundred strains, but if you wanna maximize the outputs, you generally want to see more microbes adding up together to create broader spectrum effects. So there is a kind of network effect, if you will, going on which probiotics you take and for what purpose you are taking them. That second category of probiotics is, well, what is your basis, right? What is your, you know, you hear all the time somebody say, oh, well, I take, I get my probiotics from kimchi or I get my probiotics from a nutritional shake or well, you get one or two strains of bacteria or you get kimchi organisms, but you can't say that that is going to therefore be equal to a strain which is proven to signal to the gut barrier or a strain that regulates cholesterol uptake or a strain that works on evacuation disorders to relieve constipation. I mean, all of these are different mechanisms and they're coming from different strains. It's why again, I think I want to emphasize consortia are so important. Which bacteria?

I mean, I mean, when you say consortia, you mean a lot of different strains that have been identified.

A lot of strains, yeah, together, together.

So, so keep going on how we know to pick the right one or the right strains.

So, so now you've kind of asked your first sequence of questions. Do I want a broad spectrum consortia for many different things or do I want something more targeted? From there you need to assess if what you're picking is good. And there's three layers to it. There's purity, there's potency, and there's efficacy. Purity means that there's the bacteria which are you list and none others. It's very simple and that's done by very good quality control. So you're sequencing at the level of individual genes, all the bacteria in your product, you know them, you get a fingerprint, every time you do a fermentation, every time you do a production, you get a fingerprint and you know that those organisms are there and nothing else is there. And so this is the most important question to ask from a sake of purity. Potency is not just what's written onto the label, because they can be very misleading. So there's products in Japan that say that we have one trillion organisms or a yogurt starter culture from Australia that says we have one trillion bacteria. There's kind of your VSL3 kind, your gastroenterologist-recommendeD-probiotics that are 300, 400 billion where you see these big, big numbers on them, you have very kind of high die-off, either very high die-off when it comes into your stomach right away, or it's typically only one strain or one species. Even if there's listed eight or nine different strains on the label, it's predominantly one. The number one gastroenterologist recommended probiotic has nine strains listed on its label, I believe, or eight, but it's 96% yogurt starter culture and the rest are small like tiny byproducts. So, you know, so, so potency is very important. Potency is very, very important. But at the level of throughout the entire gastrointestinal tract is something that I take very seriously. There's model, there's, there's sequenced.

In other words, in other words, you could take a probiotic looks good in the bottle, everything's in there, but you eat it, take it as a pill and it gets digest in your stomach and kllls everything, right?

Yeah. Or it's never even, what's listed is never even alive by the time it makes it. And so maybe you see 100 billion written on the label, but there's 99% die off by what reaches the colon. So you're not going to get much organic acid production with 99% die off before it even gets where it needs to go.

Mmm. so the bacteria you have to make sure you know you're taking a multiple consortium of what you call a consortium of bacteria that all have different scientific evidence behind them. Because there's a lot of stuff out there that doesn't, but there's a lot of evidence around a number of bacteria that have very specific effects on the GI tract, on the immune system, on heart health, on metabolic health, on immune health. So, we can use that data to start to design probiotics that actually make sense, right?

It's exactly the approach that I believe is best. Yeah, it's exactly the approach that we took.

For say, or seed. Your company is seed, right?

Which is, yeah, seed produced a probiotic called DS01. And it follows the design principle that you just stated, which is many different organisms from this similar species that have many different effects on many different organ systems. And so it's a consortia of abundance of it is a very broad spectrum from a microbial genomic standpoint. And this is the approach. Yeah.

And also, you know, you seed is the company that you are involved with that produces this unique probiotic that this is one of the most rigorously studied and then for sure the components in our regularly studied and, and evaluate in ways that make sure that you're getting what you, what you buy, that what it says on the label is what's in the thing, that it gets in your gut, that it does the right thing. So you, you have metrics for tracking all that, right?

