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

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 feal microbiome transplants that you can actually help people improve health through microbiome intervention um and that if you followed a drug development you know rigorous pathway you could actually identify the subset of that fom 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 hey everyone welcome to the drive podcast I'm your host [Music] AA 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 thanks for having me we're gonna take advantage of being in Austin 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 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 are but maybe give folks 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 that you of course were doing your PhD there so what what did you do your PhD in again 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 postto at Northwestern um we were uh looking for Diagnostic markers for uh pediatric Wilms tumors um and then I moved out to the bay 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 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 have been a lot of unlocks and DNA sequencing technologies that would allow this entirely nent field of science and medicine called the microbiome to produce real products and so here we are 10 years later in it so we'll definitely spend some time talking about products and um 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 the microbiome is essentially all of the microbes so the bacteria the viruses fungi yeast 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 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 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 and in fact really the primary initial seating of the microbiome is um through the delivery you know in the vaginal canal and so um this is we're going to get gross for a second but literally as as you're being delivered you are consuming feal matter that is in the vaginal canal and that's your first seating of microbes and infants have you know 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 uh when is Peak diversity approximately what decade of life 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 oh so that's actually quite young I mean certainly for me that would have been as a teenager exactly yeah when I could indeed eat a bowl of cereal for every meal with no consequence yep um okay so and by by Bowl I mean a bowl the size of my head so it's a box per Bowl per meal um so okay so we have a relatively early peak in life for diversity um again you hear all of these sort of bumper SLP stick slogans about the gut biome oh it outnumbers US 10 to one is that true 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 2 to one I think is relatively probably not that important but what is important is that they make up a huge portion of your body uh mass as well as functions and so it's an important key part of call it even one to one so let's just say so the idea is there are many cells from that are not you between your mouth and Uranus as there are you exact now obviously just to get have someone wrap their head around that we're made up 70% 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 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 biochemist so everything's going to 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 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 cellular level 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 lot of function that's associated with the microbiome that's super important so I remember in my first and only biology course as a kid because I didn't take bio again until I decided to go to med school and um but in in ninth grade or whatever we learned about procaryotes and ukar and I still remember to this day the the joke of our teacher Mr Jefferson he said do you know what a uar out 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 bad horrible joke but I still remember it so um I'm going have to cut this part out of the podcast it's so bad where are we going 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 because there are some fundamental differences between these called procaryotes and ucars 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 in 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 maybe this is this it's sort of its own entity um own living organism every cell is a living organism um and then you know they divide really really rapidly some of them as you know quickly as 10 to 15 minutes you you're dividing and so there's this other component which is that some of these uh bacterial strains because they divide so quickly and because they're also under the pressures of evolutionary you know processes is that they can evolve super quickly and so we as humans we have a long evolutionary timeline because you know it comes in the form of you make a kid who makes a kid who makes a kid now imagine if that was happening every 10 minutes you can evolve really really rapidly and so that's part of kind of the antibiotic crisis out there which is to say that you know these things can become resistant to antibiotics because of this division time so you alluded to this already but they're they're also highly you know they have the capacity to secrete things significantly we think of bacteria and we hear it as a bad term right right like we think of a bacteria is a bad thing and there clearly are some bad bacteria but would I be oversimplifying if I said that most bacteria enjoy a a kind of um uh what's the word kind of complimentary relationship with us as their host is that is that fair in terms of Flora such as the bacteria on our skin in our nasal passages in our gut well I mean we've co-evolved with these microbes and these bacteria and so generally speaking when you're co-evolving with something there's some mutual benefit um and even I sort of cringe when people talk about good bacteria and bad bacteria although I do it as well because it's the ecosystem and the context of these bacteria that's actually more relevant um you know a good bacteria can become a bad bacteria in a certain situation and you know likewise a you know bad bacteria can become beneficial in a different context and so I think that it's important to know they're they're all kind of part of these different Pathways and what they're doing together so you know for example cherium defil is something that I think people think is a terrible pathogen and it's so bad for you and oh my gosh you better never get it almost all of us have cherum defil in our guts but at the level that it's at and in the context of the ecosystem of our strains um it's not having that kind of really nasty pathogenic impact and so it really there aren't really in my opinion there aren't really bad bugs that's interesting you know people hear me rail about good cholesterol and bad cholesterol being meaningless terms and of course cholesterol is simply cholesterol it's where it ends up that can be good or bad so that's a that's actually a great analogy um while we're on the topic of cluster defil which we'll come back to in more detail what is the prevalence of that as a function of total gut biome in a in a person who's healthy and not otherwise in a pathologic state well this is sort of the um convoluting part about the microbiome which is that if you sequence and do really deep sequencing and even biochemical assays across a person's microbiome and then you say all right now I want to do population studies what you find is that the difference between people is huge and so the the um human microbiome project in which they kind of looked across 10,000 plus people at all ages and different demographics really demonstrated that at the strain level people are pretty different from person to person when you start to look at the functions that's where you start to see some redundancy so it's hard to say for a particular strain you know if someone gives you an actual number and they don't give you a range um that's probably not correct wow interesting um tell me more about that project so you know what were the observations it it it landed at Visa 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 the gut biome in these 10,000 people how did the um how did those differences magnify in in the out in the outcomes 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 and looking at before and after so it really was just a a onetime observation onetime observation saying okay we just look across a population of people what are the and this is super early on so we didn't know anything about the microb 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 gene that kind of all microbes have or should you do the whole genome sequencing that's going to 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 10,000 people from you know skin to gut to uh you know vaginal microbiome what does it look look like that was a huge Endeavor and of course coming out of that have been a ton of longitudinal studies and um studies where people have done actual interventions 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 the pie chart like that look like in terms of function who's doing I mean it I'm guessing the bacteria are doing the majority of the work you know I do feel pretty comfortable saying viruses are bad I 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 um well this field is really nent so I I 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 you know I think we also don't really know what the role of viruses are in the microbiome but 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 so I I wouldn't say the jury's totally out of my mindes on that yeah that's that's a good point um do we know any anything about how our microbiome Compares in complexity to that of other animals 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 got cancer you're made 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 that it have for health so even one more step remov 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 and has anybody looked at animals that are not living in captivity and not you know of genetically so ridiculous like the typical you know black six 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 and they do they more closely resemble us or again is it purely a function of what they're eating it's a function of what they're eating 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 every night you know so um when you when they look look at pets I think that's also hard because it it is 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 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 this is completely not what would ever happen in real life 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 anerobic are they gram positive are they gram negative which is simply a a strain a staining technique I guess I should explain that aerobic are bacteria that require oxyen for respiration anerobic 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 yeah I think that the um the aerobic versus anerobic 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 Anor robic 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 in 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 well fortified gut lining there are strains that that live in that mucin layer and so that's a different type of a strain they feed off of mucin versus you know many other things that sort of feed off of um things like the the foods that you eat are prebiotics 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 anes in the mouth but I I know from the little bit I remember about working in an ER whenever somebody received a bite you know you would think ah 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 U 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 measuring here to here like you have to understand the Tor you know the listener would have to understand how tortuous the small intestine and the colon can be yeah I mean the the primary thing that changes is this Anor robic 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 anerobic 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 and then you get to the the recess 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 really interesting opportunity because you know the kind of what's happening in the mouth maybe 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 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 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 a extended period 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 this is just going to 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 and it turns out if you look at the the microbiome of a hyena they make an incredible amount of antibiotics and so um 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're getting ready to give him antibiotics and he he said no I don't want antibiotics it's going to it's going to decimate my microb furthermore I know that because I got bit by hyena I'm not going to get an infection they have the cleanest mouths and they assign 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 all right so what is the classification how how do you like what's the org chart of these bacteria well they're B so yeah now we're going to get back to kind of seventh grade biology where you have you know the philm 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 I don't even remember that anymore say it again it's the the philm the family genus species strain um and and so the what DNA sequencing has enabled us to do is to really look at strains and kind of 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 our understanding as well so for example you know methylation 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 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 going to see that definition maybe evolve as we learn more do you mostly operate in a world where you're thinking of the strain then 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 replicate um most of them basically every 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 assads 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 yeah I mean it's hard for me to kind of