Why some people gain weight eating the same food | Dr Karen Corbin

What if weight gain isn't just about how much you eat, but how much of your food your body actually absorbs? Is it possible that two people can eat the same meal with the same number of calories, yet one extracts more usable energy than the other? Not because of willpower, not because of discipline, but because of their gut microbiome. Today's guest, Karen Corbin, is a registered dietitian and scientist working at the cutting edge of nutrition, metabolism, metabolic health, and the gut microbiome. In this episode, we separate what's solid from what's speculative, unpack how the microbiome fits into all things energy balance and weight gain, and explore what's coming down the pipeline in this incredibly fascinating area of science. It does get detailed at times, but alongside this deeper science, Karen also shares practical evidence-based takeaways for building a healthier microbiome. Okay, let's get into it. Karen, is it possible that someone who's gaining weight, or perhaps having trouble losing weight, is actually absorbing more calories from their food because of their gut microbiome? It is possible. And if that's true, what are the implications of this for human health? For explaining today's chronic disease rights and perhaps how we may prevent or treat conditions like type 2 diabetes, for example? I think the most concrete way to look at that is think about when you look at a food label on a package of food, it tells you a number of calories, but those calories are entirely based on the human side of the metabolism equation, and they don't take into account the variable amount of energy that you could absorb once the foods that are not digested and absorbed in the small intestine make it all the way down to the colon, where the community of microbes that resides down there has the chance to ferment them and make energy basically out of those undigested foods. So if we make this super practical, let's say you and I go in and buy something from the grocery store, we buy the exact same product, and we eat the same amount, let's say 100 calories of that food, it might be that I absorb more of those calories than you do and therefore I have great potential for storing fat and accumulating excess body fat over time. That's right, you might absorb 97 and I might absorb 82, which doesn't sound like a lot, but if you think about the cumulative effects of that differential absorption across many, many different foods than it could add up. Is this a new novel understanding that we've only kind of come to learn over the last five, 10 years or how long have scientists been aware of this? So I personally became aware of it around 2004 when the first publication came out showing that in rodents that didn't have a gut microbiome, they absorbed fewer calories, but the translation of that into humans and actually in a reliable quantitative way figure out exactly how many calories different can it be in a person? That's work that originated from our team here at Advent Health that we published back in 2003 and the reason that it took that long is because you really have to have all the various components of the energy part of the equation on the human side, measured in a very comprehensive and precise way, and then the technology around measuring what the microbes themselves are doing has also evolved since that first aha moment back in 2004. So I would say as far as a reliable quantitative determination of what that difference could be, that's fairly, fairly new and I'm happy to say that our team here contributed to that knowledge. I want to come back to those studies that you've been involved in, but before we get to that, just so people are familiar with you and you're kind of background here, can you walk us through your journey as a registered dietician and a scientist and how you came to focus on the microbiome in the first place and why this is something that you feel is a really important area to study? Yeah, so I started my career as a registered dietician back in 1998 and I actually started undergraduate studies as a biology major, but I made the pivot to clinical nutrition because I really wanted to use science to help people, science that people could apply to their lives. And so I spent five years taking care of patients with diabetes and heart disease and congestive heart failure. And in that journey, I almost immediately noticed something. I could follow all the things I'd learned in school and give the best nutrition prescription that I could come up with. And some of my patients did great and some of my patients did terrible, even if I believe completely that they were adhering to what I was saying, I still saw quite a lot of variation. And so that really led me to say, I want to dedicate the rest of my career to the science that will help us maximize the healing powers of nutrition because nutrition is something that is fundamental to our health. And knowing that we don't all respond the same way, I knew we needed more science to figure out how to capitalize on that. So that was my pivot to from that point forward from when I made that decision. I went and obtained my PhD and have been thinking about this in many, many different ways for almost three decades now. And you feel as though a large portion of the different responses that people have to food is explained by differences in the microbiome? I don't know if I can say large because we'd have to take into account everything else like genetics and epigenetics. But what we do know is that the portion that's different is clinically important. So the difference we found when we took people and fed them exactly the amount of calories they needed to eat to maintain energy balance. Basically, we were measuring energy out and the energy we fed them matched that energy out. When we did that with those two different diets, the difference in energy absorption on average was 116 calories a day. So that's that's a decent number that over a year is 42,000 calories that you put into your mouth, but you didn't absorb. So that's a really good starting point to know that it's significant enough to over time and we haven't done the study in persons with obesity, but over time, it could add up to