283 ‒ Gut health & the microbiome: improving and maintaining the microbiome, probiotics, & more

1. 0:00 – 0:34

   Intro

   1. CCColleen Cutcliffe0:00

      The microbiome is really interesting because it's mutable, and you could develop things that could help people. There is a lot of evidence suggesting through these fecal microbiome transplants that you can actually help people improve health through a microbiome intervention, um, and that if you followed a drug development, you know, rigorous pathway, you could actually identify the subset of that fecal microbiome transplant that could help people. And if you could figure out how to manufacture them, you could really, you know, have a product with efficacy here.

   2. PAPeter Attia0:25

      [upbeat music] Hey, everyone. Welcome to The Drive podcast. I'm your host, Peter Attia.

2. 0:34 – 3:08

   Colleen’s background and current focus

   1. PAPeter Attia0:35

      Hey, Colleen. Thank you so much for making the trip out to Austin to sit down. It's always more fun to do these in person.

   2. CCColleen Cutcliffe0:40

      Thanks for having me. We're gonna take advantage of being in Austin. [chuckles]

   3. PAPeter Attia0:44

      [chuckles] Yeah, I know. Uh, so, uh, this is a topic that we've received a lot of, um, you know, interest on, and people have always wanted to go deeper on this topic. And my reluctance to do so has been, um, in part driven by a couple of things. One is just my general lack of clarity around finding people that can speak about the topic with, um, you know, with some degree of, of rigor. And then secondly, it's just, it's a market of products that seem so sketchy. And so when you and I met, um, God, it's probably been six months ago, and connected, I remember we went for this walk, and I re- I was thinking, "Ah, this is, this is, like, the most I've learned about this." And, and, you know, the rest is history, and so here we are. But may- maybe give folks a, a bit of a sense of your, your background scientifically. So, um, I know I think when we met, we figured out pretty quickly we had both been at Hopkins at almost about the same time. But you, of course, were doing your PhD there. So what, what did you do your PhD in again?

   4. CCColleen Cutcliffe1:46

      Yeah, my PhD was in biochemistry and molecular biology, so really thinking about enzymes and pathways and how they all interact with each other. Um, and then I did a postdoc at Northwestern. Um, we were, uh, looking for diagnostic markers for, uh, pediatric Wilms' tumors. Um, and then I moved out to the Bay Area, and I worked in pharma. We were developing drugs for Parkinson's disease. Um, and, you know, I sort of followed a pretty traditional path of a scientist into pharmaceutical drug development. Then I did what everybody does in Silicon Valley. I joined a startup company, [chuckles] and this was a DNA sequencing instrument company. Um, and we went through rapid growth. We went public, and on the other side of that, I started this company Pendulum. And it was really premised in the fact that things like probiotics and yogurts have been on the shelves for decades, but there actually hasn't been a new ingredient introduced in over 50 years. And that's because microbiome science wasn't a real science until DNA sequencing technology enabled us to really be able to survey the microbiome and create these metabolic maps and start to approach it like a biochemical problem and, and a systems biology problem. And all of a sudden it seemed like, wow, there had been a lot of unlocks in DNA sequencing technologies that would allow this entirely nascent field of science and medicine called the microbiome to produce real products. And so here we are 10 years later [chuckles]

3. 3:08 – 12:37

   The basics of the microbiome

   1. CCColleen Cutcliffe3:08

      in it.

   2. PAPeter Attia3:08

      So we'll definitely spend some time talking about products and, um, and, and, and, and, and the evolution that you've had in that, in that path. But, but let's talk more broadly just kind of about this, um, this field, right? So first of all, how do we define the microbiome?

   3. CCColleen Cutcliffe3:25

      The microbiome is essentially all of the microbes, so the bacteria, the viruses, fungi, yeasts that reside in and on us, and they are on our skin, they're in our nasal passages, they're in our lungs, uh, and, and they're in our guts.

   4. PAPeter Attia3:38

      Got it. Now, our guts, which run mouth to anus, are outside of our body, right? So people don't think of it always that way, but of course they are. So what, what allows the colonization of that? I mean, is that something that is set at birth? I mean, for-- So maybe taking a step back. When, when a, when a child is in his mother's or her mother's womb, there's amniotic fluid that's flowing through that spot. Is that a sterile area?

   5. CCColleen Cutcliffe4:07

      Well, interestingly, for a long time, uh, as you know, we've all believed that was an entirely sterile environment, and there were no microbes there at all. Um, and some recent studies have started to kind of elucidate that there are some strains, and so the, the-- but it's, but it's very minimal. When we think about the gut microbiome of an adult versus, you know, somebody who's in the womb, I mean, it's, it's incredibly much more diverse once you become an adult. And in, and in fact, really the primary initial seeding of the microbiome is, um, through the delivery, you know, uh, uh, in the vaginal canal. And so, um, this is-- We're gonna get gross for a second, but literally, as, as you're being delivered, you are consuming fecal matter that is in the vaginal canal, and that's your first seeding of microbes. And infants have, you know, a, a very small diversity of microbes that, uh, are really kind of tied to mother's breast milk. And then as you start to eat foods and as you start to get exposure to other environments, then the diversity of your microbiome starts to really grow and flourish. And then at some point on the aging process, the opposite starts happening. You start to become less diverse in your microbiome as we age. So there is this... You start out almost like a blank slate, you get a lot more diverse, and then as we age, you start to lose that diversity and, and therefore some key functions in the microbiome.

   6. PAPeter Attia5:23

      Uh, when is peak diversity approximately? What decade of life?

   7. CCColleen Cutcliffe5:26

      Well, uh, obviously it varies from person to person, but if you can remember a time where you could eat or drink whatever you wanted to, and you didn't have to worry about it, that would probably be the time. [chuckles]

   8. PAPeter Attia5:34

      Oh, so that's actually quite young. I mean, certainly for me-

   9. CCColleen Cutcliffe5:37

      Teenagers

   10. PAPeter Attia5:37

       ... that would've been as a teenager.

   11. CCColleen Cutcliffe5:38

       Yeah.

   12. PAPeter Attia5:38

       Exactly, yeah, when I could indeed eat a bowl of cereal for every meal with no consequence.

   13. CCColleen Cutcliffe5:44

       Yep. [chuckles]

   14. PAPeter Attia5:44

       Um, okay. So and by, by bowl, I mean a bowl the size of my head.

   15. CCColleen Cutcliffe5:48

       [chuckles]

   16. PAPeter Attia5:48

       So it's a box per bowl per meal. Um, so okay. So we have a relatively early peak in life for diversity. Um, a- again, you hear all of these sort of bumper slit-- stickers, slogans about the gut biome. Oh, it outnumbers us 10 to one. Is that true?

   17. CCColleen Cutcliffe6:04

       I, I think those numbers, uh, have, have definitely come into question. I mean, they're, they're nice to kind of give people a framework for the fact that you have a ton of microbes in you, and I think that's the important part, is that they are-- whether they outnumber you 10 to one or two to one, I think is relatively probably not that important. But what is important is that they c- make up a huge portion of your body, uh, mass as well as functions, and so it's an important key part of your health.

   18. PAPeter Attia6:30

       Call it even one to one. So let's just say there are, there are-

   19. CCColleen Cutcliffe6:33

       Yeah, even one to one is huge

   20. PAPeter Attia6:33

       ... there-- So, so the idea is there are many cells from-- that are not you between your mouth and your anus as there are you-

   21. CCColleen Cutcliffe6:41

       Exactly

   22. PAPeter Attia6:42

       ... cells. Now obviously, just to get-- have someone wrap their head around that, we're made up seventy percent of water, so most of our mass is water, not the cells-- not, not the cells minus the water. Are these largely anhydrous cells? Like, how do they weigh so little relative to the rest of us?

   23. CCColleen Cutcliffe7:00

       Oh man, I don't know the water content of bacteria, but maybe I think about it a little bit differently, which is more about the, um... And again, [laughs] I'm a biochemist, so everything's gonna come back to that. But it's more about the biochemical functions. What's the output of each of these cells, you know, versus the output of our cells? And I think when you look at it that way, these are real workhorses.

   24. PAPeter Attia7:18

       Mm.

   25. CCColleen Cutcliffe7:18

       So those-- You know, there's, there's definitely redundancy among bacterial cells, but each of them is having multiple functions and multiple outputs. And so when you think about it at a cellular level, I would think more about what are the things being produced by the cell, and bacteria tend to secrete a lot of things that they're producing, unlike the cells in our body. Um, and so there's a, a lot of function that's associated with the microbiome that's super important.

   26. PAPeter Attia7:42

       So I remember in my first and only biology course as a kid, 'cause I didn't take bio again until I decided to go to med school, uh, and, um, but in, in f- ninth grade or whatever, we learned about prokaryotes and eukaryotes, and I still remember to this day the, the joke of our teacher, Mr. Jefferson. He said, "Do you know what a eukaryote is?" And everyone was like, "No." And he goes, "It's a portaging term," referring to, you know, portaging when you carry canoes back and forth between rivers. Anyway, no, so ba-- horrible joke, but I still remember it. So, um, [laughs] I'm gonna have to cut this part out of the podcast. It's so bad. But-

   27. CCColleen Cutcliffe8:16

       It's like, where are we going? [laughs]

   28. PAPeter Attia8:18

       Yeah. Where I'm going with this is can you, um, explain to people listening, uh, what the difference is between our cells and bacterial cells? 'Cause there are some fundamental differences between these things called prokaryotes and eukaryotes.

   29. CCColleen Cutcliffe8:32

       Yeah, I mean, I think that, you know, first of all, every cell in our body, uh, kind of needs the other cells and the organs and the whole system in order to be able to survive and, and do their job, whereas bacteria, they don't need anybody else. And so every bacterial cell, every unit is its own living thing that can replicate, perform functions, lose functions, uh, be genetically modified and all of that. And so it's a, it's an-- m- maybe this is [laughs] this is-- it's sort of its own entity.

   30. PAPeter Attia8:59

       Yeah.
4. 12:37 – 17:42

   The study of the human microbiome

   1. PAPeter Attia12:37

      Wow, interesting. Um, tell me more about that project. So, you know, what were the observations it, it, it landed at vis-a-vis, um, how various factors, both modifiable and unmodifiable, either genetic or age, uh, and diet being the most obvious modifiable factor, how did that impact the, uh, the gut biome in these 10,000 people?

   2. CCColleen Cutcliffe13:00

      How did the, um, how, how did-

   3. PAPeter Attia13:02

      Those differences magnify-

   4. CCColleen Cutcliffe13:04

      Oh

   5. PAPeter Attia13:04

      ... in, in the out- in the outcomes.

   6. CCColleen Cutcliffe13:06

      Well, in those-- that study or, or that, um, initiative was-- didn't have a longitudinal component to it or a perturbation of the system in looking at before and after. So it really was just a-

   7. PAPeter Attia13:18

      A one-time observation

   8. CCColleen Cutcliffe13:19

      ... one-time observation saying, "Okay, we just look across a population of people, what are the..." And this was super early on, so we didn't know anything about the microbiome. We barely knew how to sequence the thing. And so-- and even things like, well, what's, what should the sample be? Should it be a scoop of somebody's stool? Should it be the entirety of the stool? Should you do 16S sequencing, which is just a, a gene that kind of all microbes have, or should you do the whole genome sequencing? That's gonna be a lot more expensive. This is a government-funded project. And so, you know, there was a lot of unknowns at that time. So even just getting this information of if I looked across, uh, 10,000 people from s- you know, skin to gut to, uh, you know, vaginal microbiome, what does it look like? That was a huge endeavor. And of course, coming out of that have been a, a ton of longitudinal studies and, um, studies where people have done actual interventions.

   9. PAPeter Attia14:08

      Going back to what you said earlier, it's not just bacteria, it's viruses, yeast, fungi. Um, what does the pie chart of that look like in terms of numbers? And then what does a pie chart like that look like in terms of function? Who's doing-- I mean, it's s- I'm guessing the bacteria are doing the majority of the work. You know, I do feel pretty comfortable saying viruses are bad. I, I, I-

   10. CCColleen Cutcliffe14:28

       [laughs]

   11. PAPeter Attia14:29

       Is there an exception to that rule? I mean, we certainly can harness viruses to do good things for us in terms of, you know, recombinant DNA technology. But if there was not a single virus on this planet afflicting humans, I, I don't-- I think we'd be in a better place, right? I'm not aware of good viruses.

   12. CCColleen Cutcliffe14:45

       Um, well, this field is really nascent, so I, I-

   13. PAPeter Attia14:48

       Uh-huh

   14. CCColleen Cutcliffe14:48

       ... hesitate to even answer the question of, you know, what is the role or the significance of all these different types of, of, um, microbes. Interestingly, uh, you know, I think we also don't really know what the role of viruses are in the microbiome.

   15. PAPeter Attia15:04

       Hmm.

   16. CCColleen Cutcliffe15:04

       But, y- you know, one could imagine that you have functions that are important and that you need to be healthy, and that maybe these viruses help accelerate, um, movement of those particular genes from one bacteria to another.

   17. PAPeter Attia15:19

       From one bacteria to another, yeah.

   18. CCColleen Cutcliffe15:20

       So I, I wouldn't say the jury's totally out in my mind-

   19. PAPeter Attia15:23

       Interesting

   20. CCColleen Cutcliffe15:23

       ... on that.

   21. PAPeter Attia15:24

       Yeah. That, that's a, that's a good point. Um, do we know anything about how our microbiome compares in complexity to that of other animals?

   22. CCColleen Cutcliffe15:35

       Well, a lot of microbiome studies are done in mouse models. And, um, I mean, having been in pharma, I feel like, um, we can cure-- If you're a mouse and you've got cancer, you're made. [laughs] We have so many different cures for you. Um, but you know, the translation of that into humans is, uh, you know, not that great. And the microbiome is even worse because animals eat different foods. Your diet is one of the biggest things that impacts your microbiome. And so now you're saying, you know, what is an animal's microbiome? How does it interact with the host? And then, you know, what implications does that have for health? So you're even o- one more step removed. So, um, there are a lot of strains that exist, you know, from, from mouse to man. But I think, again, because it's context, it's not totally clear that you can really use these animal models to predict what will happen in a human.

   23. PAPeter Attia16:21

       And has anybody looked at animals that are not living in captivity and not, you know, sort of genetically so ridiculous, like the typical, you know, black 6 mouse and things like that? I mean, do we know what the-- what our pet dogs look like or what animals in the wild look like?

   24. CCColleen Cutcliffe16:39

       Yeah.

   25. PAPeter Attia16:39

       And do they, do they more closely resemble us? Or again, is it purely a function of what they're eating?

   26. CCColleen Cutcliffe16:44

       It's r- a function of what they're eating i- is such a big driving factor. So if you look at your pet dog, I mean, it really does depend on what you're feeding them. Some people feed their dogs pretty much a grain-based diet. Some people are cooking chicken for their dogs [laughs] every night, you know? So, um, when you-- when they look at pets, I think that's also hard because it, it is y- it just ends up being parsed out by what you're feeding them. Um, and you know, just to get back to the reality of these genetically modified animal, uh, you know, mouse models, it's even more extreme in microbiome studies. So they literally make, I call them, like the bubble boy of, of mice. So they try to entirely deplete these mice of microbiomes. So they're taking a mouse that has no microbiome, and then they're infusing them with a human microbiome, and they're saying, "Okay, what happens now to the mouse?" Um, and so these are germ-free mouse models that are really commonly used to understand the impact of a human microbiome on the health of the animal. But it's, it's completely not-

   27. PAPeter Attia17:40

       Yeah

   28. CCColleen Cutcliffe17:40

       ... what would ever happen in real life. [laughs]

5. 17:42 – 27:51

   Categories of bacteria, and the implications on health of the rapid evolution of bacteria

   1. PAPeter Attia17:42

      So for folks listening, again, who might not, you know, think much about bacteria, um, my vague recollection of microbiology is, you know, one line in the sand we draw to divide them is are they aerobic? Are they anaerobic? Are they gram-positive? Are they gram-negative, which is simply a, a strain-- a, a staining technique. I guess I should explain that aerobic are bacteria that require oxygen for respiration. Anaerobic are animals that generate ATP without oxygen. And then you have facultative of each, where they prefer to do it one way, but they can do it the other way. Um, any other divisions worth talking about as we explain the, the types of bacteria?