wrap my head around that because even though I acknowledge what you're saying with a 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 Mera is right so so you know but does it mean that there's like a new Mera every you know pick your favorite period of time where even something like every month there's a new MCA in the hospital kind of thing that fortunately always still seems to be responsive to Vanka but at some point it won't be like I guess there's V right Bank resistant enaka so um 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 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 because that's their food they're living in your gut they're waiting for you to feed them so in other words sort of interrupt you but the reason that as you know MCA and V are evolving is to escape the antibiotic yes 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 exactly it's evolving to survive what we're feeding them and the environment that we're creating for them interesting okay so very very fluid it is it is and and 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 because you're not used to having them and you're you're really you can Whole Hog change your mic around that's actually what really drew me to this field because when you're talking about you know human genomics and human systems the way in which you can impact them is limited because it's an already existing system that's relatively immutable without some real serious external Force you have to introduce a chemical small molecule to change a pathway that has five backups to it in your system but the microbiome is incredibly mutable and we're doing it all the time and so when you think about the ability to change it and to have real Health implications that's where it's at it's that's why it's an exciting field 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 20 years ago that would have cost close to a billion dollars today that's about $1,000 still not the most practical test in the world because 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 Snips 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 yes so um it's actually quite similar when it comes to understanding the the the microbiome so you can do uh shotgun sequencing where 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 tell folks what that is so they understand yeah because it's it's a bit complicated um so it's kind of exactly how it sounds short read DNA sequencing gives you so let's let's assume let's take a you know example you've got a thousand bases of DNA that you want to sequence um what short by the way what's typical for um a bacteria has typically how many genes and how many base pairs it really is a huge range of of uh of sizes um but let you know let's so if you're if you're trying to measure a a a certain piece of DNA you can use short weed sequencing Technologies which allow you to with high accuracy get these short pieces of your your sequence so you get maybe 200 base pairs and so you would have a few of these and then you Pace them together based on kind of the overlapping yeah and each piece 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 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 this 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 it turns out it matters and so um oh man I'm not going to remember the name of this bacterial strain but um there is a strain that's been studied pretty well that um metabolizes dexin uh and a drug that's used to treat arrhythmias 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 it's hard to know what's the right amount to to prescribe to somebody wait does it treat arhythmia or heart failure it's heart failure yeah yeah yeah anyway that's how long I've been away from the game um and and I'm no clinician so I but but what they found was that there's a microbe that can metabolize dexin and so people who needed higher doses to have efficacy had higher amounts of this strain but then in 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 it could metabolize your less than five it couldn't so getting back to actually and that means that that bacteria exists high in the GI tract presumably because if that were just something in your seeum or 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 it has such an impact on the bioavailability of that drug right I can't remember now now I really don't know where it but I think isn't dejin an orally yeah so um yeah I actually don't remember the location of this bacteria but I remember this part about the number of genes being important as to whether it could even metabolize a thing or not because normally we think a lot about the num the the different genes in the P4 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' 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 yeah and these are mostly gut microbes so it really is especially for these oral um uh drugs there is some inter 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 to your your sequencing question the number of replicates matter so if you imagine you have these short Snippets and you you're sort of it's sort of a guessing game as to um well gee is this an actual just replicate or was it only there one second exactly and so that's why you need the kind of long sequencing so you can it sort of becomes your template to put these short reads on um that costs several thousand dollars per sample to do and so it's it's even today even today because you're you're really trying to get a comprehensive and then just imagine that and now it's every bacterial strain out there and PS there's a lot of redundancy in bacterial strains and we also you know for a a large number of them we don't even know what like the human genome we don't even know what are these real bacteria what do they do um and so there's just still a lot of kind of uncataloged genes and so um it's that's a ro Endeavor and then then the the second way is to really look at um a qpcr based uh where you're really looking at a specific strain and you're trying to understand how much of that exists tell folks why the PCR would work that way like what you have to use and how you have primers and why that's kind of analogous to the let's look at your cancer genes approach yeah so you might have a um uh you know a lot of uh bacterial strains kind of in your ecosystem but you don't know how they how much they they are relative to each other so you can get a catalog of everything that's in there but you don't really know how much of each one is in there from these sequencing methodologies um although there are some really interesting tools that people are starting to develop to try to get at that but the more accurate way to get it the quantitation or how much of this strain is actually in the microbiome is this quantitative PCR you basically make primers that are specific to that strain and then you're using PCR in a quantitative way to understand well how much of it is in there compared to say some other strain or compared to the the entirety of all the different bacteria in there and now you have an idea of is this constituting 1% of my microbiome 10% of my microbiome and so you get this sort of quantitative piece if you're low in specific microbes or specific functions this becomes the way that you would really look that but there's an added very important complexity that the microbiome has that the human genome doesn't have and that's around this replication and everchanging thing and so it's really not good enough as we talked about with the human microbiome project it's not good enough to get one snapshot in time you really want to understand what is your Baseline microbiome and then you know if you ever change your diet you travel you go on antibiotics there's all kinds of things that can change your microbiome in very acute ways your microbiome all becomes all of a sudden becomes a different microbiome and so it really this longitudinal data really matters and then additionally because every microbe is replicating at a different rate the um the the Constitution or the the fraction in which one microbe might be in your gut today might be different tomorrow and so you you need longitudinal data that gets you the quantitative piece plus you know who are the players um and so and then the third part is because they're also mutating you need to understand what did the functions change so if you really want understand the microbiome I mean we were spending you know5 to $6,000 per sample to understand longitudinally what's happening what are the different functions how are these things changing um so it's pretty hard to do and what are the ideal functional assays because I think it's important that we don't lose sight of what actually matters it's what clearly matters when we look at our cells um I think we're really understanding that today in in in humans that function matters more than genome so it's you know the protein is more important than the gene um what do we look at in the gut biome are you looking at secretory products how are you determining the health of the function versus just the genome which obviously must be correlated with it but not exact right yeah we're um we are super interested in carbohydrate metabolism and so we look at the output of that as the short chain fatty acid so be propionate acetate and so you can take an individual strain feed it a substrate depending on you know where in that biochemical pathway it is its substrate might be slightly different and then look at how much of those small molecules are being produced on a gas chromatographer and so we're essentially looking you're you're running a um enzymatic reaction if you think about the the the the bacteria as the enzyme you're giving a substrate and you're basically doing uh your your old-fashioned uh michaus men curves where your you're giving it increasing amounts of substrate and you're basically looking at the um uh the enzymology of going from substrate to that uh short chain fatty acid so let's use that as an example right so uh you eat a piece of bread starch polysaccharide um digestion of course begins in the mouth amalay starts to break that down it continues further in the stomach by the time it gets to God the you know the junam I mean it's mostly just glucose monomers right oh I think that's still being figured out actually what is the um State of Affairs and things arrive I mean it's actually really hard to survey what's happening in the gut microbiome because we don't have good sampling methodologies and so um people are I think working pretty hard to figure out can they make that's super interesting so you're saying even if you dropped like in you know a tube down somebody's throat and you just sampled the slurry at the distal end of the dadum at the proximal end of the junam presumably that's kind of a you know you know I mean I've seen what it looks like you see when you operate on somebody we can't tell what the composition of matter is there I think the problem and this isn't I'm not squarely in this but I haven't seen anything pop out that was really compelling the problem the the the the pushback all of those Technologies get is the ease with which things can get contaminated and so essentially you might be able to get a sample but then in the process of pulling that back out it gets ex it kind of becomes contaminated with the other things that are along the track could be done in operatively could potentially be done would be I mean that anyway hopefully someone is doing that right because like it you know if you're if you're in there operating otherwise now the problem is you wouldn't be operating on somebody without a bowel prep and so you've completely destroyed the system yeah that also you're not operating on somebody in an Anor robic chamber those strains might the second they get exposed to oxygen it's sort of different okay so explain how carbohyd 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 one phosphate I think of glucose 6 phate I think of pyruvate I think of acetal COA I think of the uh kreb cycle I think of um you know lactate as a byproduct of oxidative phosphorilation 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 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 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 berate 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 role 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 used by every other cell and so when you don't have enough berate 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 glp1 from these L cells in the microbiome so it also plays a role in sort of this gut metabolism axis um and so uate 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 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 yeah that's really where we're focused in on is these insoluble fibers and insoluble fiber I guess is most readily aail a in vegetables correct exactly are there what vegetables and fruits yeah 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 polyphenol but it's clearly not a substitute for the fiber just based on the practicality like you wouldn't you can look at the ingredient label like there isn't enough fiber in this to be 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 going to 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 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 now you have to get them in the in the volumes um needed uh but they can be pretty impactful for your microbiome as well how many I mean what what are what are typical recommendations of fiber like how many grams per day 1830 something like that 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 20 and 30 gram a day to imagine getting that in a supplement yeah and but and I think actually your average Americans consuming like one to two I it's really we're way off base on how much fiber we're consuming yeah so going back to but just to get to your question though there's also a delivery component to this too 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 tic 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 if you might be able to get away with a lot less oh interesting why is that I mean 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 