Absolutely. So we were the first, I think, to do a capsule in capsule system, and we had to do about 50 different iterations of this. If it opens too late, you miss the small intestine, so you miss some of those immune benefits. If it opens too early, the stomach acid is going to kill a large percentage of those strains. And so it was really an exercise of finding this Goldilocks zone of upper small intestine, but complete release of all of your organisms. And this is something that we tested in XVivo and in vitro models to mimic the entire gastrointestinal system. I think this is very, very important. Some people say that probiotics don't have to be alive to work, but they're not really talking about probiotics, they're talking about something else. I'm not going to rule it out. I'm not going to rule it out that a dead bacteria could be positive. There's some data I've seen that maybe the immune system still picks up on its cell wall But it'll never, in my opinion, be more than if that effect is still happening, but the bacteria is also alive and it's able to be metabolically active. And so this kind of targeted release, you know, we did it. We were one of the first to do it. I think a lot of people now are trying to follow suit and make a delivery release profile really kind of a new standard, right? And I would love to actually see people engage more with companies on this type of data because it's very valuable to know where the bacteria are going to go and what percentage of the bacteria on your label actually have a chance of entering into your colon and being metabolically active.

Yeah, fascinating. And, the other thing that's unique is you also have prebiotics in there, but they're not the typical kind of prebiotics. They're actually polyphenols, which people don't think of as prebiotics, but I think they're their food for the bacteria. And, you know, for example, we know this with akkermansia that particularly loves green tea and pomegranate and cranberry polyphenols, and then that makes it flourish, whereas, you know, other bacteria might need other things. So how did you come up with this concept of what we call a synbiotic, which is a combination of a pre and probiotic?

Yeah, I remember in 2015 or 2016, the term prebiotic was almost exclusively used to talk about these types of fibers, not polyphenols, not flavonoids, not these other juicy compounds from the plant kingdom, but mostly fiber and types of fiber that were derived. And I think that's interesting. I think that there's a role for it. I think it's not for everyone. But most importantly, I think that the dosage of that needs to be very, very high. If you have a low fiber diet and you want to take it from supplementation, you need a lot of it to have a prebiotic effect. For our symbiotic, and my philosophy on non-fermentable prebiotics more generally, or prebiotics that are metabolized by the gut microbiome into these secondary tertiary metabolites, these very powerful molecules is the gut microbiome loves flavonoids and polyphenols, and it's more than just mucin degrading organisms that like to feed on them. You can find pathways in hundreds of different species of bacteria for secondary and tertiary, just basic conversions of these polyphenols. The reason is that polyphenols are very big molecules. That was one of our first discoveries, that polyphenols are very large. structurally, physically, they're very large. And so about, I think it's less than 5%. I want to say 4%, but I believe it's less than 5% of polyphenols are actually absorbed into your circulation and into your bloodstream directly. And so it's this very, very powerful way to impact the gut microbiome because you're just sending so much of them there. and they love it and they break it down into a lot of different things. And how we landed on pomegranate prebiotics fibers from pomegranate was because we began tracking these secondary conversions of how microbes metabolize different food compounds and found an exceptionally strong signal for a certain class of bacteria that was only found in ellagic acid, ellagitannins, and specifically in pomegranate, polyphenols, punicalagin, and pomegranate type ellagic acids. And so, I don't want to get too technical, but this had a twofold effect. So, one, and this research will be published in Q1 of next year, after a course of antibiotics, we found that the that DS01 and specifically the prebiotic that we use, which is whole fruit extract, actually starts to enrich back the gut microbiome and the bacteria which are able to degrade these plant compounds. So not only is your gut microbiome breaking this down, but your polyphenols are changing your gut microbiome. So it's a two-way relationship. and it's very powerful. You know, these are metabolites that get directly into muscle that are responsible for regulating mitochondrial activity. These are very interesting metabolites.

So have you been able to measure people's blood levels of uridine, for example, after taking seed, the probiotic?