   2. CCColleen Cutcliffe18:26

      Yeah, I think that the, um, the aerobic versus anaerobic is definitely one of the most important things when you think about you've got bacteria on your skin that definitely loves oxygen, and then what we call the gut microbiome is actually a strictly anaerobic area of, um, the distal colon, so there's literally no oxygen. Those strains can't even grow in the presence of oxygen. One other thing might be localization, so, um, your, your GI tract and the gut microbiome, there's, uh, you know, this so-called gut lining, so the cells, the, the epithelial cells where there's this mucin layer. That's an important part of having, um, you know, a, a, a well-fortified gut lining. There are strains that, that live in that mucin layer, and so that's a different-

   3. PAPeter Attia19:10

      Hmm

   4. CCColleen Cutcliffe19:10

      ... type of a strain. They feed off of mucin versus, you know, many of the other strains that sort of feed off of, um, things like the, the foods that you eat or prebiotics.

   5. PAPeter Attia19:21

      How does the, um, characteristic-- Let's just focus on the bacteria. How does the characteristic of the bacteria change from mouth to anus? Obviously, you're going into less and less oxygen as you go down, so presumably you don't have pure anaerobes in the mouth. But I n- I know from the little bit I remember about working in an ER, whenever somebody received a bite, you know, you would think, "Uh, how bad can a bite be?" We, we were really conditioned to remember that those are some of the dirtiest wounds a human can have, and no less dirty than a feces-soiled wound. So even at the proximate end of that, um, of that bacterial lining, it's-- these are really frightening bacteria. Um, but, but can you tell me anything about how the bacteria change as you progress along that, the length of that? Which is, by the way, that's a very long tube. So it's not just-

   6. CCColleen Cutcliffe20:16

      [laughs]

   7. PAPeter Attia20:16

      ... measuring here to here. Like, you have to understand that tort- You know, the listener would have to understand how tortuous the small intestine and the colon can be.

   8. CCColleen Cutcliffe20:23

      Yeah. I mean, the, the primary thing that changes is this anaerobic part. So obviously your mouth, there's a lot of oxygen exposure, and then as we said, when you get to the distal colon, there's no oxygen there. So all along that path there, and so from the mouth to the stomach, I think, is kind of where you have a reasonable amount of oxygen exposure. Once something gets through the stomach, it-- there's sort of this, uh, kind of in between the strict anaerobic, uh, and the aerobic area. And a lot of the Lactobacillus and Bifidobacterium strains that are on the labels of probiotics out there today, they kind of reside in that kind of small intestine area.

   9. PAPeter Attia20:55

      Hmm.

   10. CCColleen Cutcliffe20:56

       And then you get to the, the recesses of the gut microbiome, which is where all the action happens. So after your stomach has broken down foods and they make their way to the distal colon, that's where an incredible amount of metabolism is happening and, and there there's no oxygen. Um, but yeah, the mouth microbiome is, is, is a really interesting opportunity because, you know, the kind of what's happening in the mouth, maybe [chuckles] the two ends that you mentioned, mouth and anus, what's happening in the mouth and what's coming out the other side give you an indication of what's happening in the middle. And so, um, I'll just tell you a funny story. Early on when I started this company, I met a guy who was really interested in hyena mouth microbiomes.

   11. PAPeter Attia21:33

       Hmm.

   12. CCColleen Cutcliffe21:33

       And the reason is because the hyena is one of these bizarre animals that can eat a carcass of an animal after it's been dead for, uh, extended periods of time, you know, a week, two weeks. No other animal will go near an animal that's been dead for that amount of time because of the bacterial overload. It's just gonna kill you. And so it's so-called rotten meat that these hyenas are able to eat. And he had this big question of why are they able to do that?

   13. PAPeter Attia21:56

       Yeah.

   14. CCColleen Cutcliffe21:56

       And it turns out if you look at the microbiome of a hyena, they make an incredible amount of antibiotics. And so, um-

   15. PAPeter Attia22:04

       Hmm

   16. CCColleen Cutcliffe22:04

       ... he had this whole theory that if you could understand, you know, what antibiotics are being generated in that hyena's mouth microbiome, it might be a new source of antibiotics for us. And he was so extreme in this belief that the hyena had such a clean mouth that in the context of doing this job of trying to get microbiomes, he got bit by a hyena. He went to the emergency room, and they were getting ready to give him antibiotics, and he, he said, "No, I don't want antibiotics. It's gonna, it's gonna decimate my microbiome. Furthermore, I know that because I got bit by a hyena, I'm not gonna get an infection. They have the cleanest mouths." And he had to sign [chuckles] all these waivers, and apparently he never got an infection. But, um, you know, the, the mouth microbiome is a source of potentially, you know, bacteria, but, but maybe other sources of new science. [chuckles]

   17. PAPeter Attia22:48

       All right. So what is the classification? How, how do you, like, uh, it-- what's the org chart of these bacteria?

   18. CCColleen Cutcliffe22:58

       Well, they're ba-- So yeah, now we're gonna get, get back to kinda seventh grade biology where you have, you know, the phylum, the family, the genus, the species, the strain. And so that's the organization of them. And, and so, uh, really we kind of, when, when I say there's-

   19. PAPeter Attia23:12

       I don't even remember that anymore. Say it again.

   20. CCColleen Cutcliffe23:14

       [laughs] It's the, the phylum, the family, genus, species, strain. Um, and, and so the, what DNA sequencing has enabled us, uh, us to do is to really look at strains. And kind of maybe one interesting thing is even within strain identity, so we give names to these strains based on their genomic makeup, um, even that part is really kind of evolving in, in our understanding as well. So for example, you know, methylation's sort of a hot topic when it comes to humans. Bacterial genomes are also methylated. It's typically used for silencing certain genes. But, you know, you sort of have this question of is it really just the genetic makeup or are these, um, kind of post-modifications also changing a strain from one thing to another? Should you define a strain by its genomic makeup, which is the traditional way we define things, or should you define it based on what it's doing and its actions? And that becomes more complicated. So I think we're gonna see that definition maybe evolve as we learn more.

   21. PAPeter Attia24:11

       Do you mostly operate in a world where you're thinking of the strain then?

   22. CCColleen Cutcliffe24:16

       Yeah. We operate in a world where we're thinking about the strain and, and the function. So we, you know, for example, as we're growing-- as we manufacture our strains, we do occasionally these sort of whole genome audits. And so because these strains do divide and, and replicate, um, most of them Basically every t-two hours. Um, you want to make sure that whatever genetic modifications are just happening naturally, uh, don't actually impact the function of the strain. So we literally do these audits where we'll take-- we'll do a whole genome sequencing of these batches. We'll do a full panel of biochemical assays to understand are they still generating small molecules at the rate that we'd expect, growth curves. And so I think that's the-- one of the, um, challenges to actually being in this area, is that these guys evolve really quickly. [chuckles]

   23. PAPeter Attia25:01

       Yeah, I mean, it's hard for me to kind of wrap my head around that b-because even though I acknowledge what you're saying with respect to the speed, um, of their multiplication or replication cycle, when I think of, like, my former life when I was in a hospital, you know, everybody knows what MRSA is, right? So, so you know... But does it mean that there's, like, a new MRSA every, you know, pick your favorite period of time where, uh, e-even something like every month there's a new MRSA in the hospital kind of thing that fortunately always still seems to be responsive to vancomycin, but at some point it won't be. Like, I guess there's VRE, right? Vancomycin-resistant enterococcus. So, um, h- it's, it's hard for me to wrap my head around the speed with which these things are mutating, so that within the span of a year of your life, does that mean that your gut biome is changing not just as a result of you changing, but because they're evolving? Like, I, I still don't understand exactly which-- who's optimizing for what. Let me, let me reframe my question. What are they optimizing for in their rapid evolution?

   24. CCColleen Cutcliffe26:09

       They're optimizing for their environment, and so again, if you, uh, sort of take diet as the primary thing that can modify your microbiome, it's the primary thing that can modify your microbiome 'cause that's their food. They're living in your gut. They're waiting for you to feed them.

   25. PAPeter Attia26:23

       So in other words, uh, sorry to interrupt you, but the reason that S, you know, MRSA and VRE are evolving is to escape the antibiotic-

   26. CCColleen Cutcliffe26:32

       Yes

   27. PAPeter Attia26:32

       ... which is against our best interest. But what you're saying is, at least if I'm hearing you correctly, it could be that the evolution of our gut biome is in our best interest because in theory it's evolving to its environment, which is us.

   28. CCColleen Cutcliffe26:46

       Exactly. It's evolving to survive what we're feeding them and the environment that we're creating for them.

   29. PAPeter Attia26:52

       Interesting. Okay. So very, very fluid.

   30. CCColleen Cutcliffe26:55

       It is. It is. And, and i-it, you know, you can go on a trip, uh, you know, to another country and eat the food there for a week and come back, and your microbiome looks totally different in just, you know, that kind of a, a short period of time. I mean, many of us have experienced that. Like, you go travel, you get GI distress from foods 'cause you're not used to having them.
6. 27:51 – 39:52

   Methods for measuring and understanding the microbiome, and key indicators of microbiome health

   1. PAPeter Attia27:52

      Got it. Makes sense. And so let's talk about how one measures these things, both in the lab, so what you would do, but also maybe, for lack of a better word, over the counter, um, and what I could do. So if, if, if, um, if, if we were interested in understanding your genes, we could do them in a number of ways, right? We could do the gold standard, which was we could do a whole genome sequence. We could sequence every nucleotide of every single coding and non-coding gene in your body. And, um, twenty years ago, that would have cost close to a billion dollars. Today, that's about a thousand dollars. Still not the most practical test in the world 'cause it yields a whole bunch of information one doesn't know what to do with, but that's-- there's the gold standard. Uh, conversely, we could go on a fishing expedition, and you could say, "Well, I'm, I'm really worried about my risk of cancer," and we could do a commercial test that looks at a whole bunch of known, uh, polymorphism SNPs, and we could sort of screen for a hundred of those things. It's a much more targeted look, and we could get that information. Um, walk me through the menu of options that you as a scientist would embark on to do this and then what a consumer can do.

   2. CCColleen Cutcliffe29:19

      Yeah. So, um, i-it's actually quite similar when it comes to understanding the m- the, the microbiome. So you can do, uh, shotgun sequencing, where you're getting the entire genomes of all the different microbes, and then you need to be able to assign which genome goes to which microbe, and there's a fair amount of redundancy. And so you use long-read paired with short-read sequencing to be able to get full, the full genome.

   3. PAPeter Attia29:39

      Tell folks what that is so they understand.

   4. CCColleen Cutcliffe29:41

      Okay.

   5. PAPeter Attia29:41

      Yeah, 'cause it's, it's a bit complicated.

   6. CCColleen Cutcliffe29:42

      Um, so it, it's kind of exactly how it sounds. Short-read DNA sequencing, uh, gives you-- So let's, let's assume, let's take a, you know, example. You've got a, a thousand bases of DNA that you want to sequence. Um, what short-

   7. PAPeter Attia29:57

      By the way, what's typical for, um, a, a bacteria has typically how many genes and how many base pairs?

   8. CCColleen Cutcliffe30:03

      It, it really is a hu-huge range of, of, uh, of sizes. Um, but let, you know, let's-- the, so if you're, if you're trying to measure a, a, a c- a certain piece of DNA, you can u-use short-read sequencing technologies, which allow you to, with high accuracy, get these short pieces of your, your sequence. So you get maybe two hundred base pairs, and so you would have a few of these, and then you paste them together based on kind of the overlapping.

   9. PAPeter Attia30:30

      The overlaps.

   10. CCColleen Cutcliffe30:30

       Yeah. And each piece is, is pretty accurate in terms of the, the sequence. Then you can do long read sequencing, which will allow you to get in one shot that entire thousand base pairs, but that tends to be a, a slightly lower fidelity read, and so you might have some errors in there. And so that's why kind of the best way to do it is to do both. So you would get your long continuous... And, and I would say the reason that that's, the s- the stitching together is problematic is because, um, bacteria have redundant genes. And so some bacteria might have, you know, five copies of a gene versus another bacteria that has 10 copies of a gene, and turns out it matters. And so, um, [lip smack] oh man, I'm not gonna remember the name of this bacterial strain, but, um, there is a strain that's been studied pretty well that, um, metabolizes digoxin. Uh, and, um-

   11. PAPeter Attia31:16

       A drug that's used to treat arrhythmias.

   12. CCColleen Cutcliffe31:18

       Yes. And, um, and one of the reasons why that drug fell from being first line is because the efficacy sort of had such a wide, broad range across people, so it's hard to know what's the right amount to, to, to prescribe to somebody.

   13. PAPeter Attia31:30

       Wait, does it treat arrhythmias or heart failure?

   14. CCColleen Cutcliffe31:32

       It's heart failure.

   15. PAPeter Attia31:33

       Yeah.

   16. CCColleen Cutcliffe31:33

       Yeah.

   17. PAPeter Attia31:33

       Yeah, yeah. Anyway.

   18. CCColleen Cutcliffe31:34

       Um-

   19. PAPeter Attia31:34

       That's how long I've been away from the game.

   20. CCColleen Cutcliffe31:36

       [laughs] Um, and, and I'm no clinician, so I... But, but what they found was that there's a microbe that can metabolize digoxin, and so people who needed higher doses to have efficacy-

   21. PAPeter Attia31:47

       Yeah

   22. CCColleen Cutcliffe31:48

       ... had higher amounts of this strain. But then in a- another double click of that, it wasn't just that strain, it was how many copies of this particular gene that it had. So if it had over five-

   23. PAPeter Attia31:56

       Wow

   24. CCColleen Cutcliffe31:56

       ... it could metabolize digoxin. Less than five, it couldn't. So getting back to actually s-

   25. PAPeter Attia32:00

       And that means that that bacteria exists high in the GI tract, presumably, because if that were just something in your cecum or l- or beyond, presumably it wouldn't have impacted it. I mean, it has to be somewhat in proximity to the liver to, to, to, to, uh, uh, it have such an impact on the bioavailability of that drug, right?

   26. CCColleen Cutcliffe32:22

       I can't remem- now, now I really don't know where it... But I think isn't digoxin an orally cons-

   27. PAPeter Attia32:27

       Yes.

   28. CCColleen Cutcliffe32:27

       Yeah. So, um, I, yeah, I actually don't remember the location of this bacteria, but I, I remember this part about the number of genes being important as to whether it could even metabolize a thing or not.

   29. PAPeter Attia32:36

       Because normally we think a lot about the num- the, the different genes in the P4 cr- P450 system in the liver, which is heavily responsible for how most drugs are metabolized, and that clearly explains a lot of the variability in human metabolism of drugs. But I'd never, I never knew about this. This is even one step beyond that, and obviously not dependent on our genome, but the genome of this host.