well so again you know the measurements of these things along the way has been uh elusive but I think that as my daughter would say sus sus um but you know we include inulin in our pill and it's an incredibly small amount it's you know in the order of 1 to 200 milligrams so it's definitely not at the dietary fiber level but the reason we included is because when we did our preclinical studies we saw that if we didn't included 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 dis dissolves these things start to get hydrated and start to become alive in very close proximity as their food that's why I think about that kind of delivery and that proximity question as being something we haven't really solved for yet 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 butter begin in the small intestine there's some bifido bacterium 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 okay and which strains of bacteria are most responsible for the metabolism of insoluble fiber and the production of berate is a as a byproduct you know it's a it's a multi-step pathway so there are clustal strains which can do this break down there are um bifidobacterium strains that can do this breakdown and then there is the strain acromania which uh was discovered in the early 2000s and um it also plays a really important role in generating these short chain fatty acids and are these strains do they belong to the same species yeah I'm I'm doing a bad job the these are the species names okay so so a strain name would have two parts to it so if I said acromania mucin Aila that would be the name of the strain but I've shortened it to acromania which really does represent the the species the higher level got it so eoli is uh strain name is actually a strain name yeah oh okay in the the pronunciation eer whatever would be the species got it got it okay so Clum is strain Clum defal sorry Clum is the species Clum defal is the strain y 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 cluster defal is as a bacteria and you already alluded to this but how does it go from being kind of a benign SL benevolent um participant in our coexistence with the the universe to one that could kill us so cladium defil 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 Clum defil that after you take an antibiotic it's killed all the different strains off but it didn't kill your Clum defil 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 Clum medifil 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 cherum defil 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 I was just about to say make sure people understand what non-success means here yes yes so uh yeah 70% success is not great when the 30% means that you're you're going to 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 kind of temper this thing down down and that's called a feal 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 when was this first done oh man this was first done this was at least in the 90s maybe earlier 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 places where the most of these have been done um but yeah has incredible success rate it's kind of gross uh yeah what was it like back in the day and how is it done today I assume today it's done through capsules well I think people are still using the methodology of actually going up through the colon but but but people have tried to create more um uh you know they try to create capsules and and try to be able to make it so that you can just drink these capsu you can sorry uh consume these cap 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 the the the enema uh um the ENA 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 oldfashioned way 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 well I think the biggest risk is you know fundamentally you're uh it doesn't feel like a therapeutic to give people so I think there's sort of this Instinct that okay this isn't safe but but there's there is a reality Rena which is that you don't know 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 already compromised um and then furthermore more because everybody's microbiomes does do have these different functions it's possible that you might cure them of the CI 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 feal microbi 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 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 what year was that is this was probably um I don't know maybe 20 years ago um but essentially these people who had uh these Physicians these patients patients families who had all experienced this benefit and then people who were in the queue to get it done essentially you know with pitch Forks 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 and revers it and let people you know you do them 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 colitis uh they get a fecal transplant and they recover the feal 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 want to 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 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's not metabolizing food as efficiently it's it it it you know kind of gives you 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 are 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 onewe boot camp where you're literally force fed everything you used to eat would that be sufficient to return your gut biome to where it was um 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 glp1 um Gip typically is secreted higher in the gut but that presumably plays a role as well yeah the 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 massive producer of a bunch of things that we've traditionally thought of as neurotransmitters so yeah serotonin dopamine Gaba you these glp1 Gip 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 inand with that so this part about the gut brain connection that involves both cravings and these neurotransmitters I think is um really really fascinating 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 the the the certainly the two biggest changes of 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 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 by the way when you say depleted tell me what that means in a technical sense uh it means that when they um what happens uh is that you have loss of functions so you start to become depleted in specific strains that have specific functions and so um you know for example this strain that I alluded to earlier acromania is one of the ones that is kind of deeply studied and uh low levels of acroman have been associated with a really wide variety of diseases ranging from obesity to immunological disorders to um you know even some of these 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 I was going to ask you about the vaginal microbiome um but right now are you saying that with respect to gut as well I'm saying that with respect to gut yep okay 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 of her cycle given that her estrogen 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 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 you want an acidic environment so it's a protection environment the goal is keep yeast in particular and other things away exactly sperm everything 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 bacteria keep the the vaginal microbiome at it can be influenced actually also by the food that you eat um and how is that well uh I I I don't know it could be that I don't know but it's not totally hallucinated but for example you know you might know that one of the things that gets recommended for um shoot what's it what's an infection a UTI uh one of the things that get 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 some work that we were doing with the Mayo Clinic early on in our company is um the idea of pre-term Labor so um pre-term 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 pre-term 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 pre-m Labor and there's even you know other idea which is that you know once you have a preey you're a lot more prone to have a preey 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 pre-term labor so um you know then there's of course the UTI and yeast infections and things like that any other systemic complications from a negatively altered uh vaginal microbiome uh so so all those things I mean I guess you could argue pre-term labor is systemic outside of the pregnancy case if you just talk about a woman who's entered menopause and is having you know cuz 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 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 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 in the microbiome it's extremely sparse and so um I think there's we just really don't know yeah 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 certainly would make sense um 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 because it gets all the headlines where you can take an obese Mouse and you can take you can do a feal transplant from a lean Mouse into an obese Mouse and make that obese Mouse a lean Mouse is that a relatively robust reproducible finding yeah a lot of people have done that that study and and then you know 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 we talked about the overlap between uh Mice and Men there is some overlap there because you can actually change the metabolism of these mice through these feal transplants so why has that not taken off in humans I mean what are the impediments to that are those studies being done those Studies have done I mean people have done fecal microbiome transplants into people with type two diabetes you know for example I think there's two big challenges you know one is of course this this safety challenge which is you know do you really feel confident that that stool donor is a stool that you want to 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 drug it's a messy drug so um I think you know we started this company the idea was the fom 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 FAL microbiome and say actually it's these four strains or these two strains or these 50 strains that the that's the tricky part 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 acromania you've already talked about yeah I think if you start to look at labels on on um kind of the supplements that are out there you're going to see a lot of lactobacillus and be 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 prob why are they easy to grow I thought Anor robes are hard to grow these are kind of Fallen to that in between their factive and so they you can grow them in some amount of oxygen in fact when an acromania is not it's a strict anob so in fact when we first started wanting to manufacture acromania we just tried to Outsource it to all these probotics manufacturers around the world and they kept sending us back dead stuff and it's because in order to manufacture a strict anob your entire manufacturing system end 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 so before we talk about that let's talk more about the the bifo and lacto why are they are they a bit of the shiny light problem and other words uh you know the keys under the shiny light why are you looking here cuz yeah so are they basic Al the ones that are most ubiquitous because they're easy to grow or is there a really good physiologic case for their utility 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 there there was just Hey I what can I culture and that's what's culturable nobody thought about strict Anor robes or how to keep oxygen out that's a pain and that's expensive so these are 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 you all the thousands of reasons why this thing is safe so it's really hard to bring 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 grass pathway generally regarded a safe pathway or an indd you're if you you want to be able to sell it directly to Consumers grass you have to go down the grass pathway are there people that are actually looking at a pure Pharma strategy where they're making an indd and going down the drug pathway absolutely absolutely there 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 feal 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 interesting I mean the closest thing that I can think of to that would be um immunotherapy using till right because you know you have immunotherapy in the form of a drug where you use something like K truda uh or a CTL you know ctla4 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 tea cells out multiply them you know a log or more and then reinus 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 indd 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 autologus transplant and save a lot of the risk 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 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 yeah yeah interesting um so what Drew you what Drew your interest in in this other um species called acromania well um I think that acromania 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 as a different microbiome from the Twin that's healthy and one of the Hallmarks that's appears to be true across different cultures and different dietary patterns is this depletion in this strain called acromania and so um that kind of was what really in absolute numbers in absolute numbers and and what's the relative difference between these populations that I don't know but I do think that it is interesting because across these different populations acromania is one of the in a so-called 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 acromania is one of the um you know comprises uh uh the microbiome on the order of somewhere between like you know 5 to 10% or 5 to 8% for a healthy individual no matter where you're living and so it's sort of being depleted or having nothing show up is is a really Stark difference oh it's that profound a difference yeah you could do you you the unhealthy person has none of it the healthy person is 5 to 10% at 5 to 10% does that make acromania the most predominant species in the gut I think it is among the most but I