providing an added benefit for managing body weight. Just on that on that study and I'm sure it's on point through this conversation, we're going to really get into the design and exactly how you conducted it and what you found. But just while it's top of mind, when you say that on a certain diet, people seem to absorb less calories, at least that's what I'm hearing. So 116 less calories. Was that because of differences in their microbiome or is that differences in the diet self, the properties of the diet? So the properties of the diet in that study were completely opposite. One diet is essentially starved the gut microbiome. So it didn't allow for that piece of the equation to be optimized because they weren't seeing the food. It was getting absorbed in the small intestine. The other diet was specifically designed to feed the gut microbiome and that is the big difference is that even though the calories at the mouth were exactly the same, we were altering the proportion of those calories that ended up making it all the way down to the colon. And those 116 calories that people were not absorbing when they were fed the diet that was enhancing the microbiome. Where did that energy end up? So we were measuring it specifically in the poop when you're talking about energy absorption or energy available to a person. The biggest way to lose it is through the excretion of that energy. And you can lose a little bit through sweat, a little bit through urine, but that's the main place that we measured it. And then the next question is, well, where did those calories go? There was more, but what type of calorie or how are those calories being used? And that is an interesting piece of the story as well. And what do you speculate there? What are your hypothesizing? So our hypothesis is based on two things. One, literature has been around for decades, actually since the 80s, where they look to see, you know, in the, in the feces, how many calories are from food that is not digested and how many calories are from the actual community of microbes. They also are an energy consumer and when you're measuring total energy, the energy that's sort of encapsulated in those microbes is also captured. So that that literature suggested that at least half of the calories that are lost in the poop are from the microbes themselves. And we also, through our collaborators at Arizona State University, who are amazing partners with us throughout all this work, they also modeled this with math, basically, and found that it was at least 25%. So I was working with the hypothesis that it was 25 to 50%. But right now, we're just about to launch the experiments where we're going to quantify that exactly. And we'll be able to say, you know, this proportion of the calories was because of they were used by the microbes to grow. And this proportion was from the undigested food. So that that's coming up shortly. We're still validating the experiments, making sure that we're confident in our method and then we'll have those data ready. 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But so at the at the top of this conversation, I brought up that example of you and I going in and picking out of food and eating the exact same quantity of calories from the same food, but perhaps absorbing a different amount of calories. But it seems that it seems that the study at least that we're talking about right here is slightly different to that. It's looking at one person who is exposed to two different diets, one diet being, let's say, very low in fiber and fermentable kind of properties. So it's mostly absorbed in the small intestine. And then the second diet, having a lot of fiber and fermentable components and there being a difference for that individual with this, say, more processed and less processed diet. But that is a little bit different to the example that we kind of spoke about at the outset. It really is, but they're related. So if you on a consistent basis, eat a high fiber whole foods diet that keeps your microbes fed and happy, then you have the machinery in place already to be able to manage anything that from that food that we picked up at the grocery store, whatever that might be where there was higher low fiber. Some of it's still going to go down there, right, to the coal and not 100% of it is going to go into the person. So you already will have the machinery to take advantage of the microbes allowing that energy to hopefully not get reabsorbed by you. But yes, a huge portion has to do with what type of food you choose because if you choose foods consistently that starved the gut microbiome, you're not going to capitalize on that advantage of absorbing less energy. So it's a diet microhost interaction. Got you. So the hypothesis is that if you have a certain microbiome composition, or say function, and we can get into what it is, it may be that more energy that reaches the large intestine is used to grow the microbiome, to fuel it as opposed to being absorbed into circulation. And therefore having the potential to increase fat storage. Exactly. That's the hypothesis. And the model to test that in is really to calorie reduce people on those two very divergent diets and see if there's an advantage to reducing calories that are optimized to feed the gut microbiome versus a diet that is still low in calories, but it's also low in the calories that the microbes like to use. So that's the experiment that needs to be done to to better understand whether this hypothesis is going to continue to to make sense. Can you just explain that for me a a little bit further how that study would look? So ideally you would take persons with obesity that you know need need to reduce their weight and you would calorie reduce them. Let's say by a specific percentage everybody gets a diet that's reduced in calories by let's say 35%. That's a pretty standard calorie reduction. So you reduce the calories, but in one group the diet is a highly processed inaccessible to the microbiome diet. The other diet still same calories, still same proportional calorie reduction, but it also includes foods that are liked very much by the community of microbes in the gut and then they could ferment them and hopefully help some of that energy be shunted towards the growth