   30. CCColleen Cutcliffe32:59

       Yeah. And these are mostly gut microbes, so it really is, especially for these oral, um, uh, drugs, there is some inner or some, you know, path that it takes where it's interacting with these microbes, and they are able to metabolize, um, these various drugs. But so kind of getting back-
7. 39:52 – 47:21

   The important role of fiber for promoting gut health through the production of butyrate

   1. PAPeter Attia39:52

      Okay. So explain how carbohydrate met- carbohydrate metabolism produces byproducts and what those byproducts are, because people who listen to this podcast, people like me, when I think of carbohydrate metabolism, I don't think of any of the things you just said, right? I think of glucose. I think of glucose 1-phosphate. I think of glucose 6-phosphate. I think of pyruvate. I think of acetyl-CoA. I think of the, uh, Krebs cycle. I think of, um, you know, lactate as a byproduct of oxidative phosphorylation. So you're thinking of things in a different level because you're obviously looking at a different host. So explain the metabolism on that side of the ledger.

   2. CCColleen Cutcliffe40:34

      Yeah. So in this case, when we talk about carbohydrates, we're really talking about these fibers. And so our microbiome is uniquely positioned to metabolize fibers, a wide variety of which we actually can't even metabolize ourselves. And, um, fiber, uh, is a, one of the primary prebiotics that feeds kind of all of your strains. And so you're right. When we think about carbohydrate metabolism from the perspective of the microbiome, it's really thinking about these fibers. And so they are-- there are, um, kind of primary and secondary fermenters in the microbiome that can metabolize these fibers into certain short-chain fatty acids, which then become precursors for the ultimate short-chain fatty acid, which is butyrate. But y- b- butyrate is this incredibly important, uh, short-chain fatty acid that's been studied in a wide variety of conditions. And so your microbiome, one of the most important molecules it makes is butyrate. Um, and so butyrate has role, a, a role in GI health. Um, the colon cells are the only cells that use butyrate as their source of energy as opposed to glucose, which is what's used by every other cell. And so when you don't have enough butyrate, that's been associated with things like colon cancer and, you know, not having good colon health. Um, but butyrate is also a small molecule that triggers G protein-coupled receptors to then, um, uh, release g- uh, GLP-1 from these L cells in the microbiome. So it also plays a role in sort of this gut metabolism axis. Um, and so butyrate becomes this really important small molecule that the gut is producing based on the foods that you're eating. Um, and, and that's kind of where we've really honed in.

   3. PAPeter Attia42:06

      So if we think about the difference between soluble and insoluble fiber, are you referring mostly here to insoluble fiber because you alluded to the fact that it's fiber we aren't able to digest and metabolize that is the food stock for these bacteria?

   4. CCColleen Cutcliffe42:19

      Yeah. That's really where we're focused in on is these insoluble fibers.

   5. PAPeter Attia42:22

      And insoluble fiber, I guess, is most readily available in vegetables, correct?

   6. CCColleen Cutcliffe42:28

      Exactly.

   7. PAPeter Attia42:29

      Are there-- What are-

   8. CCColleen Cutcliffe42:29

      Vegetables and fruits. Yeah.

   9. PAPeter Attia42:30

      Other fruits as well. Yep. So, um, by the way, I, I was asked recently by a patient, you know, "I drink this, like, green drink every morning." And they're like, "You know, why do you drink it? Do you think it's a substitute for having vegetables?" And I said, "I really don't." I think-- I said, "I think it's a substitute for having vegetables with respect to the vitamins you get and probably even a lot of the polyphenols, but it's clearly not a substitute for the fiber, just based on a practicality." Like you wouldn't-- You can look at the ingredient label. Like there isn't enough fiber in this to be a, a, a substitute. So at the end of the day, like, there doesn't appear to be-- If, if you buy the argument, which I think we're gonna discuss, that fiber is essential for gut health, which by extension means essential for human health, you have to be eating a ton of fiber, insoluble fiber, right?

   10. CCColleen Cutcliffe43:23

       Yeah, you, you, you do. Although, I mean, there have been a, a, um, you know, myriad of studies showing that you getting fiber from these external sources, these powders, and you have to get them in the, in the volumes, um, needed, uh, but they can be pretty impactful for your microbiome as well.

   11. PAPeter Attia43:38

       How many-- I mean, h- what are, what are, what are typical recommendations of fiber? Like how many grams per day? Eighteen? Thirty? Something like that?

   12. CCColleen Cutcliffe43:46

       Yeah, I, I think that the-- I actually don't know what the current kind of standard recommended dose is, but I think it's somewhere between twenty and thirty grams a day.

   13. PAPeter Attia43:55

       Yeah, it's hard to imagine getting that in a supplement.

   14. CCColleen Cutcliffe43:58

       Yeah. And, but, and I think actually your average American's [laughs] consuming like one to two. I can't even-- It's, it's really-- We're way off base on how much fiber we're consuming.

   15. PAPeter Attia44:07

       Yeah. So going back to-

   16. CCColleen Cutcliffe44:09

       But, but just to get to your question, though-

   17. PAPeter Attia44:11

       Yeah

   18. CCColleen Cutcliffe44:11

       ... there's also a delivery component to this too.

   19. PAPeter Attia44:13

       Hmm.

   20. CCColleen Cutcliffe44:13

       So taking the fiber kind of in a, you know, where you mix it in a drink, um, you know, might be a lot less impactful, or you might need a lot more of it, I should say, than if you were to take it in a enteric-coated capsule that got through the stomach acid and then, you know, closer to the distal colon. Then you're, you're-- it's a delivery question, so you might be able to get away with a lot less.

   21. PAPeter Attia44:34

       Oh, interesting. Why is that? I mean, w- w- I thought that given that it's insoluble fiber, it would be impervious to the gut and the environment all along the way. Is that not the case?

   22. CCColleen Cutcliffe44:45

       Well, so again, you know, the measurements of these things along the way has been, uh, elusive, but I think that-

   23. PAPeter Attia44:51

       As my daughter would say, "Sus."

   24. CCColleen Cutcliffe44:52

       [laughs] Sus. Um, but you know, we include inulin in our pill, and it's a, an incredibly small amount. It's, you know, in the order of one to two hundred milligrams, so it's definitely not at the dietary fiber level. But the reason we include it is because when we did our preclinical studies, we saw that if we didn't include it, the strains really didn't colonize as well. So the concept behind that is that by having the inulin right there next to the strains, as soon as that capsule deso- dissolves, these things start to get hydrated and start to become alive. In very close proximity is their food, and that's why I think about that kind of delivery and that proximity question as being something we haven't really solved for yet.

   25. PAPeter Attia45:32

       Interesting. Okay. So you eat a piece of celery, which is basically all insoluble fiber, um, and you know, that, those, you know, you mechanically break it into smaller pieces, but functionally it's still cellulose that's making its way down. At what point in the gut? Does it have to wait till it's in the colon or does the metabolism and production of butyrate begin in the small intestine?

   26. CCColleen Cutcliffe45:58

       There's some Bifidobacterium in the small intestine that can help start to break that down, but I think the general thought is that the majority of that, uh, metabolism is happening in the distal colon.

   27. PAPeter Attia46:09

       Okay. And which strains of bacteria are most responsible for the metabolism of insoluble fiber and the production of butyrate as a, as a byproduct?

   28. CCColleen Cutcliffe46:21

       You know, it's a, it's a multi-step pathway. So there are clostridial strains which can do this breakdown. There are, um, Bifidobacterium strains that can do this breakdown, and then there is the strain Akkermansia, which, uh, was discovered in the early 2000s, and, um, it also plays a really important role in generating these short-chain fatty acids.

   29. PAPeter Attia46:41

       And are these strains-- Do they belong to the same species?

   30. CCColleen Cutcliffe46:45

       Yeah, I'm, I'm doing a bad job. Th- these are the species names.
8. 47:21 – 53:25

   The case for manipulating gut bacteria via fecal microbiota transplant (FMT)

   1. PAPeter Attia47:21

      Okay. Um, let's pivot for a moment and actually talk about C. diff because that's one of the most compelling arguments for an intervention in, um, treating human disease by manipulating the gut bacteria. So tell folks what Clostridium difficile is as a bacteria, and you already alluded to this, but how does it go from being kind of a, a benign/benevolent, um, participant in our coexistence with the universe to one that could kill us?

   2. CCColleen Cutcliffe47:58

      So Clostridium difficile is a strain. It exists, and many of us have it in low levels in our gut microbiome, and we walk around perfectly healthy and, and fine with it. Um, when you take an antibiotic, that's essentially almost like a nuclear bomb to your microbiome. It kills everything in there. Um, but in some cases, it doesn't kill everything. And so there are these strains of Clostridium difficile that after you take an antibiotic, it's killed all the different strains off, but y- it didn't kill your Clostridium difficile strain. And the problem with killing off all the other strains is now all the competition is gone. So you imagine, you know, you have all these-- this ecosystem of different microbes, and now you've just gotten rid of all of them. So now you have this strain that has no competition, and it can start to propagate unchecked. And so it's when you start to have these really high levels of this strain, Clostridium difficile, in your microbiome, that's when it starts to make you really sick, and actually ultimately it's fatal. And so the way in which we treat infections is through more antibiotics. And so when you have this Clostridium difficile infection, um, which is a result of having taken an antibiotic, almost ironically the cure also is another antibiotic. And really what you're trying to do is to get an antibiotic that can kill that strain, uh, and get it back to its low levels until your microbiome can reconstitute itself through the food that you eat. Um, the kind of success rate of those antibiotics, you know, varies from person to person, but overall it's something like 70% successful. And remember, fatality is on the other side of this, [laughs] and so-

   3. PAPeter Attia49:27

      I was just about to say, make sure people understand what non-success means here. Yeah.

   4. CCColleen Cutcliffe49:31

      Yes. Yes. So, uh, yeah, 70% success is not great when the 30% means that you're, you're gonna die on the other side. So one of the concepts was really to kind of go in the reverse direction and say, "Okay, if the problem is that now there's no competition and this guy can propagate unchecked, what if we just load up the, the person's gut with, uh, you know, all these different microbes, reestablish an ecosystem, and then that's the way to kinda temper this thing down?" And that's called a fecal microbiome transplant, where you... It's exactly what it sounds like. You literally take feces from a person and transplant it into another person. That thing has, like, a 99% success rate. So-

   5. PAPeter Attia50:08

      When was this first done?

   6. CCColleen Cutcliffe50:09

      Oh, man. This was first done-

   7. PAPeter Attia50:11

      I feel like this was at least in the '90s.

   8. CCColleen Cutcliffe50:13

      Yeah.

   9. PAPeter Attia50:13

      Maybe earlier?

   10. CCColleen Cutcliffe50:14

       Well, it was definitely done as one-offs before people were doing real studies with it, and actually a ton of them were, have been done in Australia. It's, like, one of the-

   11. PAPeter Attia50:21

       Yep

   12. CCColleen Cutcliffe50:21

       ... places where the most of these are, have been done. Um, but yeah, it has an incredible success rate. It's kinda gross. Uh-

   13. PAPeter Attia50:27

       Yeah, what was it like back in the day, and how is it done today? I assume today it's done through capsules?

   14. CCColleen Cutcliffe50:33

       Well, I think people are still using the methodology of actually going up through the colon, but, but d- but people have tried to create more, um, uh, you know, they've tried to create capsules and, and tried to be able to make it so that you can just drink these caps- You can, sorry, uh, consume these capsules, capsules with a drink, and then it gets there. And, and those seem to be effective. They're, they're not as effective as when you just sh-

   15. PAPeter Attia50:55

       The enema

   16. CCColleen Cutcliffe50:55

       ... the, the enema, uh, [laughs] um, the enema version. Um, and it's, and because probably in the, in the process of kind of getting that, um, stool into a freeze-dried format or into a pill format, you're losing probably some of the diversity that you just get when you do it the, the old-fashioned way.

   17. PAPeter Attia51:13

       And there are risks associated with this or not? Are they overblown? I mean, there's certainly been... I know there was some hoopla about this at the FDA at one point. What, what was that about?

   18. CCColleen Cutcliffe51:23

       Well, I think the biggest risk is, you know, fundamentally your, uh, it doesn't feel like a therapeutic to give people shit. [laughs] So I think there's sort of this instinct that, "Okay, this isn't safe." But, but there's, there is a reality around it, which is that you don't know w-w... The, the source of that person is, is really important, right? How do you know that that's a healthy, so-called healthy stool donor? And so what if they've got some weird pathogen that now you put it into this person, uh, who's already in a depleted state?

   19. PAPeter Attia51:52

       Who's already compromised.

   20. CCColleen Cutcliffe51:53

       Right.

   21. PAPeter Attia51:54

       Yeah.

   22. CCColleen Cutcliffe51:54

       Um, and then furthermore, because everybody's microbiomes does, do have these different functions, it's possible that you might cure them of the C. diff, okay, great, and you might not have given them a new pathogen, that's fine, but you might have changed their metabolism of foods in a way that's not beneficial to them. And so for example, there are some of these, uh, case studies of someone getting a fecal microbiome transplant, and now all of a sudden they have obesity issues that they never had before. And so all of those things sort of... What really is at the heart of it is that we're very early in understanding microbiome science. And so I think the FDA, you know, their job is to make sure that people are safe, and so they have to decide, is it more safe to kind of give people this cure that has this incredibly high success rate when fatality is on the other side? Or is it more safe to say, "Hey, let's keep learning more about this before we actually introduce it into clinical care"? And they actually tried to shut the whole thing down. They essentially said FMTs are not approved by the FDA. They're not safe until we learn more about the science. And-

   23. PAPeter Attia52:52

       What year was that-ish?

   24. CCColleen Cutcliffe52:54

       This was probably, um, I don't know, maybe 20 years ago.

   25. PAPeter Attia52:59

       Okay. Oh, that-

   26. CCColleen Cutcliffe52:59

       I do have a... Yeah.

   27. PAPeter Attia53:00

       Okay. That long ago.

   28. CCColleen Cutcliffe53:00

       Um, but [laughs] essentially these people who had, uh, these physicians, these patients, patients' families who had all experienced this benefit, and the people who were in the queue to get it done essentially, you know, with pitchforks in hand, went to DC and said, "This is crazy. Like, this thing has such a high cure rate. How could you possibly take it away as an option for people?" And so they put their tail between their legs-

   29. PAPeter Attia53:22

       Reversed their position

   30. CCColleen Cutcliffe53:22

       ... and reversed it [laughs] and let people, you know, u- do them.

9. 53:25 – 59:16

   Dynamics of the microbiome: the gut-brain connection and how antibiotics, nutrition, stress, and more impact the microbiome's diversity and function

   1. PAPeter Attia53:25

      Let's, let's talk about an example you just gave there, which I know is sort of theoretical, but I'm sure there are many cases like it, where you take a, you take a lean individual who's hospitalized for some reason. They're given an antibiotic. In the process, they develop C. diff colitis. Uh, they get a fecal transplant, and they recover. The fecal transplant came from somebody who was obese, and now they develop obesity. So the hypothesis here has to be pretty clear that the, uh, gut bacteria of the obese individual is playing a causal role in their obesity. So I wanna tackle that topic. But first, why wouldn't the habits of the recipient immediately override the bacteria that they got on the receiving end, given that their habits are more in line with being lean? In other words, given the rapid evolution of these bacteria, why do they persist in their phenotype?