don't uh actually don't know that there's a current telling of winners because there's a such a difference from person to person in terms of you know the composition of the microbiome now you said something a second ago that's very interesting which is you said regardless of where a person lived if they're a very metabolically healthy individual I'm paraphrasing a little bit they're about 5 to 10% acromania but presumably that also means it's independent of diet because you can point to people who are on radically different diets who are metabolically healthy so how is that explained right you can have people who are on an allplant diet who are metabolically healthy and presumably eating a 100 grams or more of fiber a day plenty of food and you can have somebody on a you know a a Paleo paleo is also a pretty high plant diet but like you could be on a carnivore diet and I've seen people on these who are very metabolically healthy I think it's an impossible diet to adhere to for someone like me who are not eating a gram of fiber but by all measurements are metabolically healthy how and then of course everything in between so given the sensitivity of this Flora to diet how do we make that explanation yeah wow that's a great question um I I I trying to think about any studies that really kind of got at the heart of of this I mean really the study that you would want to do is you want to take one of these individuals you know measure their microbiome and you'd want to put them on a series of different diets and just sort of see like is this something that is not changeable like no matter what you eat or what diet you're on you know this particular strain stays stays high in which case you would argue that the microbiome is a readout of their metabolic Health not the cause of their metabolic Health could be um I mean we do know that the I was going to go in a slightly different direction which is to say that you know perhaps the host themselves play a much larger role in the composition of your microbiome than we really understand so the as you change your diet you would expect your microbiome to change but if there's something about the host that part never changes that that might be the the influence so I I to be honest I just don't think we know wow I mean that's that's interesting and by the way it's possible that these studies haven't been done across a broad enough dietary Spectrum so even though there's Geographic diversity maybe there isn't as much dietary diversity and that would be interesting as as well I suppose like for example you know you know not that we could go back and do this but if you go and look at the Inuit who you know prior to the adoption of Western food we're eating a seemingly ridiculous diet and yet we're quite metabolically healthy yeah I don't think that that's looked I mean it's interesting though it does make me wonder uh I go back and look at this too I mean there are um tribes in South America that have been relatively untainted by anything outside of you know where they are um and so I know that there is there are definitely microbiome studies that are happening in some of those tribal groups that could be sort of the beginnings of this kind of a study quickly the difference between a probiotic and a Prebiotic oh boy yeah the vocabulary lesson and then and I'll introduce another one that's become popularized which is the postbiotic 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 and so you would call you know biotic yeah um when and then maybe one more term ology 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 okay so when people are consuming yogurt they're consuming a Prebiotic presumably no actually they it's the bacteria in it that they're trying to they 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 and what what is the perceived believed or realized efficacy of consuming massive amounts uh of lactobacillus and and bifido back factor I think the most um well documented and even reported from consumers you know impact of consuming lactobacillus and bifidobacterium you know probotics 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 kind of 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 if you go and buy like yogurt off the shelf how much lactobacillus is naturally within that I think they add it in so it varies it's not something that naturally occurs in yogurt I think it is naturally curan 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 yeah although yeah for sure if you're buying like Fruity flavored yogurts um by the way I want to come back and talk about sugars in a second but um go I want to go back to kind of 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 cfu Colony forming units can you explain what those are yes some brilliant marketer decided that that was going to become the metric the name of the game for probiotics um so Colony forming units again little 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 you know again 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 it's 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 post biotics 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 Flo cytometry versus Colony forming units and when you do flow cytometry what do you stain for which which surface um receptors or molecules are you staining for uh I don't know the answer to that I think there's two that we stain for but I actually don't remember okay and it varies by bacteria I'm assuming yeah well there's some common ones among almost all bacteria but yeah um so lacto is you said 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 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 yeah it's really about um you know stabilizing something that's meant to be inside the body 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 vets if you ever been to a brewery or a Vineyard you see these big vets sort of the same in these manufacturing plants you you grow these strains in a 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 a paste of cells how slowly do you need to spin them to prevent them from dying lacab and bidos 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 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 meia you take this paste of cells and then you um 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 can throw them in a pill um and and you're Off to the Races the biggest 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 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 free 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 some of that is kind of you know freeze drying actually work 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 lazers 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 it's like baking you put your paste in this flat pan you slide into the laizer 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 the sublimation process of removing the liquid from the cells directly into a gas again we're going back to seventh grade biology 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 acromania it absolutely had to be refrigerated I mean within hours it would die um and we have essentially sort of worked 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 that's right that's how it dies exactly because there's no right there's no substrate for it um and uh and and so and 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 is supposed to secrete secrete The small molecules is 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 improve the you know viability you know Forex you have to like go to the other side and say okay now I got to a human and see if I got the same output so it's a it's pretty lengthy process and by the way do you think that that 90% loss is typical on the on the most common strains that are used commercially no and I mean we even grow some of those strains and you know you can maintain 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 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 a lot of it depends on the um encapsulation that you're using so if you have you know as I said you kind of these inter coated capsules you can make through the stomach acid uh and then you can use these time relase capsules so that uh it it takes a certain amount of time and you're making some assumptions around um GI Transit 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 little of it gets to the actual Destin so it wouldn't make sense to be drinking a probiotic in a liquid then you could get a lot more efficacy if you took it in a pill format yeah because 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 and is that where it seems that lacto and bifido need to be seated is just outside the stomach 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 and what is their functional output do they make pate lactobacillus tend to produce uh you know lactic a yes lactic um and then uh bifido bacterium various of those strains can produce short chain fatty acid s um they need to be paired with you know secondary fermenters in order to get to the kind of final berate now lactate is also a great substrate fuel for ocytes correct yes and so I think maybe that's why these kind of exist you know all along the track and and therefore um so in that sense is the primary function of the lactobacillus to make food for the gut I don't think we know exactly the answer to that but definitely the you know products of those lactobacillus strains are uh there are a bunch of other strains that are dependent on having you know lactobacillus and is it does it also in that 5 to 10% prevalence um I actually don't know the answer to that okay lots of companies out there are selling lactobacillus uh probiotics you should put them in the fridge and you should hope that their manufacturing process is such that you're getting 80% instead of 10% of what they claim yeah this is where I think our government could maybe have an important role which is to um you know put some guidelines and requirements around labeling like I'll give you an even like more crazy thing the even the cfu let's say you think cfus is a perfectly fine metric the cfu that get gets put on that label could be the cfu at the time of manufacturer or it could be the cfu if I say this thing's got a two-ear shelf life stability it could be the cfu at the 2-year time Mark and you're really depending on on is this company going to tell me the higher number or are they going to try to legitimately tell me what the thing is at the end of the shelf life and so that's not even really regulated and is cfu by definition always alive because presumably if they form a colony they were alive yeah yeah and typical cfu so so are there any recommendations one would make about how many cfu you need of each of those two bacteria well I think people tend to kind of uh converge around this like oh you need billions you know I don't know I mean I guess maybe I would ask the question in a slightly different way which is what are you trying to do problem are you trying to solve exactly so if you got a problem you're trying to solve I generally think most people should operate under I just need I want the minimum viable product to solve my problem so for you that might be 10 billion for somebody else it might be you know 10 to the sth and so I think that's a unfortunately I think because of marketing a lot of people are taking things and they don't even really know why they're taking them well it gets difficult when you don't know what the problem is that you're trying to fix and I think that there in lies a big challenge which is what am I objectively fixing now it could be something symptomatic as you said it could be boy if I take a probiotic my GI symptoms vanish I'm not bloated great so just titrate to the 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 you know I don't know I don't know I have not investigated that but this these Clum defil infections arise a lot of times when people are getting antibiotics uh that they're taking you know prior to surgery so there must yeah you're right it's Pro I'm sure now that I think about it people do get C diff colitis from IV antibiotics right so there so it must have that's a good point so what do we know about the ideal response to helping your gut out when you take anti biotics this past year I had to do two courses of uh Augmentin which is a pretty powerful antibiotic Kicking and Screaming I did it but I had a Fingal absis 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 okay am I just lucky or should I have done something 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 and 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 were going to clean up your diet that's a good time to do it because you're starting with a new blank slate of 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 is 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 feal 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 acrania 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 seating 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 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 sephos sporin you have the first gen the second gen the third gen so you know at one point 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 sephos born 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 anerobic bacteria versus these guys that are totally aerobic why does an antibiotic even mess with the gut biome yeah I think their antibiotics are a lot more broadspectrum than than maybe uh people or or the you know Physicians that are recommending them no I mean 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 broadspectrum antibiotics 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 broadspectrum they kill more and more different things whereas you really want to go in this opposite direction which is you want Precision antibio a lot more Precision around them um and so I think that's a 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 seiff infections do you have a sense of just quantitatively um so 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 10 days like augmenting very broad powerful antibiotic what's the log fold reduction in viable bacteria I actually don't know the