and function of the microbial community versus all of it just getting reabsorbed back into the person which could also happen. Is that a study that you are aiming to conduct? One thing that we really want to understand is the magnitude of this difference in energy absorption because the number I gave you before was 116 calories a day that was on average across the study that we did at range from somewhere around 100 to 400 calories fewer absorbed per day. And we think that this variation is not because we didn't account for confounders or that there was error in the measurement. We think it's an actual biological variation that then could be capitalized upon by people who who happen to be very, very good at shunting more energy towards the growth and function of the microbial community. So the study we want to do is to and that we've submitted for funding and are waiting for a decision is take people across the spectrum of body mass index which as imperfect as it is it's a relative way to look at people that have that have normal weight versus overweight versus obesity and put them all on the microbiome enhancer diet which we haven't even labeled it what this high fiber whole foods diet is but that's what we call the microbiome enhancer diet. Put everybody on that and determine if feeding them all at energy balance like we did in the first study how much of a gradient of difference in absorption do we get and could it be that persons with obesity no matter how well you feed your gut microbiome they don't have the capacity to either expand the biomass or expand the the microbes that are going to be protective against that energy reabsorption and maybe that's a contributor to the obesity epidemic. So that's the first study we want to do we feel like that's fundamental we want to really know how big of a delta could it be and is there an advantage in people who do not have obesity where they're able to appropriately channel this energy because if that's the case then it just opens the door right up to doing the calorie reduction diet ideally I do them both sequentially do do the the study at energy balance and then randomize the persons with obesity into the calorie reduction arm that just takes a whole lot more money than is usually allowable on on grants so so we decided to do it as a two step but who knows maybe I'll be able to do them both sequentially soon enough. Energy balance has come up a bit and it's something that's going to continue to come up I think in today's conversation perhaps you can can simply I guess define what what energy balance actually means and and connect the dots here to why why that is such an important concept in something that is it is worth studying in the context of better understanding metabolic conditions like type 2 diabetes and metabolic dysfunction associated fatty liver disease for example. So at Advent Health Translational Research Institute, I often say we're obsessed with energy balance. We are very particular and conscientious about measuring every piece of that equation because at the end of the day, energy imbalances are what drive differential regulation of body weight. They also can drive something like diabetes. Diabetes at its core is an inability to appropriately utilize blood sugar. And it also applies to metabolism dysfunction associated's deutotic liver disease or mass-old as we call it today because the liver is this amazing organ whose job it is to take excess energy and hold onto it in the liver for a little bit and then eventually it just gets oxidizer or burned essentially or used up. So all of these conditions at their foundation have some sort of energy imbalance. And there's two sides of the equation. Energy in is eating food is pretty much the only way and that's a highly regulated process because energy is the currency of life. We must have the ability to make and utilize energy just to be alive. So there are lots of processes, gut brain communication that influence your desire to eat, how much you might choose to eat, what type of food you might choose to eat, but that's energy in and then energy out is sometimes people call it burning calories. So that's essentially the energy that's utilized by all your organs. So if you're at rest all day on the couch, maybe binge watching, stranger things and you didn't move really at all, you still need to blink, your heart needs to pump. So that is your basal metabolic rate. So that's the biggest component of energy out, but exercise is a controllable piece of energy out. So you choose how much you want to move and that impacts that energy outside of the equation and then there's sort of other things like perhaps the gum microbiome that could influence the energy outside of the equation and things like maybe you might have conjured because those are the energy powerhouses and when those processes get altered, that could also impact the energy out. So there's a lot of interesting energy out components like the gut microbiome that aren't going to explain the whole thing because energy in is still such a key piece of it, you can't exercise your way away of eating three packs of Oreos at once, that's just not going to happen. But I think they're fine tuners and at the end of the day maintaining a healthy weight is not easy. It takes a lot of effort and doing a lot of small little things that could together add up to being beneficial for not just your weight but your health could be a strategy that people can use rather than just worrying about I have to eat cardboard and celery all day because I need to lose weight. Well, no, maybe we capitalize on some of these other pieces of the energy out equation and that's why I think the gut microbiome is so exciting because it could be an important fine tuner. Not to mention when you feed the gut microbiome, you're doing a lot of beneficial things for your own metabolism because a high fiber whole foods diet is, in essence something that's been tried and true for so many decades as having multiple metabolic benefits. When you say the microbiome may be affecting the energy outside of that equation and it brings us back to the 116 less calories that were absorbed that I believe I heard correctly, they ended up in the stool and that was some combination of just energy