   2. CCColleen Cutcliffe54:27

      Well, first of all, these are case studies, so they're, they're, these are not clinical trials. And so I think, uh, you're dealing with the uncontrollable nature of, of humans. But I would say one of the interesting things is that these people's habits did not go back to what they used to have. And one of the things we're learning about the microbiome is, uh, through this gut-brain connection, your microbiome can actually influence your food cravings. And, and we actually have some data supporting that as well. And so if you think about this new microbiome as kind of maybe having a leaning towards a, a, you know, it, it's not metabolizing food as efficiently. It's, it, it, it, you know, kind of gives you a predilection towards obesity. But on top of that, it changes your food cravings. You've actually now got a double whammy against you that keeps you from being sort of your old self. And so I think the microbiome, you know, this gut-brain connection, its ability to generate neurotransmitters, its ability to change cravings, it's still at a, you know, early stages of understanding. But it can basically change your behavior, so you're not really the old person you were

   3. PAPeter Attia55:28

      Profound. Um, two thoughts. The first is you could be-- could you be in that situation forced to eat your old way, right? So you're, you're literally like you're going to go to a one-week boot camp where you're literally force-fed everything you used to eat. Would that be sufficient to return your gut biome to the way it was? Um, h- talk about how the, um, how the gut and the brain connect. So, you know, my vague recollection is serotonin plays a role here. You've already talked about GLP-1. Um, GIP typically is secreted higher in the gut, but that presumably plays a role as well.

   4. CCColleen Cutcliffe56:09

      Yeah. The-- a- again, this is in the early stages, and we're, we're going to learn so much more over time, but the gut is a m- massive producer of a bunch of things that we've traditionally thought of as neurotransmitters. So yes, serotonin, dopamine, GABA, um, you know, these GLP-1, GIPs. So I think that we don't totally understand, um, the-- And then I would also say there are neurons in the gut. And so there's this relationship between the neurons in the gut and the neurons in the brain. The neurotransmitters being generated by the gut can make their way straight to the brain through the vagus nerve. And so, um, there is, you know, potentially an opportunity, for example, to tackle stress and anxiety through the gut microbiome, where you have these gut microbes that can produce large amounts of GABA, um, which has been shown to be able to reduce stress and anxiety. And so, you know, is there an, an opportunity to go after the gut to reduce stress and anxiety? And again, kind of getting back to this cravings thing, it's really interesting for anybody who's ever felt stress or anxiety, you know actually your food cravings oftentimes change and, and kind of are hand in hand with that. So this part about the gut-brain connection that involves both cravings and these neurotransmitters, I think is, um, really, really fascinating.

   5. PAPeter Attia57:24

      How much of that do you think is regulated by things outside of food? Uh, meaning the, the gut flora as it, as it comes to changing function, which then changes, you know, sort of our physiologic state. I mean, we, we've talked about food. We should talk about it some more. Clearly a very important piece. Um, you've already talked about antibiotics. What are other modifiable factors that change this?

   6. CCColleen Cutcliffe57:46

      The, the, the-- Certainly the two biggest changes in your microbiome are the things we've talked about, antibiotics and nutrition. Um, but beyond that, what we know is that there are, uh... and this is especially with regards to diversity and loss of function of your microbiome. We know that as you age, your microbiome starts to become depleted. We know that when you go through periods of in- intense stress, your microbiome becomes depleted. We know that when your circadian rhythm gets disrupted, so you travel and day becomes night, night becomes day, that changes your microbiome.

   7. PAPeter Attia58:16

      By the way, when you say depleted, tell me what that means in a technical sense.

   8. CCColleen Cutcliffe58:21

      Uh, it means that when they, um-- what happens, uh, is that you have loss of function.

   9. PAPeter Attia58:27

      Hmm.

   10. CCColleen Cutcliffe58:27

       So you start to become depleted in sp- specific strains that have specific functions. And so, um, you know, for example, this strain that I alluded to earlier, Akkermansia, is one of the ones that is kind of deeply studied, and, uh, low levels of Akkermansia have been associated with a really wide variety of diseases, ranging from obesity to immunological disorders to, um, you know, even some of these c- kind of stress and anxiety and, and, and, um, GI issues. And so basically, the depletion means you're losing certain strains and certain functions. Um, and then for us women, when we go through menopause, there's like a massive change in the microbiome on the other side of that, uh, lovely experience. [laughs]

   11. PAPeter Attia59:06

       I was going to ask you about the vaginal microbiome, um, but right now, are you saying that with respect to gut as well?

   12. CCColleen Cutcliffe59:14

       I'm saying that with respect to gut, yep.

   13. PAPeter Attia59:15

       Okay.

10. 59:16 – 1:03:46

    Factors that influence the vaginal microbiom

    1. PAPeter Attia59:16

       Um, what are the factors that influence the vaginal microbiome besides the most obvious, which must be menopause, you know, or, or, you know, pregnancy or anything that has a dramatic shift in endometrial lining and changes? So presumably, if you sample a woman's vaginal microbiome across the month of, uh, uh, of her cycle, given that her estrogen and progesterone levels are fluctuating, you're going to see differences. But I assume there's a quote-unquote healthy versus an unhealthy. How does that manifest itself, um, and what, what does one do about that?

    2. CCColleen Cutcliffe59:50

       Well, I'm not an expert in the vaginal microbiome, but certainly, um, these lactobacillus strains are some of the more important strains in the, in the vaginal microbiome. And, and the name of the game there is actually production of acid. And so you, you want these, you know, lactic acid producing and, and other kind of ac- You want an acidic environment there.

    3. PAPeter Attia1:00:08

       So it's a protection environment.

    4. CCColleen Cutcliffe1:00:09

       It's a protection environment.

    5. PAPeter Attia1:00:10

       The goal is to keep yeast in particular and other things away.

    6. CCColleen Cutcliffe1:00:13

       Exactly. Sperm, everything. [laughs] So I think there's a, uh, you know, kind of-- there is a healthy, you know, vaginal microbiome, which is really associated with the acidity level that these ba- bacteria keep the, the vaginal microbiome at. It can be influenced actually also by the food that you eat. Um, and-

    7. PAPeter Attia1:00:30

       How is that?

    8. CCColleen Cutcliffe1:00:31

       Well, uh, I, I, I don't know. It could be that I don't know, but it's not totally elucidated. But for example, you know, you might know that one of the things that gets recommended for, um... [laughs] Shoot, what's a, what's an infection? A UTI. Uh, one of the things that gets recommended for UTI-

    9. PAPeter Attia1:00:47

       It's like cranberry juice

    10. CCColleen Cutcliffe1:00:47

        ... is cranberry juice. And you're not, like, inserting that into your vaginal canal. You're consuming it. And so there's definitely this connection between the food that you're eating and then the composition of your, um, vaginal microbiome. Pregnancy is also another thing that really changes it. And one of the implications that we did kind of look into, this was, uh, some work that we were doing with the Mayo Clinic early on in our company, is, um, the idea of preterm labor. So, um, preterm labor has been highly associated with bacterial vaginosis, and that is, um, essentially, you know, it's a broad name because I think we don't fully understand what it means, but it's an infection of the-- or a disruption of the, you know, vaginal microbiome that then somehow, um, you know, this infection triggers Uh, preterm labor. And so one of the ideas here is that, well, if you could prevent bacterial vaginosis, you know, you might be able to reduce the incidence of preterm labor. And there's even, you know, other idea, which is that, you know, once you have a preemie, you're a lot more prone to have a preemie again, and maybe there's something about your-- And, and these women usually also have this bacterial vaginosis, which happens right before that they deliver the baby. So maybe there's something about your vaginal microbiome that makes you more susceptible to, um, bacterial vaginosis, which then leads to this preterm labor. So, um, you know, and then there's of course the UTIs and yeast infections and things like that.

    11. PAPeter Attia1:02:11

        Any other systemic complications from a negatively altered, uh, vaginal microbiome? Uh, so, so all of those things-- I mean, I guess you could argue preterm labor is systemic. Outside of the pregnancy case, if you just talk about a woman who's entered menopause and is having, you know, 'cause I'm guessing being on hormones versus not on hormones is going to have a profound impact on that. Um, do we know if any of the problems associated with menopause, beyond the obvious ones like vaginal dryness and hot flashes, have their roots in a change in that, um, microbiome?

    12. CCColleen Cutcliffe1:02:47

        I think that work is still pretty early on, so I would hesitate to, to kind of go too far there. And even the gut microbiome too, there are microbes that can, um, kind of remove, uh... Now, I'm not an expert in menopause or these hormones, but I believe that estrogen has a, uh, kind of m-modification that gets made that is a signal to the body to not put that estrogen back into circulation, but to kind of, I guess you must urinate it out. But there are microbes in the gut that will actually-- their job is to remove that modification, and so it-- the effect is that it could potentially increase your circulating estrogen. And so, but this is all super early stage. If you go try to look up studies around menopause and the microbiome, it's extremely sparse. And so, um, I think there's-- we just really don't know.

    13. PAPeter Attia1:03:37

        TBD.

    14. CCColleen Cutcliffe1:03:37

        Yeah.

    15. PAPeter Attia1:03:37

        Yeah. But there could be a day, presumably, when there are bacterial products that are used to kind of address some of these issues. It, it certainly would

11. 1:03:46 – 1:06:25

    The effect of gut microbes on obesity and challenges with fecal transplants in people

    1. PAPeter Attia1:03:46

       make sense. Um-

    2. CCColleen Cutcliffe1:03:48

       Yeah

    3. PAPeter Attia1:03:48

       ... going back now to the example you gave, how robust is the evidence in humans? And maybe we can start by the evidence in mice 'cause it gets all the headlines, where you can take an obese mouse and you can take-- you can do a fecal transplant from a lean mouse into an obese mouse and make that obese mouse a lean mouse. Is that a relatively robust reproducible finding?

    4. CCColleen Cutcliffe1:04:10

       Yeah, a lot of people have done that, that study. And, and then, you know, uh, even to take it one step further, they can make these mice obese or lean using a human, uh, microbiome transplant. So they basically would take the microbiome from an obese woman, put it into a lean mouse, and see that lean mouse become obese. And so, you know, when we talked about the overlap between, uh, mice and men, there is some overlap there-

    5. PAPeter Attia1:04:33

       Mm-hmm

    6. CCColleen Cutcliffe1:04:33

       ... because you can actually change the metabolism of these mice through these fecal transplants.

    7. PAPeter Attia1:04:37

       So why has that not taken off in humans? I mean, what are the impediments to that? Are those studies being done?

    8. CCColleen Cutcliffe1:04:44

       Those studies have do-- I mean, people have done fecal microbiome transplants into people with type 2 diabetes, you know, for example. I think there's two big challenges. You know, one is, uh, of course this, this safety challenge, which is, you know, do you really feel confident that that stool donor is a stool that you wanna have in your body and move forward with? But more profoundly is a, and, and maybe linked to that, is the ability to reproduce the effect. So if you are-- even if it's always Joey who's providing the stool, I mean, Joey travels, Joey goes on antibiotics, Joey changes his diet. You may not always be getting the same stool from that donor. And so in order to generate consistent results and to really understand, you know, we do in drug development, you know, dose response curves. You're really trying to understand in this small molecule, in this setting, you know, how much of it do you need and what effect, effect will it have? You can't do that if your intervention is a fecal microbiome transplant because that thing is different from person to person and even from the same person from time to time.

    9. PAPeter Attia1:05:44

       It's a pretty messy drug.

    10. CCColleen Cutcliffe1:05:44

        It's a messy drug. So, um, I think, you know, when we started this company, the idea was the fecal microbiome transplant is super compelling data. That tells you that there's something in that microbiome that can change your physiology. But the name of the game is, how do you figure out what are the components of that microbiome that are conferring that benefit, and how do you make a reproducible manufacturing and quality process so that you know every time I deliver this pill to you, I know exactly what's in it, and it's the same every single time? And so that becomes a challenge. How do you take that whole kitchen sink, the whole micro-- fecal microbiome, and say, "Actually, it's these four strains," or, "these two strains," or, "these 50 strains"? That, that's the, that's the tricky

12. 1:06:25 – 1:16:35

    Beneficial strains of gut bacteria and strains commonly found in probiotics

    1. CCColleen Cutcliffe1:06:25

       part.

    2. PAPeter Attia1:06:26

       So let's talk about what those strains might be and what their function is. So, um, for folks listening, what are the, what are the strain names that we have to know here? Lactobacillus, you've already talked about. Akkermansia, you've already talked about.

    3. CCColleen Cutcliffe1:06:41

       Yeah, I think if you start to look at labels on, on, um, kind of the supplements that are out there, you're gonna see a lot of Lactobacillus and Bef- Bifidobacterium. Those are the two primary, um, species that are, that are pretty much in every product. Um, and so those are kind of-- those strains are relatively easy to grow. It's, it's one of the reasons why those are the strains that are in a lot of probiotics.

    4. PAPeter Attia1:07:00

       Why are they easy to grow? I thought anaerobes are hard to grow.

    5. CCColleen Cutcliffe1:07:03

       These are-- kind of fall into that in between. They're-

    6. PAPeter Attia1:07:05

       The facultative anaerobe?

    7. CCColleen Cutcliffe1:07:05

       ... they're facultative, and so they-- you can grow them in some amount of oxygen. In fact, when-- and Akkermansia is not. It's a strict anaerobe. So in fact, when we first started wanting to manufacture Akkermansia, we just tried to outsource it to all these probiotics manufacturers around the world, and they kept sending us back dead stuff. And it's because in order to manufacture a strict anaerobe, your entire manufacturing system end to end has to keep all oxygen out. A single molecule of oxygen kills the whole batch. And so, um, there's a real manufacturing challenge to some of these next generation, uh You know, probiotic strains

    8. PAPeter Attia1:07:39

       So before we talk about that, let's talk more about the, the bifido and lacto. Why are they-- are they a bit of the shiny light problem? In other words, uh, you know, the key's under the shiny light. Why are you looking here? 'Cause-

    9. CCColleen Cutcliffe1:07:51

       Yeah

    10. PAPeter Attia1:07:52

        So are they basically the ones that are most ubiquitous because they're easy to grow, or is there a really good physiologic case for their utility?

    11. CCColleen Cutcliffe1:08:00

        They're easy to grow, and so they're prevalent. And so that's why so many-- so much work has been done on them. It, it was absolutely-- because there was no microbiome science when these strains started making their way into the market in the '70s. They-- there was just, "Hey, I-- what can I culture?" And that's what's culturable. Nobody thought about strict anaerobes or how to keep oxygen out. That's a pain, and that's expensive. So these are the things that have been around since the '70s, and furthermore, they got grandfathered in by the FDA as safe because they'd been on the market for so long. You want to bring a new strain to market, you have to go through the entire process of the FDA that says, "Hey, it's a new strain, but let me demonstrate to you all the thousands of reasons why this thing is safe." So it's really hard to bring-

    12. PAPeter Attia1:08:40

        And just to be clear, from a regulatory standpoint, if a company wants to put a new strain into a probiotic, they're going down a GRAS pathway, a generally regarded as safe pathway, or an IND?

    13. CCColleen Cutcliffe1:08:53

        You're-- if you want to be able to sell it directly to consumers-

    14. PAPeter Attia1:08:56

        It has to be GRAS

    15. CCColleen Cutcliffe1:08:56

        ... you have to go down the GRAS pathway.

    16. PAPeter Attia1:08:58

        Are there people that are actually looking at a pure pharma strategy where they're making an IND and going down the drug pathway?

    17. CCColleen Cutcliffe1:09:07

        Absolutely. Absolutely. There are, there are pharmaceutical drug, uh... Actually, they're all startups, so, um, but pharmaceutical drug companies that are using the microbiome to-- as, as the therapeutic and filing INDs and, um, you know, doing these studies. And in fact, you know, uh, this, this fecal microbiome transplant in the form of a pill, that's a, you know, that's a therapeutic. There are multiple companies out there that are developing that as a drug therapy.