answer to that I mean that's probably published in lots of places 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 cuz 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 I think it's primarily as you said you know um these high-fiber foods and then 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 acromania um I mean avoid the high fat high sugar foods because you know 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 I think it's mainly that it's it's not feeding so it's it's maybe the that what they don't it's not about the detrimental effects of them it's actually about what they don't contain so so don't eat McDonald's because it's low in fiber not because it's high in sugar and fat yeah I guess you're right 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 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 yeah and and polyphenol okay let's talk about artificial sweeteners for a second um highly contentious topic yes 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 it's a 15,000 word treat 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 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 kilo calories per gram it's broken down into one part glucose one part fructose we understand the metabolism of those things and we understand that have consumed in excess you have probably some harm Beyond just the caloric side Visa 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 sucrose well first of all I'm going to give all the caveats that you are clearly a far deeper expert in all this and I am I spent hardly any time thinking about I know nothing about the impact on the gut really just just the observations clinically about you know what we see in terms of sugar cravings and other repetitive behaviors 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 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 I think it's relatively early stage a lot of Studies have been done in 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 in my my mind the jury is 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 rapid Evolution you replicate your I mean there's bacteria that can metabolize small molecule drugs they've definitely never seen never seen yeah 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's that linked to met you know the m i mean my takeaway is is all of that and then layered on to 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 dexin and they're going to have five different PKS 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 sucalo sacran 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 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 wow 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 topoo 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 asp tame environment versus the adaptation of another person in the context of a high like my my wife drinks Diet Coke right like I say that like it's somehow bad like but she she freaking 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 she's as healthy as a horse yeah 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 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 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 wash out period or maybe just switch them over do a crossover and see what because 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 going to 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 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 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 know 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's 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 acromania you know 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 levels of acromania that was associated with all the metrics of um responding better to the diet in terms of BMI hip to waste 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 think there's something about the microbiome that can help you or hurt you as you go through these kind of nutrition changes to me a coraly 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 acromania it is harder for you to have a favorable response to an 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 I think that is definitely um that would be data that's what that data points to yeah that kind of a hypothesis um well let's let's talk about acromania then so um it comes from so it's you know going back to it is the species there are several strains of it or when you refer to it are you always talking about the same strain most of the work out there has been done on a particular strain called acromania mucil um there's other acromania out there but that when people talk say the word acromania they're really referring to that strain how is it grown you've already alluded to the fact that it's a hardcore anoro 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 yeah 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 anoro survives without oxygen I understand that biochemistry I don't remember the biochemistry of why oxygen is toxic yeah oh man that's such a good question I don't know how the oxygen is it must be a free radical thing or something yeah yeah they're insanely sensitive to it yeah amazing yeah which is crazy because 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 Anor robes 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 the same issue which is that you have to create this you know end to-end closed system and so all of us who were 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 okay so were there people out there trying to grow acromania without with without super super strict controls 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 acromania you know dead acromania 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 so the FDA has no ability to regulate like there are lots of products out there that supposedly sell that supposedly include acromania right no no no no and there there we have a whole um game of wack-a-mole happening at our company for what we're calling fake or Manas so these are people who will throw a supplement on Amazon and say this is acromania and you can test all these things most of them just have lactobacilus or bipo bacterium in them um and they're just so they're not even trying to fake it false advertising just false advertising okay so walk through the process so to grow acromania you have the same vat but now what do you have to pump into it nitrogen how do you get rid of oxygen how do you create a no oxygen environment you get rid of oxygen by pumping in a competitor nitrogen and so at some point we should have you come visit the manufacturing site we'll get you all gwn up and take you on a tour but essentially it starts with a freezer um Master stock of the strain so we always go back to the freezer stock because of this genetic component so you know we have a master stock of you know the strain which has been very heavily characterized and um we don't want to just keep growing this thing and then go off of that growth and go off of that growth I can understand why you would want to start with the master stock because of the profound genetic drift um so what do you what do you now do you you grow this in the in a n a pure nitrogen environment um you're actually pumping in multiple other gases nitrogen is is one one of the primary ones but you're pumping in and actually the the mix of gases matters so that's actually part of the secret sauce of growing The Strain the the mix of gases matter and your everything is Anor robic so in the beginning when you just have kind of the small stock and you're doing the smaller cultures you're literally operating in an Anor robic chamber so you've got the you know the gloves going in this chamber and you're you're working in that fashion um and then we we literally there is a you know physical tube that goes from that chamber into an entirely closed then you know bag where these things it kind of transports out into this bag filled with media and then you're kind of growing it at these uh you know larger scales but everything no oxygen everything is an entirely closed lock system and you're pumping in these other gases in order to keep keeping in order to continue to keep oxygen out because really no matter how close the system is what we found is that oxygen makes its way in so one of the most expensive parts of this process is the pumping in all these other gases and you know if you come visit our site uh you'll sort of see we just have have you know um walls and walls lined with just these tanks of these other gases that are getting pumped in um and then after that you know again everything you know through lyophilization has to remain Anor robic and then once it's freeze dried now it's in a stable state so I could leave acromania powder you know out on this table for weeks and it would be fine um so it's really just leading up to that freeze dried State wow so freeze dried acromania I guess that kind makes sense because a capsule presumably still allows for diffusion of oxygen absolutely and and the and the freeze dried State you basically put them into you know a dormant state so they're not metabolically active at that moment which is why uh they're kind of and it's so interesting so you don't have to keep them in a freezer at home a fridge is good enough that still keeps them even though they had to be cooled to a much lower temperature presumably to be freeze dried they can be warmed to as much as a refriger Ator which is probably what 38° or something yeah well actually acrania the just the the single strain is room temperature stable so you can actually have those pills at room temperature and that still doesn't permit enough heating yeah it's it's stable at that the body temperature is what's necessary to heat it um well even then you know when you consume acromania the it's it's the hydration you know along with that heat that really it's it's the hydration that's actually your big problem once you're in free dried State you're basically trying to keep that guy dormant and so once it's freeze dried the uh you know and when you buy our our bottle you'll see we have you know desicant packets in there we have desicant line bottles when we do our clinical trials it's all about keeping moisture out so as soon as now now once they're in a freeze D State now once water enters the game that's what brings them back to life and then they die because now there's oxygen so once they're in their capsule form some people tell me like oh I throw out that little you know packet I'm like don't throw that out because that's what's going to help you keep these guys stable wow okay so what's that process take in terms of time you know the time varies for each of the different strains and obviously also the concentration and the number of bottles that you're trying to make so the people who do this obviously this is a a high touch industry they they were doing what before this industry like this is something that's done where you mean before do manufacturing probiotics um well you know there there are lots of PE probiotic manufacturing has been happening around the world for a very long time using this sort of you know High intense anerobic process oh yeah I'm actually we built this thing from scratch so we had PhD scientists and microbiologists who were taking kind of these smallscale methodologies and then trying to figure out how do you grow them at larger scale so in fact I mean our manufacturing plant is in San Francisco because that's where all of our PhD microbiologists were were living you know and so um we actually have a pretty young team of people that are coming almost some of them straight out of their post dos how are you doing the flow cytometry on the anaob without introducing oxygen the flow cytometer is in an Anor robic chamber I mean I used to do flow citometry every day they're huge yeah we have custombuilt anerobic Chambers for all this stuff wow how does the person go in are they just putting their arms in are they wearing yeah you just you just have these gloves and you you shti your arms in and the and the whole and you you so basically you have this anerobic chamber yeah yeah but but to prepare for the facts you're mixing the antibodies your puts and around you're rinsing you do all that through these little glove Chambers all of it is done through these gloves that's hell on Earth and then there's a little box on the side that you know you you open it up you put your thing in there you close it you have to De oxygenate it and then it open a submarine it's like a submarine the double chamber so it's it is I think people get pretty Adept at using these gloves I'm terrible at it but they can do really fine work with them aside from the fact that acromania from an epidemiologic standpoint always shows up now that you guys have and how long have you has your company been selling an acromania probiotic we've only been selling it for a couple of years I mean we really spent about a decade doing um you know Dev work and R&D work and pre-clinical and clinical work so you know want to make sure that thing did what we thought it was going to do but so we've been selling are you comfortable saying how much money you spent on that r a lot 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 piis to do work with these strains I mean I think if you want to build a product that has real efficacy behind it you we there's a lot of kind of blueprint from pharmac itical drug industry that that we've adopted um because the incredible rigor that they have around developing products with efficacy yeah and and your industry is not one that's known for riger would would be putting it mildly yeah 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 Consumer so we'd always had this this idea that the microb 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 FAL microbiome transplants that you can actually help people improve health through microbiome intervention um and that if you followed a drug development you know rigorous pathway you could actually identify the subset of that fom microbiome transplant that could help people and if you could figure 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 advocacy 