Yeah.

And do you see increases in before.

And after in serum and urine?

You do. That's amazing because, you know, this is something we've talked about on the podcast before. Uridine is a postbiotics, something made by your bacteria that then is absorbed and regulates everything from your mitochondrial function, mitophagy, the regeneration of new mitochondria, muscle strength, cardiovascular fitness, inflammation, I mean, the list goes on. And, it's not something that most of us actually can make because our gut bacteria are not that healthy and you need to write bacteria to actually make this particular postbiotic. And, and, and yet what you're saying is that if you use the polyphenols, particularly from pomegranate, which actually is where a lot of the urolithin A comes from. With the right bacteria, you can actually see increases in urolithin A in the blood, and then we'll have these systemic effects.

An interesting thing about this data is the effect was wiped away after a course of antibiotics, but over a course of a 12-week period of time slowly came back. So, not only did we show that you're increasing these levels, but also that perhaps you're guiding the microbiome back after a course of antibiotics into a state which is more able to utilize these compounds that are not just found in DS01 but also from your diet. Yeah, so it sounds like antibiotics are a big problem.

And, you know, we've all been on antibiotics. I don't think there's anybody almost on the planet that hasn't been on antibiotics at some point, very rare. And, do they have permanent effects on damaging the gut microbiome? Can you recover from it? What does the research show about this? And how is sort of DS01 potentially helpful in this? I know you're doing a study with Health Canada on using DS01 after antibiotic use and seeing its effect on the microbiome.

Yeah, absolutely. So antibiotics are the harshest, most acute, that your microbiome will ever experience. However, the microbiome does recover to its original, not its original composition, but to its original abundance. Studies vary sometimes between six months and sometimes up to two years afterwards, you see the biomass return. But what's interesting is that you never really come back with the same microbiome. So every time you take it, you come back, and you have a different microbiome, you have a different relationship between species and different, sometimes the loss of rare species you had before that are now completely gone, and other times you have new organisms. And so every time you take a course of microbiome modulating drugs, antibiotics being the strongest, you play a little bit of roulette in which microbiome comes back, but the microbiome always does come back. If you're living in the world, the microbiome will always come back to what it's able to in the environment that you're in. The study that you described actually is finished and it was very exciting analyzing this data because the trial had four arms and so the trial had one arm that came in and they didn't take antibiotics, they took a placebo and then they took DSO1 They had another arm that came in and they took a placebo antibiotic and a placebo probiotic. It had another arm that took real antibiotics and DS01, and a fourth arm that took real antibiotics and a placebo probiotic. And so this really is a perfect trial design if you're trying to interrogate not just the effect that antibiotics have on the host, but the effect that probiotics can have. after a course of antibiotics that are unique to antibiotics or a period of time when the microbiome is disrupted. And we found some very interesting things. So first we found that the microbiome returned more or less after 12 weeks to the same abundance of organisms that they had after antibiotics and everyone who took antibiotics but that there were dramatic differences between the group that took antibiotics and DS01 and people that took antibiotics and had a placebo or spontaneous recovery.

What was the difference?