    18. PAPeter Attia1:09:31

        Interesting. I mean, the closest thing that I can think of to that would be, um, immunotherapy using TIL, right? Because, you know, you have immunotherapy in the form of a drug where you use something like Keytruda, uh, or a CTL, you know, CTLA-4, uh, inhibitor where you have a single molecule that is an actual drug that triggers the immune system to do something. But then you have, you know, tumor-infiltrating lymphocytes where you go and harvest a patient's tumor, grow those T cells out, multiply them, you know, a log or more, and then re-infuse them. Actually, several logs, and then re-infuse them. But of course, then every patient has their own designer drug. That's still a purely regulated FDA, you know, IND problem. That sounds a lot more like the fecal microbiome transplant, which is every patient has a different drug. The difference there is it's not coming from them. Um, by the way, begs the question, like, should every patient going to the hospital have a banked stool sample so that they can be their own transplant? You could have an autologous transplant and save a lot of the risk.

    19. CCColleen Cutcliffe1:10:39

        Yeah, I think that would probably be a super smart thing to, to do, um, bank your own stool. You could do it in your own freezer. [laughs]

    20. PAPeter Attia1:10:46

        Right. Just leave a stool sample in your fridge when you go to the hospital, and if you can make it home and you're fine, you can pitch it.

    21. CCColleen Cutcliffe1:10:52

        Yeah.

    22. PAPeter Attia1:10:53

        Yeah, interesting. Um, so what drew you-- what drew your interest in, in this other, um, species called Akkermansia?

    23. CCColleen Cutcliffe1:11:05

        Well, um, I think that Akkermansia has sort of become an incredibly, uh, interesting strain over the last decade. But when we first were-- became interested in it, it was really centered around this, um, trying to understand the difference in people with metabolic syndrome versus people who don't have metabolic syndrome. And, um, you know, we did and a variety of people have done these twin studies. These twin studies are, are really interesting because you take, you know, a twin, um, uh, pair, and you, you're looking for discordant twins where one twin is healthy, the other twin has diabetes or is obese. And you're looking at their microbiome, and you're basically saying, "Hey, man, genetically, these two people are the same. This is clearly a, you know, nature not-- uh, this is a nurture not nature problem." And so you start to look at their microbiomes, and you start to see patterns. Around the world, if you compile this data together, you start to see that the, uh, twin that has obesity or type 2 diabetes has a different microbiome from the twin that's healthy. And one of the hallmarks that appears to be true across different cultures and different dietary patterns is this depletion in this strain called Akkermansia. And so, um, that kind of was what really-

    24. PAPeter Attia1:12:15

        In, in absolute numbers.

    25. CCColleen Cutcliffe1:12:17

        In absolute numbers, yeah.

    26. PAPeter Attia1:12:18

        Okay. And, and what's the relative difference between these populations?

    27. CCColleen Cutcliffe1:12:22

        That I don't know, but I do think that it is interesting because across these different populations, Akkermansia is one of the, in a so-called h- I mean, we, we don't have to get into this, but the so-called healthy gut microbiome, which is yet to be defined, um, you know, across the world, it-- Akkermansia is one of the, um, you know, comprises, uh, uh, the microbiome on the order of somewhere between like, you know, five to ten percent or five to eight percent for a healthy individual, no matter where you're living. And so it sort of being depleted or having nothing show up is, is a really stark difference.

    28. PAPeter Attia1:12:57

        Oh, it's that profound a difference.

    29. CCColleen Cutcliffe1:12:59

        Yeah, you could do-- you-

    30. PAPeter Attia1:13:00

        It's-
13. 1:16:35 – 1:21:47

    The difference between a probiotic and prebiotic, and how CFUs are a measure of the “active ingredient”

    1. PAPeter Attia1:16:35

       the difference between a probiotic and a prebiotic.

    2. CCColleen Cutcliffe1:16:38

       Oh, boy. Uh yeah, the vocabulary lesson. And then, and I'll introduce another one that's become popularized, which is the postbiotic.

    3. PAPeter Attia1:16:44

       Mm.

    4. CCColleen Cutcliffe1:16:44

       So, um, essentially, you know, the, the, the microbiome when we talk about is all these, you know, bacterial and, and, and yeast strains. That's the probiotic. So the probiotic is the living organism itself. Prebiotic is the food that feeds those organisms. So we talked about, you know, fibers and inulin and, and polyphenols and things like that. Those are prebiotics. So prebiotics are the food, the probiotic is the organism itself, and then what these organisms produce or what they secrete is called, now being called the postbiotic.

    5. PAPeter Attia1:17:13

       Mm.

    6. CCColleen Cutcliffe1:17:14

       And so you would call, you know, for-

    7. PAPeter Attia1:17:16

       Butyrate would be a postbiotic

    8. CCColleen Cutcliffe1:17:16

       ... butyrate would be a postbiotic, yeah.

    9. PAPeter Attia1:17:19

       Um, when-

    10. CCColleen Cutcliffe1:17:21

        And then maybe one more term [laughs]

    11. PAPeter Attia1:17:23

        Yeah

    12. CCColleen Cutcliffe1:17:23

        ... terminology that people might start seeing is synbiotic, and all synbiotic refers to is you've mixed two or more of these things together, the pre and the probiotic together or the probiotic and the postbiotic. So a synbiotic has, you know, multiple.

    13. PAPeter Attia1:17:35

        Okay. So when people are consuming yogurt, they're consuming a prebiotic presumably?

    14. CCColleen Cutcliffe1:17:43

        No, actually they're-

    15. PAPeter Attia1:17:44

        Or it's the bacteria in it that they're trying to-

    16. CCColleen Cutcliffe1:17:47

        Yeah. They're, they're lactobacillus bacteria that are in that yogurt, um, that can, that, that stay alive in the context of yogurt, and so that-that's really what you're consuming.

    17. PAPeter Attia1:17:56

        And what, what is the perceived, believed, or realized efficacy of consuming massive amounts, uh, of lactobacillus and, and bifidobacteri-bac-bacter?

    18. CCColleen Cutcliffe1:18:10

        I think the most, um, well-documented and even reported from consumers, you know, impact of consuming lactobacillus and bifidobacterium, you know, probiotics in general and yogurts is around GI symptoms. So things like gas and bloating and diarrhea and constipation. A lot of people report, and there have been studies kinda showing both sides of it, but, but basically there have definitely been studies showing and people reporting they have better GI when they're consuming these probiotics or these yogurts with probiotics.

    19. PAPeter Attia1:18:42

        If you go and buy like yogurt off the shelf, how much lactobacillus is naturally within that? Or is it-

    20. CCColleen Cutcliffe1:18:48

        I think they add it in.

    21. PAPeter Attia1:18:49

        They do.

    22. CCColleen Cutcliffe1:18:49

        So it, it varies.

    23. PAPeter Attia1:18:50

        It's not something that naturally occurs in yogurt.

    24. CCColleen Cutcliffe1:18:53

        I think it is naturally occurring in yogurt, but the, but all the things that you're buying off the shelf, they're also supplementing with additional lactobacillus. The real question to ask yourself when you're buying yogurt is how much sugar is in it? [laughs]

    25. PAPeter Attia1:19:03

        Yeah, although, uh, y-yeah, f-for sure if you're buying like fruity flavored yogurts. Um, by the way, I wanna come back and talk about sugars in a second. But, um, go-- I wanna go back to kinda this, this, um, probiotic. Um, how much? Like, what is the dose effect, right? So I know that if you look at a bottle of pick your favorite probiotic, it usually uses something called CFUs, colony-forming units. Can you explain what those are?

    26. CCColleen Cutcliffe1:19:30

        Yes. Some brilliant marketer decided that that was gonna become the metric, the name of the game for probiotics. Um, so colony-forming units, a-again, we'll remember back to seventh grade biology where you might have been given a petri dish and you had to like Swab your mouth or swab your hand or put your finger on it, and then you see what grows. That's, that's basically that, that tool. So you take your, um, you know, your pill or, or whatever, your yogurt, and you, you basically spread it out on a Petri dish, and then you count how many colonies form, and that gives you a number. So you'll say, "Well, gee, this pill has, you know, 10 to the 9th colony-forming units in it." So, you know, some marketer decided that that's the most important thing is the number of colony-forming units, and I have, you know, 10 times more colony-forming units than somebody else. I... You know, again, th- that's maybe, that's interesting, but it's less relevant than, than the function of what's happening in your pill. Um, and moreover, it only gives you a, uh, one piece of data about what's in that pill. So when you do that, the only thing you get to see are what's able to form a colony. But actually, in almost every supplement, every probiotic out there, the majority of what's in that pill is dead probiotic, and you don't see any of that when you use this technology. There's a different tool that can be used called flow cytometry, um, and essentially what you do is you take your capsule, you put it into this flow cytometer, and what it pops out, its readout is live cells, dead cells, and kind of in between cells. It's based on a, you know, staining of the membrane, and so it tells you, you know, which of these cells is viable, like the membrane is really intact, which of them have a compromised membrane, and which ones are kind of somewhere in between. Um, and now you know exactly what's in your pill because even if you could have the same number of live cells, it turns out that those dead cells and those in between cells, they actually have a role to play. They have a function in there. So these so-called postbiotics, that's what those guys are, and so you're missing... You don't really know what's in your pill unless you're using flow cytometry versus colony-forming units.

    27. PAPeter Attia1:21:30

        And when you do flow cytometry, what do you stain for? Which, which surface, um, receptors or molecules are you staining for?

    28. CCColleen Cutcliffe1:21:37

        Uh, I don't know the answer to that. I think there's two that we stain for, but I actually don't remember.

    29. PAPeter Attia1:21:41

        Okay.

    30. CCColleen Cutcliffe1:21:41

        Yeah.
14. 1:21:47 – 1:31:12

    Considerations about how probiotic strains are produced, and more on the meaning of CFU

    1. PAPeter Attia1:21:48

       so lacto is you said a... It, it's basically able to use oxygen and not use oxygen, so obviously if you're going to produce it, you're going to produce it in under the conditions of oxygen because it's cheaper and easier. Um, I hear things about some of these things need to be refrigerated, some don't. What's, what's the specificity of that?

    2. CCColleen Cutcliffe1:22:08

       Yeah. It's really about, um, you know, stabilizing something that's meant to be inside the body. [laughs] And so I think that, you know, a lot of these Lactobacillus and Bifidobacterium strains, because we've been manufacturing them for so long, uh, you know, we've figured out how to get them to be stable through this process. So just to maybe take a step back and what is the process, you take these strains, and you're basically growing them into these, you know, big vats. If you've ever been to a brewery or a vineyard, you see these big vats, sort of the same in these manufacturing plants. You, you grow these strains in a c- a culturable media, and then when they get to a certain, uh, density, optical density, you then harvest them. So centrifugation is one of the most common ways. You basically spin down, you know, the cells, you get rid of the media, and now you have this kind of paste of cells.

    3. PAPeter Attia1:22:53

       How slowly do you need to spin them to prevent them from dying?

    4. CCColleen Cutcliffe1:22:57

       Lactobacillus and Bifidos, at least the ones that are on the market today, they're pretty hardy. You can spin them awfully fast and be done with this whole process pretty quickly.

    5. PAPeter Attia1:23:04

       Mm.

    6. CCColleen Cutcliffe1:23:04

       And there's other strains that are a lot more sensitive, so you have to do this process much more slowly. And so I think that's, uh... that, that depends on the strain. Um, but you essentially throw away the media. You take this paste of cells, and then you, um, you, you, you freeze dry them, and so that gets them into a powder form. And once they're in a powder form, they tend to be pretty stable, and then you could throw them in a pill, um, and, and you're off to the races. The biggest-

    7. PAPeter Attia1:23:30

       What's the yield on that? How much loss do you have in live bacteria? Assuming you start with 100% live in the paste, when you just go through the act of freeze drying them, what's your yield?

    8. CCColleen Cutcliffe1:23:44

       It-- That is where everybody dies. I mean, basically you are-- a lot of times you're losing like 90% of your cells just through that freeze drying process. They're, they're-- it's a pretty harsh process. So what people do is you try to figure out what cryoprotectants you can add that are not going to harm the bacteria, uh, you know, on the other side of it, but that they're going to help them through this cryo, uh, phase, and, and some of that is kind of, you know, physical.

    9. PAPeter Attia1:24:08

       How does freeze drying actually work?

    10. CCColleen Cutcliffe1:24:10

        It's literally what it sounds like. You, you... It's a, uh... It's both pressure and temperature. Um, there are these instruments called lyophilizers, and, um, you know, a lot of them use these sort of flat pans, and so you would, you know, put your paste in this. It's lit- [laughs] it's like baking. You put your paste in this flat pan. You slide it into the lyophilizer, and then, um, over a period of time, it's basically using temperature and cold to remove the liquid from the, um, uh... kind of go through this sublimation process of removing the liquid from the cells directly into a gas. Again, we're going back to seventh grade biology.

    11. PAPeter Attia1:24:44

        Yeah. Hmm.

    12. CCColleen Cutcliffe1:24:45

        Um, and, and on the other side of that, you have this powder, and, and that powder may be stable at room temperature. It may still need to be refrigerated. Um, but, but the-- what you're trying to figure out is what are the additives that you can, um, uh, you know, incorporate that help it get through this freeze drying process and remain viable. Um, but the things that have to stay refrigerated, it's, it's even after that process, they're still relatively unstable, so you still have to keep them in the refrigerator. Um, and you know, for us, for example, when we first started making Akkermansia, it absolutely had to be refrigerated. I mean, within hours it would die. Um, and we've essentially sort of worked-

    13. PAPeter Attia1:25:22

        Meaning once you freeze dry it, you sort of shut its metabolism down completely, and then the minute it gets even a little bit warmer, it basically warms enough to the point where it's no longer cryogenically preserved, but there's no substrate for it, and it dies? Is that the actual mechanism by which it dies?

    14. CCColleen Cutcliffe1:25:38

        That's right. That's how it dies. Exactly. 'Cause there's no sub... Right. There's no substrate for it, um, and, uh, and, and so it can't handle the heat, and so it dies. And so, you know, we-- trying to figure out what you can add to it... Because the, the most important part is You, you do want it to be able to get through this freeze-drying process, and of course everybody wants shelf-stable product. But the most important thing is that when you ingest the strain, it actually makes its way to the gut microbiome, is able to reconstitute and to, you know, perform its function, secrete the proteins it's supposed to secrete, secrete the small molecules it's supposed to secrete. And so when you do this process, every time you make a mod where you're like, "Oh my gosh, we just improved the, you know, viability t- you know, 4X," you have to like go to the other side and say, "Okay, now I got to put it in a human and see if I got the same output." So it's a, it's a pretty lengthy process.

    15. PAPeter Attia1:26:27

        And by the way, do you think that that 90% loss is typical on the, on the most common strains that are used commercially?

    16. CCColleen Cutcliffe1:26:35

        No, and I mean, we even grow some of those strains and, you know, you can maintain m- you know, higher viability. You're, you're never going to get 100% through, but I think those kind of, you know, it's more like on the order of between 50 and 80%. So you're definitely above the halfway mark.

    17. PAPeter Attia1:26:49

        Okay. And then how many of those make it into the person? So in other words, once they're reheated, how many of them die along the way?