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 is not going to go read clinical trials or necessarily compare you know your ingredients to ingredients on all the other labels or do all that leg work it becomes 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 well even if you are selling to doctors I mean quite frankly it's complicated I mean it's not like doctors would necessarily understand this uh I I I struggle to understand this let's explain what acromania 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 kind of go back to the to the science of this there's a clear and obvious correlation as to why acromania is beneficial but that doesn't explain mechanistically what it's doing do we have an insight into why acromania is something that lowers an individual's blood glucose or response to a glucose load yeah so we'll do kind of a a deep dive into acromania and what we know to knowing that we're going to learn all kinds of other stuff but at a very fundamental level this is primarily through the glp1 pathway so what we know about acroman and just to get people excited about that if you're if you're hearing this and you've heard of OIC you've heard of glp1 so OIC is a mimic of glp1 yes so um what we know about acromania 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 amuk 1100 um that 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 got microbiome and L cells are the cells that secrete glp1 so um a lot of people don't know this you know your microbiome is really the guy secreting glp1 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 glp1 so acromania has this you know surface protein called amuk 1100 it also secretes a protein called P9 um and P9 binds to these IAM 2 receptors in the L cells which are also known to stimulate them to um produce glp1 and then the third thing that macromania does is it's able to produce a short chain fatty acid called propionate and propionate is Upstream of um berate and so there are a bunch of strains which can take propionate convert it into butyrate butyrate binds to G protein coupled receptors 42 and 44 also in these L cells and stimulates glp1 secretion and so these are all um kind of ways in which acrania can stimulate G1 secretion and by the way there are two strains um there are only two strains to be able to directly stimulate glp1 one is acromania mucil the other is Clum butterum and they actually act kind of together because Clum butum as its name indicates is a butter rate producer and so um and then gop1 uh is is sort of has multiple uh benefits you know one of which is that it helps your body know to I your you know all this stuff way deeper than I do but 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 induces Sati 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 produce gp1 um and so the result of that is that your body will produce glp1 when you're eating 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 glp1 so you get these benefits of lowered blood glucose reduced food cravings you know lowered A1C and and the body weight impact so 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 acromania and you're feeding at the right food a couple things happen it sounds like one of them is not at all related to a production that it or secretory product but rather just this surface receptor I think you said it was the amch 1 1100 or something yes it has a very fancy name yeah yeah so and that surface protein by itself just stimulates L cells in the um in the entos site and that we know that that makes glp1 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 so it secretes P9 it secretes propionate propionate gets converted to butyrate by another bacteria which ones there is a a class of um clal strains that will do that secondary conversion and Clum butterum is sort of the most well studied of those got it what about diff ail is he doing anything good for us there actually don't know we haven't studied whether and maybe people are afraid to bring that into the lab yeah yeah and what does P9 do and so P9 is directly stimulates L cells yes it binds to this IAM 2 receptor on the L cells and stimulates them IAM receptor 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 well and that is uh you know for we we have not done studies around that but for sure that is a area of heavy interest um yeah by vague recollection I mean we're literally going back 25 years is that when you when a person is uh for example septic right you have all of these cam modules that lead to you know vasod dilation leaky capillaries secretion of monocytes out into the pereral tissue is macroasia um but sounds like this is a distinct process here 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 Acres stimulate uh these L cells to produce glp1 but acany has another role which maybe is very much tied to this um you know which is that uh 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's it's it's a real this so-called leaky gut or GI issues that that become a result of not having enough acromania 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 and then tell me what's the fate of the butyrate made of the proprionate it binds to these G protein coupled receptors um and that's also what stimulates the L cells to then go release glp1 got it so sort of multiple methods to multiple these small molecules that you know uh are the signaling molecules for these receptors on the L cells so all roads point to more acromania more glp1 what differs from someone taking OIC is they just have a mega high dose of glp1 all the time and what you're talking about here is as you said kind of a waxing and waning dose of glp1 that is more physiologic because it comes with your meal that's right so one would not expect this type of intervention to produce the amount of weight loss you would see with carpet bombing somebody with glp1 absolutely not and and one of the other big differences is that the you know gp1s are injected so you're it's going right into the bloodstream whereas here here you know it's it's a microbiome effect and to your point you get the waxing and waning sort of more physiologically relevant uh but it's not going to be the same as just hammering a bunch of gop1 straight into the bloodstream all the time all day all night so um yeah yeah so so again again this is so so now let's talk about the data so what was what was the first study that demonstrated that acromania could play a role in from an intervention persp perspective from um impacting metabolism vis a blood sugar yeah some of the earliest studies are really done I mean first of all was discovered by Dr Lee Kaplan over at MGH um and he's a bariatric surgeon and so his initial interest was you know what's what's happening to the microbiome we do the spatrick surgery and and kind of came to really be one of the first people to really look at these microbes and discovered that acromania um appeared to be you know associated with with or inversely associated with obesity and then started doing these inv vitro studies to figure out like what is it doing so you know the the work really has to go credited back to him in the early 2000s and and I want to point out one of the observations that came from his work which is a really remarkable observation which is um at least as far as the ru and Y gastric bypass which is a real organization a reorganization of the plumbing uh of a person's gut that you took a person who was Beast with type 2 diabetes and you do a ruiny gastric bypass on them and within days of surgery their glycemic control improves even before they've lost weight this is a very important point because nobody would find it that surprising if a person after a gastric bypass loses 100 pounds and their diabetes goes away that would be a o Shu of course moment it's why does their diabetes result ol in the days following surgery when the real weight loss hasn't started and there have been lots of suggestions to this right one could be the fasting you know you're you're not eating anything a day before surgery or a day or two after surgery that's a pretty significant fast that depletes all of the glycogen in the muscles and you know much of it much of the liver glycogen is that enough to kind of Kickstart them um but it's hard to ignore that you're also completely changing their gut biome by re-plumbing their GI system so can you say more about because I'm not familiar with those data in terms of what they saw as far as pre- and posts surgical gut biome yeah I think um I'm also you know not an expert in these in these surgeries but I they have been a source of a lot of Publications um have sort of used them to try to understand you know what are the key gut microbes out there you know and and I don't think it answers this question of you know why do you see such an immediate response you know sometimes hours after the surgery um just kind of thinking about the you know time length of these different Pathways to have effect it's most likely something hormonal right and so um but I don't think we have the answer to that it's hard to imagine it's not something related to glp1 yeah so I don't think we have the answer to that uh specific question um but definitely that was where acroman was was born out of and then they they do these gastric bipass surgeries in you know there've been a bunch of animal models this was some of the very early work really just trying to lay the foundation for the fact that your microbiome could play a role in you know weight loss or weight gain and so they would take these microbiomes you know before and after the surgeries and then they would you know put them into these Mouse models and they would show that you could change the metabolism of the mouse so that's kind of really you know I think um it's been really hard in the field to take take that data that Fe microbiome data where you feel like oh there's a glimmer of hope here and to distill it down to what are the things that are actually doing that that that's the big challenge of the field we're not there you know that That's So when you say like oh what did they find was well they found that the whole Gish could change things but we don't really know what in there is doing that yeah so one hypothesis is that acromania is doing part of that at least yes and so the easiest way to test that would be to give people acromania okay so you guys did an experiment like that who who did you do that in collaboration with so we did um you know the clinical trial I'll point to the clinical trial that's published um in in bmj because I think that was probably the most rigorous trial that we've done and then I'll talk about why I think trials the downside of running too many trials in in things that involve humans um but in that trial we didn't just have acromania we actually had it in combination with four other strains um the idea here is as I said acroman can produce propionate but without the help of another strain it can't produce berate and so we had this idea of you know let's include primary and secondary fermenters let's not make acroman the only primary fermentor let's add some more in there and really thinking about this you know what is the um kind of uh team members that you'd want in here that can metabolize fiber into deuterate trying to optimize her beate production and then having acroman in there which has then actually at the time we did this study we nobody even knew what P9 was or amuk 1100 we just knew that acroman was able to you know kind of um uh we thought it was only playing a role in the muin regulation we didn't even really know that it was able to stimulate gp1 even at that time so um we really thought it was these butter producers that are doing that so we did this trial where we actually have which are the claustral strains yep which are these clustal strains um and then also this bifido bacterium infanta strain which is also a primary fermentor so we basically Al did a placebo control double blinded randomized Tri where we had three arms one was Placebo one was this full formulation of all five team members and then the third one was a subset that did not include acromania and um we what we and and these were in people with type two diabetes um and uh initially we wanted it to be people who just had type two diabetes but weren't on any medication it turns out that's like almost impossible to find yeah it's a hard study to find yes so then we said okay will have it with people on Metformin in anyway a lot of people are on Metformin so if your thing is going to benefit people it it should it ought to work on top of Metformin um so then we we did that and then that was also like recruiting into clinical trials is hard it takes a long time we were a startup company we're like we're going to run out of money if we don't expand this out so then we started including people on sulan uras so finally you know we get all all all the people in trial it's still a pilot trial 76 people you know across these three different arms and what we found is that compared to the thebo group the people who who were on the full F strain formulation um over a 90-day period saw their A1C go down by 6 and their uh blood glucose spikes go down by 34% and that was done using measured how yeah that was done using a pretty old school oral glucose tolerance test they literally came into the clinic they got their sugar and then they just had blood drawn every 15 minutes for two hours so um that was the and and the reason we did that rather than a CGM was because we wanted to use all the kind of gold standard traditional methodologies you know that this we don't want anybody to think that the data was weird or and so that was um so so hemoglobin A1c came down by. 3% which is a pretty big drop 6% compared to Placebo yep compared to Placebo in 90 days yep and um Peak glucose level fell by about a third you said area under the curve so the entirety the area of the curve y okay fell by about a third yep got it and that was placebo to five strains acromania plus four strains to do the conversion of proprionate into berate well that we also have strains that do the same the Redundant function of acromania which is they'll do that primary you know fiber into