For example, if you took DS01 alongside antibiotics and 12 weeks following, you had a greater rebound in what's called rare species. And this is species that had less than 1% abundance in the microbiome. prior to taking a course of antibiotics. And so this was a very interesting microbiome mediated effect, right? So there was a kind of kick starting of that cross-feeding reaction that happened concurrent to antibiotics that kind of allowed some of those low biomass organisms to come back after antibiotics instead of get out competed in the microbiome fighting to come back after the course of antibiotics. I think that was a very interesting finding. We also found it in enrichment in butyrate-producing organisms. And so, although what's interesting is that although you didn't see an increase in butyrate, you had an increase in butyrate-producing organisms. And I don't want to get too nerdy or too technical here, but I think it's worth mentioning this because you talk about butyrate a lot. I think your audience has heard about butyrate a lot. People take butyrate sometimes itself as a postbiotic. But butyrate is actually the reason why it's so powerful is because it's used up by your colonocytes. Your colonocytes actually use it as a primary source of energy. And so the hypothesis of this trial and what this data showed is that when the microbiome is challenged, when it's threatened, you may not see, you're unlikely to see butyrate coming out in the stool when you're testing for it or enrichments in the blood because everything is being utilized. You have a bloom of these butyrate producing organisms, but it's being used to help that microbiome recover back to its baseline state and to help those tissue, those mucosal linings. And so this is a very kind of interesting finding. Yeah, I mean, I could go on and on. Probably the third and most important finding from this trial is that antibiotics themselves damage the gut barrier. So, there's this very invasive test which is called the lactulose mannitol test. It's you, you drink.

I used to do that all the time in my patient. That's not nasty.

No one likes doing it. They have to hang around for 10 hours and get tracked afterwards, see what passed through and what was absorbed in. But it's one of the purest tests, even though it's simple, it's one of the purest tests that tell you what molecules are gonna make their way across the barrier and into circulation or be absorbed. And the results here were quite striking. So there was like greater than 90% damage across the board from antibiotics to the gut barrier. And so you saw acute massive increases in epithelial barrier permeability, so gut barrier permeability after a course of antibiotics. What was striking about DS01 is that compared to placebo, we showed a very strong rescue effect and an almost complete rescue effect of that gut barrier with effects that persisted out weeks after the course of antibiotics. This is something which is, again, it's very interesting. You think about your environment, you think about disruptions, you think about what could probiotics be good for. Here's data that says that in a disrupted environment, probiotics and DS-01 in particular can have a rescue effect on those barrier disruptions. It can kind of return the gut barrier to a less permeable state.

So, you stopped sort of having a leaky gut. That's amazing. So, what are the other things that actually the DS-01 does? It's a multi-strain symbiotic. It has benefits beyond the gut, digestive health, gut barrier integrity we talked about. what are the other things that you discovered that actually work? And tell us a little bit more about it.

Yeah, so DS01 is a very complex probiotic consortia. There's 24 different strains and across 12 species.

So.

It'S complex in the sense that there's a very high number of unique genes. So DS01 has more unique microbial genes than any other probiotic that I'm aware of on the market and we've tested this extensively. It is about 50 billion AFU. The potency is about 50 billion active cells and these are live cells that have active in the sense that we use flow cytometry, which means that their cell wall is intact. That's how we measure our viability. and the strains themselves have very strong data across many different organ systems of the body. And so it's a kind of baseline probiotic. It's a many in one probiotic with strains that have targeted different organ systems in the body. And so the gastrointestinal system and the digestive system is definitely one, you know, things like intestinal transit time, stool consistency, stool quality, evacuation, gas production. There's a very big panel of markers that were assessed gastrointestinally, in healthy people as well as now we've done trials in IBS, in IBS-M. Outside of the gut, I think one interesting thing about DS01 is that there's data on The gut skin axis, there's data and inflammation on the skin. This is done in a healthy population as well as in a model of psoriasis and atopic dermatitis. There's data to suggest that specific organisms in this consortia lower cholesterol reuptake and so they can have a positive modulatory effect on cholesterol. I think it's a very loaded topic. I tend to believe that High cholesterol isn't necessarily bad for very nuanced reasons that you've discussed on this show many times. But for people that have elevated cholesterol, it can have this regulatory effect and other areas of the body and other such axes. So it's this broad spectrum approach. It's this very multi-use kind of product concept.