    18. CCColleen Cutcliffe1:26:58

        A lot of it depends on the, um, encapsulation that you're using. So if you have, you know, as I said, you know, kind of these enteric-coated capsules, you can make it through the stomach acid. Uh, and then you can use these time-release capsules so that, uh, it, it takes a certain amount of time and you're making some assumptions around, um-

    19. PAPeter Attia1:27:17

        GI transit. Yeah

    20. CCColleen Cutcliffe1:27:17

        ... yeah, GI transit. Um, and then there's kind of the, the least expensive version, which, you know, probably, uh, kind of all falls apart in the stomach and very f- little of it gets to the actual destination.

    21. PAPeter Attia1:27:28

        So it wouldn't make sense to be drinking a probiotic in a liquid then.

    22. CCColleen Cutcliffe1:27:33

        You could get a lot more efficacy if you took it in a pill format.

    23. PAPeter Attia1:27:37

        Yeah. Because-

    24. CCColleen Cutcliffe1:27:38

        But, but, but part of it too is, you know, we talked about these Lactobacillus that are in yogurts. Part of it is that if you just have to get to that, you know, just on the other side of the stomach and the small intestine, you know, that is a different thing than trying to get all the way to the gut microbiome.

    25. PAPeter Attia1:27:52

        And is that where it n- seems that Lacto and Bifido need to be seeded, is just outside the stomach?

    26. CCColleen Cutcliffe1:27:58

        There you can-- I don't, I don't know that the answer to that is known, but you can actually find them, you know, all along the tract and even into the, you know, distal colon. So-

    27. PAPeter Attia1:28:07

        And what is their functional output? Do they make butyrate?

    28. CCColleen Cutcliffe1:28:11

        Lactobacillus tend to produce, uh, you know, lactic acid.

    29. PAPeter Attia1:28:14

        Lactate besides that. Yeah.

    30. CCColleen Cutcliffe1:28:14

        Yes, lactate. Um, and then, uh, Bifidobacterium, various of those strains can produce short-chain fatty acids. Um, they need to be paired with, you know, secondary fermenters in order to get to the kind of final butyrate.
15. 1:31:12 – 1:39:58

    Mitigating the effect of antibiotics on the microbiome

    1. PAPeter Attia1:31:12

       point where that's, where that's true. Going back to antibiotics for a second, um, for most people, taking antibiotics is almost always oral. But of course, if you're in the hospital, it's not uncommon to take an intravenous, uh, antibiotic. So for example, if you're having surgery, it's not uncommon right before the surgeon cuts your skin for them to administer an intravenous antibiotic, usually something that covers for skin flora and, you know, that reduces the risk of surgical wound infection. Do intravenous antibiotics also have the same obliterating effect on the gut biome that oral ones do?

    2. CCColleen Cutcliffe1:31:47

       You know, I don't know. I don't know. I have not investigated that. But- This, these Clostridium difficile infections arise a lot of times when people are getting antibiotics, uh, uh, th- that they're taking, you know, prior to surgery. So there must-

    3. PAPeter Attia1:32:04

       Yeah, you're right. It's pro- there, y- I, I'm sure now that I think about it, people do get C. diff colitis from IV antibiotics.

    4. CCColleen Cutcliffe1:32:09

       Right.

    5. PAPeter Attia1:32:09

       Yeah.

    6. CCColleen Cutcliffe1:32:09

       So there, so it must have-

    7. PAPeter Attia1:32:10

       That's a good point.

    8. CCColleen Cutcliffe1:32:11

       Yeah.

    9. PAPeter Attia1:32:12

       So w- w- what do we know about the ideal response to helping your gut out when you take antibiotics? This past year, I had to do two courses of, uh, Augmentin, which is a pretty powerful antibiotic. W- kicking and screaming, I did it.

    10. CCColleen Cutcliffe1:32:33

        [laughs]

    11. PAPeter Attia1:32:33

        But I had a pharyngeal abscess, and that's a no messing around type of infection, and so I'm on steroids and, uh, you know, Augmentin trying to avoid surgery. Luckily, I did. Um, but truthfully, I did nothing after the fact, and I seem to feel okay. Am I just lucky, or should I have done something?

    12. CCColleen Cutcliffe1:32:55

        Well, you know, we know that you have a ecosystem in your microbiome. You take an antibiotic that pretty much kills everybody, and then over some amount of time, you get a new microbiome from the food that you're eating, the environment you're in. Um, and for, you know, a lot of people, that new microbiome is the same as your old microbiome. But for a lot of people, it's not. And, and one of the really interesting things are studies that have been done in kids where they show that kids who are systematically on antibiotics later on in life are more prone to things like obesity, type 2 diabetes, even things like ADHD, um, celiac disease. And so there's something, I think, in those developing years where, you know, post-antibiotic, you've got a different microbiome than pre-antibiotic. So, you know, that's just something to consider on the other side of an antibiotic. If ever you are going to clean up your diet, that's a good time to do it [laughs] because you're starting with a new blank slate, uh, of your microbiome. And I think what happens for a lot of people is post-antibiotic, they're actually starting to feel better and feel well, and then they're craving, you know, foods that maybe they haven't been able to eat, and so you maybe aren't giving yourself the best shot at a good microbiome on the other side. Um, I used to believe that taking a probiotic during an antibiotic course seemed illogical because the antibiotic's just going to kill that probiotic. But there have been studies coming out showing, um, that, I think in particular this, this, this study that's really compelling showed that if you did a fecal microbiome transplant, um, kind of after taking the antibiotics or, you know, at the tail end of that, um, or if you were taking probiotics during, uh, the, the time of taking antibiotics that, um, somehow on the other side of that you had a, um, what we'll call, you know, a healthy gut microbiome, so you're able to have some of these functions that we've talked about, the development of short chain fatty acids. Um, you've got Akkermansia in there. And so the idea here is that even though that antibiotic is killing these strains, you might be doing some kind of a seeding, uh, at maybe very low undetectable levels that's allowing you to have, you know, a healthier, um, microbiome on the other side of the antibiotics. You know, so I guess if I were going to go on antibiotics, I would probably, you know, double down on the probiotics that I'm taking. But again, I think on the other side of that, really coming in hard and strong with a high fiber diet would be your best chance of reconstituting with really, you know, good microbes.

    13. PAPeter Attia1:35:24

        Kind of a maybe a naive question, which shows how little I understand microbiology. Antibiotics seem very specific, right? Like when you take Augmentin, you're really targeting a certain set of antibiotics. You know, you have, oh, this really targets this gram-negative strain, and you know, this really targets these gram-positive bacteria. And that's why, you know, there are so many different types of antibiotics, right? I mean, it's not just the class of drugs like cephalosporins. You have the first gen, the second gen, the third gen. So y- y- y you know, and at one point I actually remembered what they all did, which I don't anymore. But the point is, there was remarkable specificity. So why is it that if you just take one antibiotic for your skin infection, which presumably would be like a first generation cephalosporin, um, it obliterates your gut microbiome, which by the way, has nothing in common with the bacteria on your skin, right? But we just described that these are all highly anaerobic bacteria versus these guys that are totally aerobic. Why does an antibiotic even mess with the gut biome?

    14. CCColleen Cutcliffe1:36:29

        Yeah, I think their antibiotics are a lot more broad spectrum than, than maybe, uh, people or, or, or the, you know, physicians that are recommending them know. I mean, y- yes, there's the gram-negative and gram-positive, but really the name of the game for people who are manufacturing and producing antibiotics is you-- it's actually more useful to create a broad spectrum antibiotic because you want your antibiotic to be the, the one, the go-to of choice from a doctor. And if it is one that can tackle most different kinds of infection, you're going to become the more popular antibiotic. So anti-- and this is actually one of the arguments in the antibiotic world, which is that antibiotics over time have become more and more broad spectrum. They kill more and more different things, whereas you really want to go in this opposite direction, which is-

    15. PAPeter Attia1:37:15

        You want precision antibiotics

    16. CCColleen Cutcliffe1:37:16

        ... have a lot more precision around them. Um, and so I think that's, uh, that's, you know, there's all these phage therapies and things where people are trying to get really specific, but that's, that's new. Most of the antibiotics out there, they really do have this, they decimate your microbiome. They don't kill everything, which is why you can have these things like these C. diff infections.

    17. PAPeter Attia1:37:33

        Do you have a sense of just quantitatively, um, so it, you know, if you took a gram of stool from me now and looked at how many bacteria were in there, and then you took a gram of stool from me after I was on an antibiotic for ten days, like Augmentin, very broad, powerful antibiotic, what's the log fold reduction in viable bacteria?

    18. CCColleen Cutcliffe1:37:52

        I actually don't know the answer to that. I mean, that's probably published in lots of places. [laughs]

    19. PAPeter Attia1:37:57

        Yeah. Interesting. Okay. So what I'm hearing you say is The best thing you can do if you're on an antibiotic is quote unquote, "Take advantage of the fact that you're starting with a new team and go out of your way to eat the best possible diet." And we're not really talking much about specifics outside of fiber, are we? I mean, we should talk about what else might be-- 'Cause what I would do now knowing this, what you've said, is I already love eating salad and vegetables and fruits, so I'd probably go on the all salad, all fruit diet for like, I don't know, a few days. I mean, that might sound dumb, but like I would go overboard on those things. Are there other things you would be mindful of either eating or not eating during that recolonization week?

    20. CCColleen Cutcliffe1:38:45

        I think it's primarily, as you said, you know, f- um, these high fiber foods and then, uh, you know, adding the fruits in is important too, because those are a source of fiber, but also, um, polyphenols. So we know that polyphenols are beneficial prebiotics for the microbiome, you know, these certain strains as well. Um, for example, we know that polyphenols, uh, consumption results in higher levels of Akkermansia. Um, I mean, avoid the high fat, high sugar foods because, you know-

    21. PAPeter Attia1:39:11

        Why? So let's be specific about each of those. What is it about dietary fat or sucrose, fructose and glucose that would be problematic?

    22. CCColleen Cutcliffe1:39:22

        I think it's mainly that it's, it's not feeding-- So it's, it's maybe the, that what they don't con- It's not about the detrimental effects of them. It's actually about what they don't contain. So we're-

    23. PAPeter Attia1:39:32

        I see. So don't eat McDonald's because it's low in fiber.

    24. CCColleen Cutcliffe1:39:35

        Right.

    25. PAPeter Attia1:39:36

        Not because it's high in sugar and fat.

    26. CCColleen Cutcliffe1:39:38

        Yeah, I guess you're right. The, the high sugar, high fat foods don't tend to be high in fiber, so I was making an assumption there. But it's really about trying to optimize for high fiber, high polyphenol foods, and so anything that doesn't have that is, you know, not feeding.

    27. PAPeter Attia1:39:50

        Okay, so you don't have to avoid eating your meat even though it's not a source of fiber. You tend to make sure you better be eating a lot of fiber.

    28. CCColleen Cutcliffe1:39:57

        Yeah.

    29. PAPeter Attia1:39:57

        And, and polyphenol. Okay,

16. 1:39:58 – 1:47:02

    What do we know about the effect of artificial sweeteners on the gut microbiome?

    1. PAPeter Attia1:39:58

       let's talk about artificial sweeteners for a second. Um, highly contentious topic.

    2. CCColleen Cutcliffe1:40:03

       Yes. [laughs]

    3. PAPeter Attia1:40:05

       Uh, and I've recently, along with a couple of my colleagues, we, we put out a very, um, lengthy, um, piece of content to our premium audience, uh, to the, to the newsletter, which is literally, it's probably a, it's a 15,000 word treatise on all things related to non-nutritive sweeteners, uh, and non-sugar sweeteners that are themselves nutritive. So, so it's a pretty broad piece. And y-you know, without recasting the entire thing, it's really clear that there's something going on with these non-nutritive sweeteners beyond their caloric or non-caloric impact. In other words, we all understand that sucrose has its, you know, four kilocalories per gram. It's broken down into one part glucose, one part fructose. We understand the metabolism of those things, and we understand that if consumed in excess, you have probably some harm beyond just the caloric side, vis-à-vis the fructose molecule and not the glucose molecule. But it's now also clear that under isocaloric conditions, high quantities of non-nutritive sweeteners are not entirely benign. And so I guess I'd start with the question of what do we know about how the gut addresses these, if for no other reason, because of the fact that these are very foreign molecules in the concentrations we consume them. I mean, we consume glucose and fructose for our entire existence. We're just seeing it in a higher concentration now, but probably not as much of a multiple in concentration as we see, you know, aspartame or sucralose.

    4. CCColleen Cutcliffe1:41:46

       Well, first of all, I'm going to give all the caveats that you are clearly a far deeper expert in all of this than I am. I've spent hardly any time thinking about it. [laughs]

    5. PAPeter Attia1:41:53

       I'm not, though. I, I know nothing about the impact on the gut, really.

    6. CCColleen Cutcliffe1:41:55

       Um-

    7. PAPeter Attia1:41:56

       Just, just the observations clinically about, you know, what we see in terms of sugar cravings and other repetitive behaviors-

    8. CCColleen Cutcliffe1:42:02

       Mm-hmm

    9. PAPeter Attia1:42:02

       ... and metabolic symptoms, which I'm kind of asking, do you think part of that is manifested through the gut? And there was that very famous paper in Nature a few years ago which sort of suggested that in mice.

    10. CCColleen Cutcliffe1:42:16

        Yeah. Well, so first of all, there have been, um, a lot of studies done in mice, and we've already talked about the advantages and disadvantages to getting too, uh, um, fired up about mouse studies. But I think, especially in the microbiome. But I think that, um, the data that's out there is conflicting around the impact of these non-nutritive sweeteners on the microbiome, and maybe it's because of what you just pointed out, which is that the, these things are not all created equal, and so by kind of lumping them together and doing these studies, um, you know, that might be causing some, some of this conflict. Uh, uh, I think it's relatively early stage. A lot of studies have been done on animals. There are studies which-- There are definitely studies which show that they can have a detrimental effect to some of these beneficial microbes. Um, but I, I-- in my, my mind, the jury's still out because I think we don't understand the complexity of these different sweeteners. We also don't understand, obviously, the complexity of a microbiome and the adaptation of the microbiome to consumption of these sweeteners. And so, yeah, evolutionarily, maybe these things haven't been around for very long. But again, because how fast-

    11. PAPeter Attia1:43:20

        Because of the rapid evolution

    12. CCColleen Cutcliffe1:43:21

        ... you replicate your-- I mean, there's bacteria that can metabolize small molecule drugs they've definitely never seen before.

    13. PAPeter Attia1:43:27

        They've never seen. Yeah.

    14. CCColleen Cutcliffe1:43:28

        So I, I think that is going to be the name of the game, is to understand how does your microbiome evolve to these and, you know, how does it help or hurt you, and, and how is that linked to meta-- you know, the metabolic pathway.

    15. PAPeter Attia1:43:40

        Yeah. I mean, my, my takeaway is, is all of that, and then layered onto that something you said earlier, which is you could take five people and give them the-- who are the same weight, and give them the same dose of digoxin, and they're going to have five different PKs. Uh, for those listening who don't understand the term PK, it refers to, like, the concentration of the drug within their body, in other words, a product of their metabolism. So, um- I would say the same is probably true for aspartame, sucralose, saccharin, all of the above, which is I have seen so many cases of people who are trying to lose weight, um, trying to improve their metabolic health, drinking six Diet Cokes a day, and they're, you know, they're saying, "Look, I'm getting zero calories in here, and nothing will budge." And I s- uh, "Do me a favor. Substitute soda water for the Diet Coke for a month. Let's see if it makes a difference." And the world changes.

    16. CCColleen Cutcliffe1:44:43

        Wow.