um you know either propionate or acetate I see okay and then how did the group absent acromania do so they were they had some efficacy but it wasn't like the five strain formulation so my uh co-founder and biostatistician would would say you know that was not statistically significant and the data is published so anybody can go look at it I would say it looked like it was in between the placebo and the five strain formulation but in any case but it could have been very underpowered and that's why you didn't see a difference it also could have been very underpowered yeah so this was a again just thinking about this now not as a scientist but as an entrepreneur this was a a Do or Die moment this was a b there's going to be a binary outcome here either we were going to be a company on the other side of this or we were probably going to close up shop because it was all in on this trial what year was that uh experiment done so this was maybe um 2018 we found it in 2012 um you know all the stuff leading up to this was we had to identify the strains we had to figure out how to manufacture them so six years of basic science six years of basic science leading up to this trial and I was already starting to think about you know I mean it's very rare that your first clinical trial out of the gates works and so this is why we did the three strain and the five strain we were like at the very least what we have to understand on the other side why yeah why didn't you just do the placebo versus the five strain because acany was so hard to grow oh so you were hoping to see that the forest strain would be great and you wouldn't have to grow acromania yeah we were hoping we didn't need the the diva in there it turns out we did so um so what's interesting scientific speically but would have added too much overhead to the study and maybe it's irrelevant if the other four are not that expensive to grow is would acromania alone how would that have performed relative to the five strain pot yeah of course if we had been able to do that you know subsequently but you know I will say that lots of people have been doing work with acrania solo and if you you know asked me to put I'd put Vegas odds down that by itself it's probably not as impactful as the formulation because you don't have the assistance in converting proprionate to berate exactly and then sorry dumb question I think you already addressed this and I've forgotten already butyrate is stable it's a short Change fatty acid why aren't we just all mainlining butyrate it's a great question um there have been a ton of preclinical and of course in vitro work showing the benefits the massive benefits of berate across a bunch of different States including metabolism and yet none of them is translated into humans even when we try to do like these enemas right like these clinical trials they've never looked the way they did in the animal studies the animal models are like blow your mind you know blow you out of the water and and the human trials really don't show that and I think for this particular pathway that we're talking about here it's a localization problem so um earlier I mentioned that butyrate is source of energy for all these colonic cells the issue is when you're delivering butyrate all along that tract as you know this berate is basically being absorbed by all these different cells um and where you need it to get to for this pathway is to the gut lining where the G protein coupled receptor is sitting bind to that g protein coupled receptor and so so it's not that acromania just makes butyrate it's that it delivers it to the place where it needs to be exactly the pro literally the physical proximity Is is what's enabling this to work wow okay so if you're GNA play Devil's Advocate um well let's go back to actually something you said a moment ago which is this trial was done in people with typee 2 diabetes average hemoglobin A1c coming in was what roughly these are kind of early diabetics they're in the sevens yeah they were in the sevens uh you know between 7.5 and 8.2 I think I think was the range for all the grp I have to go back and double check that so is there any sense and I know you didn't do this in the study because you said it was only 90 days but is there any plan to redo this to find out what happens if they had stayed on for a year in other words could you take someone with type 2 diabetes and actually knock you know 1.2% off their hemoglobin A1c which for many people would now take them straight out of the diabetic range yeah absolutely we have we have multiple ongoing studies and maybe this will get back to kind of the the the personal story of the entrepreneurship which is that on the heels of this study we were like holy we we made something that works now we got to figure out how to commercialize it but before we do that we should probably replicate the study or maybe we should do them you know in parallel um and so we we actually launched by the way did you get any push back from your investors on that doing another study 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 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 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 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 you just sort of see this game kind of happening and our underlying premise was if you could deliver something that actually help 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 you have to have a study and 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 no this claim around lowering A1C and blood glucose spikes is we are stand alone in making we yes we are the only ones that make that somebody else could do a study and make that claim currently nobody else can 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 aize and and we have um investors that have gotten behind gamechanging 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 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 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 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 is 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 paper but a doctor can that we go through healthc Care 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 going to see more than a pilot and they're also going to want to see it run by somebody that's not yourself and so we immediately launched these studies and then Co hit and every study one by one got brought to its knees because people with diabetes um you know uh are more prone to kind of coid complications that that came out a little a little bit later on but you know people were getting coid and then you're like well I don't know what this Co is doing to the microbiome and then people were totally not adherent to any protocols they couldn't come into 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 because we're not going to 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 sort of built up some momentum so it's all third-party pis and academic and clinical institutions um that we 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 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 yeah I mean and I I do think that there's a but that's good so there's interest there were piis 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 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 great so how many such trials are underway right now right now we have um about a dozen and around the world that are happening and and not all them not all of them are for type two diabetes we we actually have several that are where investigators have their own hypothesis about what these trains 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 milen Institute that is looking at the role of acromania in bipolar disorder I mean that's kind of amazing if you really think about it so you've got basically a dozen piis 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 very reputable journal and that alone has generated that much interest that they're finally willing to study a commercial product well I don't think it was just that study there there's like over 3,000 Publications on acromania that people around the world have been publishing on you know mostly academics um and so there's a lot of data but those studies weren't intervention studies no a lot of them are correlative studies that's my point right like this is what you did is quite unique in that you finally bridged a gap right which was correlate correlate correlate but until you can test an intervention under blinded randomized conditions you can't know if there's an associative link and you've at least suggested that absolutely and I think that you're right the fact that we can make it and that it was able to have this efficacy does give people some belief that okay well if I want to go test an intervention these are the people that have made it and it works right because they they could never invest in the capex to go and make it no I mean our manufacturing plant I mean we it cost us $10 million to make that plant 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 yes so pendulum glucose control is marketed for people with type two diabetes you know lower A1C lowers blood glucose spikes and it is the exact formulation that was in that clinical trial and do you still use that same quality control metric of actually doing flow cytometry on those products yeah 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 it says AFU active fraction unit and what does it report it in it reports it in it it's in uh the number of um cells that appeared in that active fraction so it's it's it's still going to look like I think it's like 10 to the e8th or 10 to the 9th for most most of the strains got it okay um what other products do you sell 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 dietitians so we were like this is going to be a solution right we're going to give you your nutrition coaching we're going to give you the test that's going to type it's work how did you offer that for free you didn't want to make money I'm guessing you losing a lot of money doing that we don't offer it now because it turns out it's not scalable and it's not econom in fact it was funny somebody even said oh my gosh everyone should go buy this product right now because these are like non-scalable so like at some point they're not going to 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 realize 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 dietitian and a personalized 101 coaching and maybe AI will help us get there you know faster than than you know we would otherwise but and what other things did you hear from customers so so presumably did you did you see in the real world comparable reductions in hemoglobin A1c it was all higher the reports we get back were higher A1C drops higher blood glucose drops um 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 I think it no actually no and and and moreover I would say you you might say well gee those people just didn't tell you but you can see it in the numbers you can see it in the return purchase rate and pendulum glucose control is $165 a month that's a real out-of-pocket expense and so it's a hugely expensive I mean I don't really know the space that well but how expensive are the top selling probiotics yeah a normal probiotic is 20 bucks a month um a premium high-end probiotic is maybe 49 bucks a month so5 is way out there and I think you've explained why it has to be that expensive you're I won't ask you what your margin is on it but I'm guessing it's not that high given your manufacturing process well what's even worse is that you're teasing me about offering this test and this nutrition coaching and how did you do that we were not only losing because of those but we were actually losing on every bottle we sold because it was costing us more to make it than the 165 we were selling for so it's all kind of a hot mess out of the gates but I think what we believed was that we knew that as we scaled a lot of those costs would go down so just like everything else if you're buying 10 bottles versus 10,000 bottles the same bottle cost you a lot less once make a bottle for less than whatever that cost is we now we now do make it less for we make it for less than what we're pricing it but we also have to ship it cold so there's also that um you know transport so and in any case I think what we really wanted to understand yeah that's an important point it arrives you get three bottles which is a three-month Supply it arrives in an ice pack in a big box just like you know if you're if you order ratha or something like a pcsk9 inhibitor same thing shows up cold you got to put it in the fridge right away can't travel with it I mean there's some logistic challenges associated with these things oh yeah there is definitely complaints but I think what we wanted to do was to give the product the best chance of success by giving people these tools to be able to help them measure and then also in a lot of people don't even know what a high fiber diet is supposed to look like and so just kind of giving those tools to people so so we got all this great feedback efficacy was higher than what we' even seen in the trial but we also got a lot of complaints hey man how is this $165 a month why isn't my insurance covering it why does it have to be cold I can't travel with it you know what am I supposed to do in in the time that I'm traveling um I don't have type 2 diabetes um and so we kind of took all that and said well let's just run some marketing tests on um a a lower dose version and so that had huge uptake and so we launched a product this year called metabolic daily and it's literally the same thing as glucose control but just at a lower dose that allows us to get down to this price point of $49 a month which feels a lot more manageable for people when they're thinking about especially if you don't have type 2 diabetes um you know but you want to help your body metabolize sugars and carbs better and things like that so and that product still has all five strains in it that product still has all five strains in it so it needs to be refrigerated yeah so actually and we all of our products really should be