You know, what's interesting to me is some of the data around TMAO. TMAO is a compound that's produced in the gut by certain bacteria when you eat certain foods like meat or human fish. And studies out of Cleveland Clinic have found that high TMAO is linked to heart disease, which is an inflammatory compound, and it's produced by gut bacteria. Now, what was interesting to me in reading about seed was that you seem to be able to actually lower TMAO when you take this probiotic. When you look at the data on this TMAO, people who had olive oil or balsamic vinegar or even red wine actually mitigated a lot of the effects of the TMAO. So I've seen patients, for example, with high TMAO levels, is seed something that you have data on that shows that it may impact their levels of TMAO and their risk of heart disease.

It's very interesting that you mentioned TMAO in our antibiotics trial. After a course of antibiotics, those who came back with DS-01 compared to those who came back with placebo had lower levels. And so the microbiome is definitely involved in mediating this. However, I do not want to represent that this would be the strongest way to modulate the microbiome. I think a group at the Cleveland Clinic has actually shown that olive oil and particularly DMB from olive oil is the most potent modulator of TMA and TMAO production in the gut microbiome. So, for those that find this area interesting, I would drink olive oil like water and you won't be able to top the effect of that from any probiotic in the world.

That's interesting. So, we can't kind of modify our gut ecosystem to sort of be able to actually do better with our diet and so forth. you've also done a bunch of clinical studies, for example, mentioned the antibiotic study, but what about irritable bowel? You know, there's a lot of issues around irritable bowel for people with chronic constipation and, and IBS. What have you found in your studies? And these have been, I think, published data. So let me share a little bit about that. Yeah.

Well, this study is, I, I think our, the team will present the abstract at, at digestive diseases. week next year. And so this is all very, very new stuff. We, yeah, we did a trial in IBS-M with Dr. Anthony Lembo. He was at Harvard and recently moved to Cleveland Clinic. And I would consider him to be one of the world's leading experts in IBS. He's spent his whole career only focused on IBS. I remember sitting across from him at a conference where he said, yeah, well, do probiotics work? Do they do this? And I had a hypothesis that yet that said yes. And he says, well, I'd love to test it. And a year later, we were doing a clinical trial together. And so this was a really fun trial to do. And basically we took IBS type C and IBS type M, although many more people came into the trial that were IBS type M. And It's very, very common IBS. I think, you know, it's about 10% of the population, if not more specifically, maybe that's number of days or for insurance purposes versus a population. Yeah, it's a very high amount.

I mean, listen, the number one reason that people visit doctors is because they have GI symptoms, whether it's heartburn, reflux, or bowel bloating. I mean, it's the number one reason people visit the doctor.

Yeah. And, and what makes it difficult to study, though, is that it's very multifactorial. So, you know, some people can have it for largely environmental factors, others, it's driven more by their genetics, others, it's driven more by microbiome. And so what we really wanted to say is, okay, well, we're not going to be able to modulate their genetics or maybe even largely their microbiome composition using a probiotic, but will that microbial inoculation in this case will just the daily administration of microbes and of certain quantities and of certain diversity impact quality of life markers and progression. Again, this is a very difficult group to study because drugs are mostly less than 50% effective in their clinical trials for IBS. The gold standards are not very good and the placebo response rate is very high. It's often in the 30 to 40% range. you're having a very little effect size using classical approaches. And so it's why I think functional medicine and personalized medicine for IBS is very effective because you're eliminating, you know, you're deconstructing environmental and then microbiome factors and then trying to add something that tilts it the right way.

So.

We We were very impressed by the effect, particularly the signal in abdominal pain was significant against placebo and it was very strong. And so in this case, we think that the hypothesis is that DS01 was signaling to the local host immune system to downregulate a cascade resulting in abdominal pain. and I think that that's something which, which could help quality of life dramatically.