    17. PAPeter Attia1:44:44

        Now, I don't know what to make of that because it's anecdotal, and I don't have perfect control over the situation. So it's certainly possible that when they started drinking all the Topo Chico and started ditching the Diet Coke, that they were also doing 10 other things that changed. So I really don't know. But I've seen it enough in both directions, where it works and where it doesn't work, that I, I do wonder if there are individual factors where in that individual for whom it becomes a productive change, there's a lack of symbiosis between the evolution of their bacteria in the high aspartame environment versus the adaptation of another person in the context of a high... Like, my, my wife drinks Diet Coke, right? It's, like, I say that like it's somehow bad, like.

    18. CCColleen Cutcliffe1:45:29

        [laughs]

    19. PAPeter Attia1:45:30

        But she, she fricking loves Diet Coke. She probably has, like, one every other day. I don't know that that's a high or low dose, but it is. Sh- she's as healthy as a horse.

    20. CCColleen Cutcliffe1:45:37

        She's in great shape, yeah.

    21. PAPeter Attia1:45:38

        She, she's as healthy as a horse. Um, if I drink it, I can't stand the taste of it, truthfully, but sometimes I'm, like, so parched and thirsty I'll drink one.

    22. CCColleen Cutcliffe1:45:44

        [laughs]

    23. PAPeter Attia1:45:45

        Doesn't seem to cause me any ills. But again, I've seen people... And, and there's clearly an association, um, between its use and, and otherwise.

    24. CCColleen Cutcliffe1:45:53

        That, that would be a super interesting study, I think, to do, where you would basically take a bunch of individuals, and you would look at their, you know, get some baseline data around their microbiome, and then you would put them, you would start them either on a bunch of Diet Cokes, uh, or you would start them on a bunch of, you know, just soda water, and then measure their microbiome over time. And then I'd do a little washout period or maybe just switch them right over.

    25. PAPeter Attia1:46:14

        Yeah, do a crossover. Yeah.

    26. CCColleen Cutcliffe1:46:14

        Do a crossover and see what happens. 'Cause, you know, it really is a question. This, this is kind of my frustration with a lot of the microbiome studies that are done, is they treat it, um, the, the way that we do, you know, drug studies, which is you just have cohorts, and you're just comparing them to each other. Really in the microbiome, the person matters. And so crossover designs are gonna give you way more information about what's doing what in that person, and then you can start to draw themes about pathways. But that would be an interesting design to do because it could be that at the onset, if there was something about these people who could, you know, live off of Diet Coke, and let's assume people prefer Diet Coke over, you know, uh, unflavored soda water, if there was something about their starting microbiomes that enabled them to, you know, lose weight, uh, in, in that way or be healthy in that way,

17. 1:47:02 – 1:58:14

    Why Akkermansia is a keystone strain with implications for metabolic health and an individual’s response to dietary interventions

    1. CCColleen Cutcliffe1:47:02

       that could be a solution. So, like, I'll tell you, there's a, was a very interesting study that was done where they took all these people, they put them all on the same diet, and I mean, you've, everybody has experienced this. You don't have to be a physician. You know, you go on a diet, somebody else goes on a diet, one person loses way more weight than the other person. So they were trying to understand, is there something about the starting microbiome that changes the way people respond to, you know, they just did a regular high-fiber diet. And, um, they found that if you start out with higher levels of Akkermansia, you know, not, not to keep going back to this strain, but it really is, like, this keystone strain for a reason. This study, you know, what they showed was that if you had higher starting le- levels of Akkermansia, that was associated with all the metrics of, um, responding better to the diet in terms of BMI, hip-to-waist ratio, um, you know, A1C, weight, all of these things. Those people did better, and it's correlative, but they, if they had higher starting amounts, they responded better to the diets. So I do-

    2. PAPeter Attia1:47:58

       Interesting

    3. CCColleen Cutcliffe1:47:59

       ... think there's something about the microbiome that can help you or hurt you as you go through these kind of nutrition changes.

    4. PAPeter Attia1:48:05

       To me, a corollary of what you just said is if your microbiome is suboptimal, which we can define in a number of ways, but let's use one very specific example. If you are completely deficient in or woefully deficient in Akkermansia, it is harder for you to have a favorable response to a healthy intervention and/or you may be more susceptible to the downside of a less healthy intervention. So on the one hand, you may be more impacted negatively by something like non-nutritive sweeteners, and you may be less responsive to dietary corrections. Is that, would you agree with that statement?

    5. CCColleen Cutcliffe1:48:42

       I think that is definitely, um, that, that would be-

    6. PAPeter Attia1:48:45

       That's, that's the hypothesis

    7. CCColleen Cutcliffe1:48:45

       ... that's what that data, that's what that data points to. Yeah.

    8. PAPeter Attia1:48:47

       Yeah.

    9. CCColleen Cutcliffe1:48:47

       That kind of a hypothesis.

    10. PAPeter Attia1:48:49

        Um, well, let's, let's talk about Akkermansia then. So, um, it comes from... So it's, you know, going back to it, it's the species. There are several strains of it, or when you refer to it, are you always talking about the same strain?

    11. CCColleen Cutcliffe1:49:04

        Most of the work out there has been done on a particular strain called Akkermansia muciniphila. Um, there's other Akkermansias out there, but that, when people talk, say the word Akkermansia, they're really referring to that strain.

    12. PAPeter Attia1:49:16

        How is it grown? You've already alluded to the fact that it's a hardcore anaerobe, and you made some insane statement earlier, which is if even one molecule of oxygen is brought in the presence of its culture, it's dead.

    13. CCColleen Cutcliffe1:49:32

        Yeah.

    14. PAPeter Attia1:49:33

        First of all, can you explain to me, I don't remember enough of my microbiology to know why that's the case. Why is oxygen... I understand why an obligate anaerobe survives without oxygen. I understand that biochemistry. I don't remember the biochemistry of why oxygen is toxic.

    15. CCColleen Cutcliffe1:49:51

        Yeah. Oh man, that's such a good question. I don't know how the oxygen is, is, is killing them.

    16. PAPeter Attia1:49:54

        It must be a free radical thing or something.

    17. CCColleen Cutcliffe1:49:56

        Yeah. Yeah.

    18. PAPeter Attia1:49:57

        Okay.

    19. CCColleen Cutcliffe1:49:58

        They're insanely sensitive to it, yeah.

    20. PAPeter Attia1:50:01

        Amazing.

    21. CCColleen Cutcliffe1:50:02

        Yeah. Which is crazy 'cause there's so much oxygen in the, in the air around us, but this is really, like, this compartmentalized, you know, body part that we have. But yeah, they, they are, um, these strict anaerobes. And, and you'll, you'll see this, especially we talked a little bit about these microbiome, you know, therapeutic companies that are developing drugs. Uh, you know, almost every single one of those companies Has had to develop their own manufacturing plant because all these next generation strains that we're talking about that are really in the gut microbiome, in the distal colon, they have this same feature, this same issue, which is that you have to create this, you know, end-to-end closed system. And so all of us who are developing these sort of next generation strains and trying to do studies with them, we all ended up having to build our own manufacturing plants, um, in order to solve for this precise problem of the oxygen.

    22. PAPeter Attia1:50:50

        Okay. So were there people out there trying to grow Akkermansia without, uh, with, without super, super strict controls?

    23. CCColleen Cutcliffe1:50:58

        Uh, yeah, for sure. I mean, for sure. And in fact, you know, there's a, um, a company that is, uh, touting, you know, pasteurized Akkermansia, you know, dead Akkermansia as, you know, the, the, the product that you really want. And so, I mean, I think it's, it's hard to not only grow the strain, but also to maintain its viability on the other side of that, you know, as you try to create a product that people can take. So yeah.

    24. PAPeter Attia1:51:23

        So the FDA has no ability to regulate... Like, there are lots of products out there that supposedly sell, that supposedly include Akkermansia, right?

    25. CCColleen Cutcliffe1:51:32

        No.

    26. PAPeter Attia1:51:33

        No?

    27. CCColleen Cutcliffe1:51:33

        No. No. And, and there, there-- we have a whole, um, game of Whac-A-Mole happening at our company for what we're calling Fakermansia. So these are people who will throw up a supplement on, on Amazon and say, "This is Akkermansia." And you can test all these things. Most of them just have Lactobacillus or Bifidobacterium in them. Um, and they're just-

    28. PAPeter Attia1:51:51

        So they're not even trying to fake it

    29. CCColleen Cutcliffe1:51:52

        ... false advertising. [chuckles] Yeah.

    30. PAPeter Attia1:51:53

        Just false advertising.
18. 1:58:14 – 2:01:45

    The essential steps necessary to develop a robust probiotic for optimal health support

    1. CCColleen Cutcliffe1:58:14

       did what it-- we thought it was gonna do. Uh, but so we've been selling it for a couple years.

    2. PAPeter Attia1:58:16

       Are you comfortable saying how much money you spent on that R&D?

    3. CCColleen Cutcliffe1:58:20

       A lot.

    4. PAPeter Attia1:58:21

       [laughs]

    5. CCColleen Cutcliffe1:58:22

       [laughs] Well, maybe I'll say this. Our company has raised $150 million, um, and we've only had products in market for about two to three years. So it, it was a, a heavy lift to build a manufacturing plant, do all the R&D work, you know, funding pre-clinical and clinical work. We fund other, you know, um, PIs to do work with these strains. I mean, I think if you wanna build a product that has real efficacy behind it, you-- we-- there's a lot of kind of blueprint from pharmaceutical drug industry that, that we've adopted, um, because the incredible rigor that they have around developing products with efficacy.

    6. PAPeter Attia1:58:57

       Yeah, and, and y- y- your industry is not one that's known for rigor.

    7. CCColleen Cutcliffe1:59:01

       [laughs] It's really not.

    8. PAPeter Attia1:59:02

       Would be, would be putting it mildly.

    9. CCColleen Cutcliffe1:59:04

       Yeah. A- and you know, this was a kind of a really, um, you know, I think, uh, pivotal moment for our company when we really decided to sell to consumers. So we'd always had this, this idea that the microbiome is really interesting because it's mutable, and you could develop things that could help people. There is a lot of evidence suggesting, through these fecal microbiome transplants, that you can actually help people improve health through a microbiome intervention. Um, and that if you followed a drug development, you know, rigorous pathway, you could actually identify the subset of that fecal microbiome transplant that could help people. And if you could figure out how to manufacture them, you could really, you know, have a product with efficacy here. Now, how do you bring that to market, and how do you choose to commercialize that? We always believed that because these are, you know, grass, these are naturally occurring strains, that you had an opportunity to bring this directly to the public that would allow you to, um, really democratize the availability of it. So if we launched Pendulum Glucose Control as a drug, we would only be able to sell it to doctors who would prescribe it to people who had type 2 diabetes. Anybody who's aging is thinking-- should be thinking about how to, you know, help their body metabolize glucose better. And so, um, we really felt like there was this natural product, things that could deliver efficacy that people could, you know, that was measurable, that would be important, and then enabling these products to be available to everybody as opposed to only through a prescription. That meant that the consumer market was really the way to go. And, like, also, a lot of people learn information about health, um, on their own. I mean, Dr. Google is the most famous doctor on Earth. And so I think, you know, we really wanted to bring it directly to consumers. The downside of that, and we've talked about this too, is it's really hard in this particular space to elevate it. I mean, everybody is a marketing genius that's selling a probiotic. There are people who make you feel like what they're selling is super innovative, and, you know, you've never seen anything like this before. But when you really look at the ingredients, it's literally the same thing that everybody else has been selling. And, you know, you-- because a consumer's not gonna go read clinical trials or necessarily compare, you know, your ingredients to ingredients on all the other labels or do all that legwork, it becomes re- a really, a different game to play where you're trying to deliver something that provides meaningful health solutions for people, but you're also having to play the marketing game of, "How do I convince people or use proxies to help them understand this works?" Because you're not selling to a bunch of doctors, you're selling to regular people. So that's been-

    10. PAPeter Attia2:01:37

        Well, even if you are selling to doctors, I mean, quite frankly, it's complicated. I mean, it's not like-

    11. CCColleen Cutcliffe2:01:41

        Yes

    12. PAPeter Attia2:01:41

        ... doctors would necessarily understand this. Uh, I, I, I struggle

19. 2:01:45 – 2:22:46

    How Akkermansia helps control blood glucose, and potential implications of Akkermansia in weight loss, diabetes management, and more

    1. PAPeter Attia2:01:45

       to understand this. Let's explain what Akkermansia does to control glucose. You've alluded to this a couple of times now. You've alluded to a product called Glucose Control. Um, but let, let's kinda go back to the, to the science of this. There's a clear and obvious correlation as to why Akkermansia is beneficial, but that doesn't explain mechanistically what it's doing. Do we have an insight into why Akkermansia is something that lowers an individual's blood glucose or response to a glucose load?

    2. CCColleen Cutcliffe2:02:14

       Yeah. So we'll do kind of a, a deep dive into Akkermansia and what we know today, knowing that we're gonna learn all kinds of other stuff. But at a very fundamental level, this is primarily through the GLP-1 pathway. So what we know about Akkerman-

    3. PAPeter Attia2:02:28

       And just to get people excited about that, if you're in-- if you're hearing this and you've heard of Ozempic, you've heard of GLP-1. So Ozempic is a mimetic of GLP-1.

    4. CCColleen Cutcliffe2:02:41

       Yes. So, um, what we know about Akkermansia, there, there's three key things that we know that it does that kind of result in this. So, um, the, the, the first thing is that it has a surface protein called AMUC1100, um, that, uh, uh, appears to be able to, um, bind to, uh, TLR2 receptors that helps stimulate these L cells. So maybe we'll take one step back, which is that you have these L cells, um, in your gut microbiome at the lining of your gut microbiome, and L cells are the cells that secrete GLP-1. So, um, a lot of people don't know this, you know, your microbiome is really the, the guy secreting GLP-1. So you have this beautiful system where you eat food, your microbiome metabolizes it, and right there are these cells that respond to that food by secreting GLP-1. So Akkermansia has this, you know, surface protein called AMUC1100. It also secretes a protein called P9, um, and P9 binds to these ICAM-2 receptors in the L cells, which are also known to stimulate them to, um, produce GLP-1. And then the third thing that Akkermansia does is it's able to produce a short-chain fatty acid called propionate, and propionate is upstream of, um, butyrate. And so there are a bunch of strains which can take propionate, convert it into butyrate. Butyrate binds to G protein-coupled receptors forty-two and forty-four, also in these L cells, and stimulates GLP-1 secretion. And so these are all, um, kind of ways in which Akkermansia can stimulate GLP-1 secretion. And by the way, there are two strains, um-- there are only two strains to be able to directly stimulate GLP-1. One is Akkermansia muciniphila, the other is Clostridium butyricum, and they actually act kind of together 'cause Clostridium butyricum, as its name indicates, is a butyrate producer. And so, um, and then GLP-1, uh, is, is sort of has multiple, uh, benefits, you know, one of which is that it helps your body know to-- and your-- you know all this stuff way deeper than I do, but it helps your body know that, you know, to secrete insulin to help you metabolize the, the sugars that are in your blood after eating a meal. But it also has this other, um, benefit, which is what is becoming really popular now, which is that it induces satiety. It makes you feel full. And it does that in two ways that are not totally understood, but one is that it sort of slows your GI transit, which gives you a feeling of fullness, but the other is that it has a, you know, some kind of a neurotransmitter, um, mechanism that allows you to feel like you don't have cravings. You're, you're full. And so, um, that it, it, it makes it a very powerful small molecule. And so what we're doing that's, you know, pretty distinct from what these small molecule drugs is doing is this is sort of the natural way. We're giving you the upstream bacteria that's enabling your body to produce GLP-1. Um, and so the result of that is that your body will produce GLP-1 when you're eating. Or right after you've eaten food, it'll go back down. It'll produce it again after you've eaten food, but it will raise your levels of GLP-1, so you get these benefits of lowered blood glucose, reduced food cravings, you know, lowered A1C, and, and the body weight impact. So-

    5. PAPeter Attia2:05:52

       Okay. A lot I want to unpack there, starting with just a quick summary. So you eat food. If you-- provided you have a lot of Akkermansia and you're feeding it the right food, a couple things happen. It sounds like one of them is not at all related to a production that it-- or a secretory product, but rather just this surface receptor. I think you said it was the AMUC one-- 1100 or something like that.