that kind of passed through undigested and then also the microbiome biomass that had grown. Something that I was thinking about when I was reading your study and just kind of trying to get my head around this is, what about energy that remains in the body, right? That is actually being used to grow the microbiome that's not passing through in the stool but is actually still in the colon. I don't know that a lot of it really remains long term once the fermentation happens and the energy is made, the primary energy source being short-chain fatty acids, it's either going to get reabsorbed and a large proportion will get reabsorbed or it's going to go out because energy can't be created or destroyed, right? That's a big bang theory physics. So the vast majority is either gonna go in or is going to come out in the stool or maybe a little bit lost in sweat or urine but at the end of the day, the in and the out have to balance each other out. - So I guess what I'm getting at is it's not as if you're growing a, let's say, quote unquote, heavier, larger microbiome that is residing in your colon because could it not be that some of the energy, I appreciate energies need to create it, nor destroyed, but it's just like you could have energy that you're consuming is going towards growing a muscle or increasing fat stores, could be increasing the microbiome biomass literally inside your body that you're maintaining, almost as if it's a larger organ. - Yeah, that's a really good point and then the question is, how much is that going to be translated into pounds or kilograms of body weight? I don't know that it'd be significant enough to see that on the scale, but we really don't know, we would have to actually sort of measure all of that. The other piece that we don't know, there's been some mouse work that has suggested that the gut microbiome is a, also expends energy. Of course, we know they expend energy. We just don't have a way to measure that in people because the microbes only are living in the colon without oxygen and all the tools we use to measure energy expenditure in humans are measuring oxygen and carbon dioxide. So you're not measuring the energy expenditure of the microbes. What I can say is in our studies, the main energy out functionality of the gut microbiome was on the fecal energy loss. That's where the biomass group went out. There was literally no difference in energy expenditure because we did measure that. Now does that mean that there couldn't be in a different paradigm, maybe a longer study or maybe a study where you're reducing calories and looking at other components of how metabolism changes during weight reduction? There could be some impact there too. We just haven't seen it yet with our experiments up to this point. Just to bring us back to the importance of this work for people as we get into the weeds, that the hope, what I'm understanding here is that if you're able to identify key characteristics of a microbiome function or composition that lead to increased absorption of energy, then there may be targeted interventions that can be trialed to see whether you can modulate that person's microbiome and sort of even the playing field. Exactly. So what we know for 100% sure is that diet is a key way to change that paradigm and give you as much of an advantage on the energy absorption side as you can. But then the question becomes, what is that community exactly? We have some idea as far as composition and we have also some data on metabolites that were either made on the host side of their microbial side. But at the end of the day, I think this field of microbiome science, which intersects so closely with my expertise, which is nutrition science, at the end of the day, we need better approaches to understand the community. Not just you have relatively more or less of species A, species B, but the community dynamics because it's so interesting. The microbial community is like a neighborhood. You know, if you live in a neighborhood and you go to your neighbor's house and you ask for a cup of sugar to bake a cake and they don't give it to you, you can't bake the cake unless you go to the store. So the microbes either compete for resources or they help each other by making something that the other person needs. And so you need to have the community that is supporting each other in the right way to be optimized for that person. And so it really, we have to move beyond just characterizing composition and implement some techniques that tell us about that synergy, that competition and more broadly the community composition. And we actually have a study where we're doing that right now with our collaborator at the University of California, San Diego. So I'm very excited about that work because if we can figure that out, I think we would be much closer to determining what can we feed the person taking into account the community they have and the community that we think is optimal for them so that we can make the right kind of transformation in not just a species or two but the whole community and then ultimately their functional capacity. My nutrition philosophy has always been pretty simple. Start with a healthy plant-rich dietary pattern built around health foods. That is the single most important nutrition move that you can make when it comes to optimizing your health. 