refrigerated that does maintain the viability for longer um so yeah so we have those two products and then we also release this the single strains that are in components of these products so we had a lot of people who came back to us and said hey I'm I'm buying your pendulum glucose control but all I really want is acromania I just want that one strain and you know we sort of like who the hell knows what acroman is this is just like some really educated people coming to us and it's not a real Market um and so we did a market test we made a thousand bottles of acromania we literally just called it acromania and we put on there like that's for gut health we made no claims about it people were coming to us for wide variety of reasons of why they wanted acromania from you know metabolism issues to GI issues to neurological disorders so we were like we just sell it as just acromania that's the value prop we made a th000 bottles in less than 10 days every bottle was gone and that's an expensive product because it's acromania right acromania is the hard you know one of the hardest guys for us to make and so um that is a product that we sell it's one of our best sellers is just pure acroman and actually a lot of practitioners use it because let's say they you know ran a gut microbiome test person's low in acromania they just want to give them the minimal viable product to kind of boost this strength Trin back up but we're really on the outskirts of knowledge here we really don't know what it's doing by itself well we know that it's you know secreting some of these proteins and and we know that for but in terms of outcomes we don't have it we don't that's more of a stretch right at this time well I would say that what we've learned from having it in the market is that people are getting a variety of different um uh measurable impact from it and one of the most interesting things that we learned is that we had bunch of people telling us actually the reason why I stay on it is because I don't have any more sugar Cravings like I went to the Christmas party and didn't eat a single cookie and I'm usually the guy sitting at the table eating all the cookies and so they we started to see this theme of sugar cravings and as we talked about earlier you know one of the Hallmarks of gp1 is reduction in sat or Improvement in satiety and so we just did a little pilot study ourselves of you know we gave we said go on this product for 90 days and you know do this kind of diagnostic test on cravings and um was it a blinded study was there a placebo arm no so this is a pilot this is just a proof of concept um and so what we see is that um people have a significant reduction in these food cravings and so what that's now being parlayed into is funding a clinical trial to look at that and so this is kind of where I think the consumer uh space is a a really interesting place to play because rather than going all in with millions of dollars on a clinical trial based on a hypothesis in your head you now can put products out there to people hear back what they're experiencing generate hypotheses from customer data get Prov concept data and then you're you feel like okay a priority I have some sense this thing's going to work and you could even get really sophisticated and say okay well maybe I'd like to know what are people starting microbiomes or what are their diet or what are their Lifestyles or their demographics to try to understand who might this thing have the most efficacy for now you also haven't done the study I'm guessing where for those you like look at your pilot study or your your your your 76 person study it would be very interesting if you go back in time if you had the funding to look at what the gut biome constitute what what the constitution of the gut biome was prior to the study after the study and if that predicted response in other words is the greater the deficit of acromania at the outset of the study a predictor of a greater response upon normalization because even though the average hemoglobin A1c came down by6 there must have been people for whom it came down by over a% and people for whom it only came down by you know 0.2 so do you have a sense of what that relationship is yeah well actually in that trial we did do we took we got four stool samples from people during the trial so one yeah Baseline um I think it was like 30 days in after the 90day mark and then we did a wash out period so you went for a month without taking anything and then we we got a stool sample and I'll tell you this we racked our brains about how are we going to get people to provide four stool samples I mean this is like a real ask and they have to bring they have to we wanted the whole sample so we literally like these cool you've seen Cool Whip uh um that that's what we gave to people and they had to literally in a bucket put it in their own freezer until they could get it to the clinic and everything had to stay frozen and so um we had 100% compliance we had people who dropped out of the study who were still sending us their I mean it was amazing how how much sample people were willing to share by the way I remember when my brother got back from like I don't know he was somewhere in Africa or something and he had some awful GI bug and eventually like he had to collect a stool sample and uh I was like looking at his fridge and there was this bag in there and I was like what's that and he's like Ah that's just some and I was like no seriously what's that he goes it's just some I was like dude if you don't want to tell me that's fine but he's like no no that's what it is that's literally what it is lit what exactly people were sending us um and so and and the reason is because as I said you know we we were an early stage startup I was like the chain of this clinical trial isn't going to work I got to know we have to have this microbiome information so that in my head I thought for sure if this thing doesn't work I want at least know it didn't work because exactly did it get delivered or not and so we really want to see the presence and absence of our strains but to your point we also really want to understand could you do this kind of um you know predictive modeling of who would be or wor responders and we couldn't it turns out that you know it could be that the end is too small it could be that we don't know about these individuals but the microbiome alone or even you know the levels of acromania alone are not enough of a predictor they're not enough of a predictor of response yeah and tell me this did everybody have anybody who took acromania have a significant increase from pre-study to post study during the 90 days and then what was the fall off from 90 days to like through the wash out yeah every participant in the study showed um an increase in all the strains um and so that was very rewarding because we invested a lot in the encapsulation to get the thing delivered so that was a great proof of concept we actually managed to deliver something that in theory is undeliverable exactly yeah step one deliver deliver the goods um and then the wash out period was 30 days so after the 90 days there was a 30-day wash out period and most people lost the strains after that period but there were about 15 to 20% of participants who were able to maintain their acromania levels even after not taking the pills anymore my that's I was exactly about to ask you that question is there any chance that those are the people who just consumed the best diets and ate the most fiber after exactly we we did not do so this is another decision that may be in retrospect you know we didn't do diet di logs and the reason we didn't do diet logs is because I'm told that uh you know people are Liars when you do diet logs and clinical trials what you get back is all the days somebody was good and then big gaps of missing days where they ate something terrible or did something bad and so it's just not really like a good um although you could you could almost think of doing a diet log here where the only thing you're asking them to log is fiber and you give them a really clear sense of fiber and it's just all we're doing is counting grams of fiber per day take a picture of everything you eat that is one of these things on this laminated card every time you eat a carrot or a celery or this or an orange just take a freaking picture of it and tell me how much of it you ate and that's it I don't care how many calories how many Diet Cokes I don't care about anything just eat all the cookies you want if you want I just want to know this metric yeah I we well I wish I'd met you when we were doing the trial design so we didn't we didn't do that what we did was we asked people you know what what are you are you an omnivore are you a vegetarian vegan so we we have all that there doesn't appear to be a correlation with that um and then we ask people please don't change your diet the whole point of this study is we don't want people have to undergo a behavioral change in order to see an improvement it should be just the microbiome intervention um but of course you know we don't know if people change their diets I I think what we want to tackle now is a much more direct thing which is to say that you can deliver people meals and they don't have to eat the meal every day but basically if you say look we're going to part of the trial is you're going to be on the product and then we're going to deliver you a you know it's basically a high fiber meal we want you to have this for lunch three days in the week and then you have your control group where they just get the pills and so I think by deliberately making sure that people are getting this added fiber you can sort of compare you know whether that fiber is helpful I mean I I it almost feels like a no-brainer the people who will have that higher fiber food will will do better but we will measure their microbiomes and we'll see whether the strains are actually even higher for them too so the next two years really is an interesting time for your company but more importantly I think just our scientific understanding of what's going on on the basis of a product your company has figured out how to make so if nothing else you guys have figured out how to make something from a manufacturing process that no one else was going to figure out there's no University that could ever have figured this out because they wouldn't have been able to put the resources in it right no one was going to spend a hundred million to figure out how to make an obligate Anor robe for you know when the maximum NIH Grant is $480,000 a year like not going to happen um and now it enables a bunch of people to ask these questions about what's the impact on depression what's the impact on ADHD what's the impact on Obesity type two diabetes um it's it's it's super fascinating in many ways it feels like the bridge between the diet and the drug right because we already have a really good sense of like you know it's not like it's rocket science from an efficacy standpoint to get somebody to lose weight by changing their diet the the effectiveness is the problem it's too hard to implement for most people um at the other end of the spectrum we clearly know now how to do it with drugs and that's really changed I think it really started in 2014 when liraglutide came out but clearly semaglutide was the GameChanger and that's three years ago was when we saw the pivot from semaglutide as just a diabetic drug to an obesity drug and it's it's exciting for me to just kind of watch this um and and and and frankly even you know look at other questions that you know haven't been answered yet like the dose response like is more better right like do we know anything about how much is too much and what's the maximal dose the the the minimum effective dose and the median effective dose like there's all this other stuff that uh I don't know it'll be five years and we'll be sitting here and hopefully having a a more interesting discussion absolutely I mean I think the dosing is is is an interesting one too because um it's really the the right question is how what is the colonization that's happening because it's not just about what you're delivering it's about what's colonizing and it's different from person to person so I think if we could crack that nut on the dose to colonization ratio and in what context that's better you know you start to see improvements but absolutely it is the gap between nutrition and then these Downstream small molecules and the microbiome is been a black box and now we've got some tools here we're just at the beginnings of it but I think for us the big name of the game is how do we get these products into as many people's hands and as many investigators hands as we can to just create more and more data around you know what is your starting microbiome what is your lifestyle how are these things tied together and what are the health outcomes that can really come from a different microbiome are there any other bacteria out there um as specific strains or even species that you think are going to be worth investigating B based on the literature today and um you know we've talked a lot about acroman and all the reasons why you had so much data to stand on the shoulders of to to to go down that rabbit hole are there others out there that you you think offer promise and that maybe in five years there are many other strains out there that people are taking so you might have in your fridge a bottle of acromania strain two strain three strain four absolutely I assume you're not going to say what they are I'm guessing that's somewhat proprietary but we there absolutely there are other I think these sort of key strains that um player and and I'll just kind of allude to uh really the um immun the the link between our microbiome and our immune response is is super interesting um and so there are other strains so we'll stay tuned yeah all right thanks Colleen thank you so much for having [Music] me w

Channel: Peter Attia MD

Views: 346,603

Keywords: Peter Attia MD, Dr. Peter Attia, Early Medical, The Drive Podcast, The Drive, Longevity, Zone 2

Id: th3UwC10EZU

Length: 168min 48sec (10128 seconds)

Published: Mon Dec 18 2023