    6. CCColleen Cutcliffe2:06:18

       Yes. It has a very fancy name. Yeah. [chuckles]

    7. PAPeter Attia2:06:20

       Yeah. So and that surface protein by itself just stimulates L cells in the, um, in the enterocyte, and that, we know that that makes GLP-1.

    8. CCColleen Cutcliffe2:06:31

       Yeah. And I think that pathway is probably the least well understood, um, of, of the, the other two. The, the, you know, short-chain fatty acid and the P9 protein have had, um, I think a lot more work done on.

    9. PAPeter Attia2:06:41

       So it secretes P9. It secretes propionate. Propionate gets converted to butyrate by another bacteria. Which ones?

    10. CCColleen Cutcliffe2:06:50

        There is a, a class of, um, clostridial strains that will do that secondary conversion, and Clostridium butyricum is sort of the most well-studied of those.

    11. PAPeter Attia2:06:59

        Got it. What about difficile? Is he doing anything good for us there?

    12. CCColleen Cutcliffe2:07:03

        I actually don't know. We haven't studied whether... I don't-

    13. PAPeter Attia2:07:05

        Okay.

    14. CCColleen Cutcliffe2:07:05

        Maybe people are afraid to bring that into the lab. [chuckles]

    15. PAPeter Attia2:07:07

        Yeah, yeah. And what does P9 do?

    16. CCColleen Cutcliffe2:07:10

        And so P9 is this-

    17. PAPeter Attia2:07:11

        Directly stimulates L cells?

    18. CCColleen Cutcliffe2:07:13

        Yes. It binds to this ICAM-2 receptor on the L cells and stimulates them.

    19. PAPeter Attia2:07:17

        ICAM receptors are receptors that are usually involved in, um, God, if my memory serves me correctly, like, kind of an immune response, right? Like an inflammatory response?

    20. CCColleen Cutcliffe2:07:27

        Well, and that is, uh, you know, for, uh, we, we have not done studies around that, but for sure that is a, a area of heavy interest. Um...

    21. PAPeter Attia2:07:36

        Yeah, by vague recollection, I mean we're literally going back twenty-five years, is that when you-- when a person is, uh, for example, septic, right? You have all of these ICAM modules that lead to, you know, vasodilation, leaky capillaries, secretion of monocytes out into the peripheral tissue as macrophages. Um, but sounds like this is a distinct process here.

    22. CCColleen Cutcliffe2:08:02

        Yeah. Well, I mean, and, and maybe I should say too, like I don't know how much of this is tied to that process. But the other thing that not, not only does Akkermansia stimulate, uh, these L cells to produce GLP-1, but Akkermansia has another role which maybe is very much tied to this, um, you know, which is that, uh, it, it helps regulate the mucin layer. And so that mucin layer turns out to be super important for, uh, if it gets too thin or if it's too thick, it, it's, uh, it's, it's a real pro-- this so-called leaky gut or-

    23. PAPeter Attia2:08:30

        Yep

    24. CCColleen Cutcliffe2:08:30

        ... GI issues that, that c- become a result of not having enough Akkermansia is really that you have too thin of a mucin layer, and so you start to get, um, you know, the ability for pathogens to infiltrate and then also obviously for these molecules to secrete out.

    25. PAPeter Attia2:08:43

        And then tell me what's the fate of the butyrate made of the propionate?

    26. CCColleen Cutcliffe2:08:47

        It binds to these G protein-coupled receptors, um, and that's also what stimulates the L cells to then go release GLP-1.

    27. PAPeter Attia2:08:56

        Got it.

    28. CCColleen Cutcliffe2:08:57

        So sort of multiple methods to-- mu-multiple of these small molecules that, you know, uh, are, are the signaling molecules for these receptors on the L cells.

    29. PAPeter Attia2:09:06

        So all roads point to more Akkermansia, more GLP-1. What differs from someone taking Ozempic is they just have a mega high dose of GLP-1 all the time, and what you're talking about here is, as you said, kind of a waxing and waning dose of GLP-1 that is more physiologic because it comes with your meal.

    30. CCColleen Cutcliffe2:09:30

        That's right. Well, and again-
20. 2:22:46 – 2:29:54

    Pendulum Therapeutics’ commitment to rigorous product develop

    1. CCColleen Cutcliffe2:22:46

       you know, in parallel." Um, and so we, we actually launched-

    2. PAPeter Attia2:22:49

       By the way, did you get any pushback from your investors on that?

    3. CCColleen Cutcliffe2:22:52

       Doing another study?

    4. PAPeter Attia2:22:53

       Yeah, because like if you were-- I mean, if you're wearing your scientific hat, that's the obvious thing to do because scientists always want to replicate things and make sure and a- and add another question. If you're an investor, you might be like, "Are you crazy? Like we just got the answer. It's the best possible answer. Don't ever ask another question." I mean, there's a reason virtually no supplement companies will ever, ever, ever do a clinical trial. They don't want to know the answer.

    5. CCColleen Cutcliffe2:23:22

       It's true. It's true. Well, there's two things. First of all, we have been super fortunate in having investors that believe in the ult- the, the kind of underlying premise of our company, and the underlying premise of the company is that the supplement space is riddled with tons of products that don't really do anything, and therefore it's very hard for anybody to own market share. It's actually a highly fragmented space. Sometimes you get a player that comes in, they take market share because they've done something, you know, fancy on the marketing side, but then somebody else comes in and takes their market share, and you just sort of see this game kind of happening. And our underlying premise was if you could deliver something that actually helped people in measurable ways, you could take that whole market over because now you've created something that works. Well, in order to know if it works-

    6. PAPeter Attia2:24:04

       Yeah, you have to have a study

    7. CCColleen Cutcliffe2:24:05

       ... we have to like see it study.

    8. PAPeter Attia2:24:05

       And then you have to make a claim. So you can now make a claim with a product. That's a very big deal. Are there other probiotic companies out there that can make claims?

    9. CCColleen Cutcliffe2:24:16

       No. This claim around lowering A1c and blood glucose spikes is we are standalone in making that claim.

    10. PAPeter Attia2:24:21

        You own that claim.

    11. CCColleen Cutcliffe2:24:22

        We st- yes. We are the only ones that make that. Well, somebody else could do a study and make that claim too.

    12. PAPeter Attia2:24:25

        Yeah, yeah, yeah.

    13. CCColleen Cutcliffe2:24:26

        But they haven't.

    14. PAPeter Attia2:24:26

        But currently nobody else can make that claim.

    15. CCColleen Cutcliffe2:24:27

        Nobody else does. The, the other reason I think our investors got behind it is, you know, first of all they, they understand that we're trying to build products that can change lives. And, and we have, um, investors that have gotten behind game-changing, category-creating, you know, products in, in the world. So, you know, Apple and, and, you know, uh, these sorts of companies that maybe didn't have a, a predecessor to them. And so-

    16. PAPeter Attia2:24:52

        But that's very different from-- I mean, not to, not to-- I mean, that's, that's a very different risk tolerance than biotechnology. I mean, biotech is the graveyard of some great investors.

    17. CCColleen Cutcliffe2:25:05

        It's true. Um, but I, yeah, I don't know what to say. They, they, they, they're, they're behind this, this mission that the thing, you know, has to work and so therefore you've got to have these studies that work. And I, I will say though I have learned by having products in market and enabling people to run their own, you know, studies on themselves, especially in the context where nutrition and your ecosystem and your microbiome are still pretty much a black box to the scientific community, we've been able to garner so much data from our customers who are just sharing this stuff voluntarily with us in order to be able to do better and better product development. So I am actually now a believer that the clinical trial is important because it gives you a very controlled environment to know whether there's a there there. But unless you can change behavior in the real world, um, and have people actually experience benefit that they can come back and tell you about, you haven't made a product that's very interesting at all. And so I think that that part i- is important. The other part to this story that's important on our strategy is that because we have this clinical data and because a consumer may not be able to go read a, a paper but a doctor can, that we go through healthcare professionals. We go directly to them, but then we also go through them to, to help, um, create, you know, credibility or knowledge for consumers. And so Um, if you want to convince a bunch of doctors that the thing you have works, they're gonna want to see more than a pilot, and they're also gonna want to see it run by somebody that's not yourself. And so we immediately launched these studies, and then COVID hit, and every study, one by one, got brought to its knees-

    18. PAPeter Attia2:26:39

        Hmm

    19. CCColleen Cutcliffe2:26:39

        ... because people with diabetes, um, you know, uh, are more prone to kind of COVID complications. That, that came out a little bit later on. But you know, people were getting COVID, and then you're like, "Well, I don't know what this COVID is doing [laughs] -"

    20. PAPeter Attia2:26:51

        Right

    21. CCColleen Cutcliffe2:26:51

        ... to the microbiome. And then people were totally not adherent to any protocols. They couldn't come into the clinic. So one by one, we ended up, we lost a lot of money on, on trials that we were trying to do follow-ups on. And then we just decided, you know, my chief medical officer said, "All right. We have to wait until everything is cleared out before we even start another clinical trial, 'cause we're not gonna jus- lose another dollar." And so literally just in this last year, 2023, is when we felt like there was enough of a handle on this that we could actually start doing clinical trials. But we've done it in a different way, which is, um, now we've sort of built up some momentum, so it's all third party PIs and academic and clinical institutions, um, that we're just giving free product to to run these trials. So, uh, we'll get that data. I do think it's important if you want to get the medical community behind you, and I think that'll be a differentiator.

    22. PAPeter Attia2:27:40

        That means they have to apply for their own grants to fund the study. They're just having a significant part of the cost taken out of it, which is the drug.

    23. CCColleen Cutcliffe2:27:49

        Yeah. I mean, and I, I do think that there's a-

    24. PAPeter Attia2:27:51

        But that's good, so there's interest. There are PIs out there who are like, "Yeah, I would happily go and seek the grants to do this study, uh, especially given that I can mitigate the drug cost."

    25. CCColleen Cutcliffe2:28:01

        Yeah. And the government is putting out, you know, NIH grants. There's, there's, there's quite a few of them centered around microbiome interventions.

    26. PAPeter Attia2:28:07

        Great. So how many such trials are underway right now?

    27. CCColleen Cutcliffe2:28:10

        Right now we have, um, about a dozen and around the world that are happening, and, and not all of them are, not all of them are for Type 2 diabetes. We actually have several that are, where investigators have their own hypothesis about what these strains are doing. So for example, you know, we sort of talked about, um, you know, the, the gut-brain axis. We have an investigator that's been funded by the Milken Institute that is looking at the role of Akkermansia in bipolar disorder.

    28. PAPeter Attia2:28:34

        And that's kind of amazing if you really think about it. So you've got basically a dozen PIs around the world on the basis of one, you know, relatively small pilot study that was very well done, published in a very well, a re- very reputable journal, and that alone has generated that much interest that they're finally willing to study a commercial product.

    29. CCColleen Cutcliffe2:28:54

        Well, I don't think it was just that study. There, there's, like, over 3,000 publications on Akkermansia that people around the world have been publishing on. You know, mostly academics. Um, and so there's a lot of data.

    30. PAPeter Attia2:29:06

        But those studies weren't intervention studies.
21. 2:29:54 – 2:38:43

    Details about the probiotic “Glucose Control” and other probiotics developed by Pendulum Therapeutics

    1. CCColleen Cutcliffe2:29:54

       plant.

    2. PAPeter Attia2:29:55

       Yeah. So okay, so how many products do you sell today? Pendulum sells the product that was tested in that trial. Is that the product called Glucose Control?

    3. CCColleen Cutcliffe2:30:05

       Yes. So Pendulum Glucose Control is marketed for people with Type 2 diabetes. You know, lowers A1C, lowers blood glucose spikes, and it is the f- exact formulation that was in that clinical trial.

    4. PAPeter Attia2:30:15

       And do you still use that same quality control metric of actually doing flow cytometry on those products?

    5. CCColleen Cutcliffe2:30:23

       Yeah.

    6. PAPeter Attia2:30:23

       So if I looked at a bottle, I, I take Glucose Control. If, if I looked at that bottle, which I can't say I've looked at and, and remember, it doesn't say anything about CFUs on the back.

    7. CCColleen Cutcliffe2:30:32

       It says AFU, active fraction unit.

    8. PAPeter Attia2:30:35

       And what does it report it in?

    9. CCColleen Cutcliffe2:30:37

       It reports it in, it, it, it's in, uh, the number of, um, cells that appeared in that active fraction. So it's, it's, it's still gonna look like, I think it's, like, 10 to the 8th or 10 to the 9th for mos- most of the strains.

    10. PAPeter Attia2:30:49

        Got it. Okay. Um, what other products do you sell?

    11. CCColleen Cutcliffe2:30:54

        So, um, actually we released Pendulum Glucose Control, and, um, we, I would say one of the, the hallmarks of our business that we've been very proud of is the, the repeat business. So we get a lot of once people try it, they really stick with the product and they stay on it. Well, we actually got a lot of feedback from people. We were getting amazing reports of, "Oh, my A1C is lowered," "My blood glucose spikes have lowered." When we launched our first version of Glucose Control, we also offered people free A1C testing every 90 days and a nutrition coach, which we had a team of registered dieticians. So we were like, "This is gonna be a solution," right? "We're gonna give you your nutrition coaching. We're gonna give you the test that's gonna tell you if it's working."

    12. PAPeter Attia2:31:32

        Wait a minute. You, how did you offer that for free?

    13. CCColleen Cutcliffe2:31:34

        [laughs]

    14. PAPeter Attia2:31:35

        You, you didn't want to make money, I'm guessing.

    15. CCColleen Cutcliffe2:31:37

        We, we don't even-

    16. PAPeter Attia2:31:37

        You were losing a lot of money doing that

    17. CCColleen Cutcliffe2:31:39

        ... we don't offer it now because it turns out it's not scalable and it's not econo- we, we-- in fact, it was funny. Somebody even said, "Oh my gosh, everyone should go buy this product right now because these are, uh, like non-scalable. So like at some point they're not gonna offer these things." And, and sure, and I laughed when I saw that. I was like, "Oh, you don't know." But then eventually I realized, though, that's true. Um, but you know, I think that it's still important for us to offer nutrition information. It just doesn't necessarily have to come through a registered dietician and a personalized one-on-one coaching, and maybe AI will help us get there, you know, faster than, than, you know, we would otherwise, but-

    18. PAPeter Attia2:32:14

        And what other things did you hear from customers? So presumably did you, did you see in the real world comparable reductions in hemoglobin A1C?

    19. CCColleen Cutcliffe2:32:23

        It was all higher. The reports we got back were higher A1C drops, higher blood glucose drops, um, we-

    20. PAPeter Attia2:32:30

        And do you think that that's just-- Do you have a sense of how much selection bias was going into that? Like, were there a good number of people saying, "What the hell?" Like, it didn't get better?

Episode duration: 2:48:48