This has been quite amazing conversation. I think, you know, just sort of zooming out a little bit, and we learned about how the microbiome is this master regulator of so many of our biological functions. It's an incredible, incredibly complex ecosystem that it's regulated by what we eat, by fiber, by polyphenols, by, by probiotics that we can take that we're learning more about the diversity of these microbes and how they influence different aspects of our health, how to actually use them therapeutically in patients, how create cocktails, for example, of the most common ones that have been well studied and are scientifically validated, as you've done in SEED, to help sort of optimize our health. And I think you're leaning into this research heavily. I think you're doing really interesting work. You're coming up probiotics around kids probiotics and vaginal probiotics. So I think it's kind of an exciting, exciting moment. Where do you see this field heading? Because right now it seems to me that, you know, that the data number I threw out before, which is that there's 100,000 petabytes of data in your microbiome. It's unimaginable. You could be the smartest PhD microbiologist in the world and never be able to assimilate or understand the complexity of those network functions and how they influence our health. So how do you see this field changing with the advances in bioinformatics, machine learning, the omics revolution, AI, and using these large data sets to help customized what we're doing and be more precise in our ability to kind of recommend things for people.

Yeah, there is a very clear and exciting future for microbiome and microbiome data, but it has to be done a very specific way. The data sets have to be big, they have to be controlled, and they have to be longitudinal. So you have to track the same people over time until you have clean data sets which offer you these features is gonna be very difficult to turn microbiome. So this is the future. The type of data set that I spoke about us building, it's 13,000 people and they're in the fifth year of a 20-year study and everything, their diet logs, their genome, their medication history, their metabolomics of their blood every year multiple times, their sleep log, their DEXA scan, their CGM response for 60 days of continuous use. I mean, this is the most deeply phenotyped data set cohort in the world. And the findings that we have from this for precision probiotics and applications of it are, again, very honestly, they're in the earliest phases. I think we're two or three years out from a world where I could say, this is the perfect network of bacteria to take for weight loss for everyone or for that is safe for you. Or if you have a, if you want to improve the gut brain axis, this is thousands and thousands of people, the super healthiest compared to different controls, major depressive disorder, anxiety, schizophrenia, you name it. You can map it, you can see everything, you can track it over time and you can say, these bacteria, this network of bacteria together is responsible for over 400 different neuroactive metabolites. So this is the formulation for depression, right? But we're not there. We're not there yet. And I want to, the future is real, but we're not there.

And we're getting there. We're gonna get there. We're gonna get there. I believe we're gonna get there.

And we're just on our way.

Yeah. Personalized pharmacogenomics. We're going to have personalized nutrition. We're gonna have personalized probiotics. And I think it's at a really interesting moment where, like you said, we're sort of just, I don't even know if we're halfway there. It feels like we're just at the beginning of this era, and I think it's going to have profound effects. And also the whole microbiome field is just upending our view of medicine in general. It doesn't comport with the way we actually learn the body is organized. So, you know, it's, it's sort blowing up our paradigm of traditional diseases. I mean, how does the microbiome affect so many things? Because it's, it's, it's, the body's a network, it's an information system, and it's not a bunch of different organs and parts that all have to be looked at separately by specialists and then treated each with their specialist drugs. It's a very different phenomena that, than we're actually, understanding in traditional medicine. So this is sort of the, sort of the breakthrough moment where paradigms are shifting, science is accelerating, the combination of microbiome science with machine learning AI, large bioinformatics analysis is going to transform everybody's health. And so in English, everybody, what I'm saying here is that we're on the precipice of an era of medicine where you're going to be able to get a stool sample, do a deep analysis, a blood sample, get a deep analysis of the metabolites of the microbes, find out what you need, customize the probiotics. And until then, we kind of have to deal with the science we have and the best probiotics out there. They still can have a profound impact. And I know in my practice, I use these probiotics regularly and I see really significant impact across the board when they're used in combination with a healthy diet. Like I said, you can't be eating your crappy diet and taking your probiotic expecting a difference, but it can make a difference in conjunction with everything else you do. If you love that last video, you're gonna love the next one. Check it out here. Delicious healthy foods eaten at a modest volume. and also eating at the right time. So it's not just, it's obviously what you eat is important and how you eat is important, but when you eat can also make a difference.