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You mentioned there we need a better approach and you sent me a review, I think it was in cell metabolism and it was pretty much the entire article was pushing for better approaches and spoke about the last two decades there's been and I think listeners of this show will certainly appreciate this. There's been really an inundation of science linking and the word that's often used is linking or associated you know certain cardiometabolic conditions or obesity or autoimmune conditions or allergies you name it associated with dysbiosis and and the question that arises from that is is it is the microbiome in all of these examples is it a driver of this disease is it a modifier or I believe in that paper they say a bystander and a lot of the research that kind of underpins this has been has been done on animals can you can you explain to us what is it that makes it so challenging to translate the findings from all of these these animal studies to humans and really work out is the microbiome playing it is it driving this disease is it modifying it or is it a bystander yeah those are really the million dollar questions and and I sent you that review because when I was reading it I felt like the authors were literally reading my mind because everything they said really resonated with the direction we're taking an advent health because I am not a microbiome scientist I am a physiologist I'm a nutrition scientist and and my interest is in how to optimize whole person health and and how do we use lifestyle modifications to do that so the reason has been so challenging in clinical studies has been a couple things first is the phenotype or the characteristics being studied in the people so for example with body weight which we've talked about a lot using a relationship to body mass index which is sort of this high level indicator of weight status that has its pluses and minuses versus something where you're looking at energy balance which is the physiology that alters body weight so part of it has to do with the clinical study designs that really get to that deep phenotyping with multiple layers of rigor so we had energy balance in our study we had body composition body weight multiple things that kind of can support each other and saying yeah this is going in in the direction that that is creating a negative energy balance that we hadn't captured before so that's the first thing the second thing and you know we really have to have a lot of grace with the microbiome field because really I mean look microbiologists are going to tell you we've known about this for so many decades and it's true it's it's just that it didn't hit the metabolism and nutrition scene really till around that 2004 time frame but the techniques to actually measure the community dynamics haven't been available it was all basically saying who lives in the neighborhood you know what DNA do we have there and who's there but but it's not telling you that you have you know 10 lawyers and 50 doctors you just know that relatively there's more doctors than lawyers in this neighborhood as just an example so that that's another piece of it and I think the the third piece and this is probably going to be my lifelong soap box the thing I care about the most is that we need to be very systematic in how we design studies and bring together the basic scientists the clinical translational scientists the scientists who understand things at the population level and all drive the train in the same direction to get answers in multiple ways to accelerate our ability to translate because if we all keep spinning in our own orbits it's just going to take much longer than it really needs to to get to a point where we can say Simon if you follow these specific dietary interventions you're going to have the most optimal gut microbiome for you because yours is going to be different than mine which is the other kind of challenging piece of this whole thing there's not going to be a single microbial community that is best for everybody so there's there's a lot of challenges but I really liked how those authors were very clear to say we haven't failed we just have more work to do and we have to take everything we've learned so far and figure out how to push it to the next level. Is the the fecal microbiome transfer research that has been done you know in animals and there is some human data but certainly I remember maybe a decade ago people were very excited by some of the things they were seeing taking the microbiome from a skinny mouse and then transplanting it into an obese mouse and then that that that mouse would lose weight is that am I am I kind of summarizing that that research accurately and what's what's kind of taken place when when scientists have taken that research and looked at it in humans does it reliably work. So in mice or other model systems there's the approach of transferring a microbiome sample either from people or from other similar models with a specific disease or phenotype and seeing if you can recapitulate that disease in in those model systems that's a very convincing evidence that there's something in that community that is impacting the phenotype directly. Now one of the challenges is that things don't colonize perfectly, they don't remain there perfectly, but in mice I think those are pretty reliable studies to say that there's something going on in that environment that is contributing to a phenotype. In humans, needless to say, when you're using rodent models, they usually have the exact same genomes, and so you're compressing a lot of variability right there. But in the human studies, the best examples of successful fecal microbiome transplant experiments have been in something like C-Diff and H-Pylaury. H-Pylaury is associated with ulcers and C-Difficile is associated with some intestinal types of disorders, because in those scenarios what's happened is that the C-Diff and the H-Pylaury has essentially taken over the whole microbiome. If you had a pie chart, it would be like 90% C-Diff or H-Pylaury, and everything else is fit into that little 10%. So when you go back and repopulate with a community that's more complete, and you eliminate that pathogenic microbe, then there's great success with improving those disease states. But anything more complex than that, I think the jury is still out, because we don't know that magical community composition that we really, really need, and we also don't know how to tailor that yet to different people, because the microbial genome is going to interact with the human genome, and we know that we don't have the same genome. So just even at that high level, it makes sense that it wouldn't be so straightforward. So it's not as simple as going to someone who's metabolically healthy, getting a sample of their microbiome and transplanting that into someone with obesity or type 2 diabetes. Unfortunately not, the studies have been either negative results or very, very small effect sizes. So we just still really need to get in there and figure out mechanism. And that's really what that review we were talking about was really alluding to is not just that something works, but how exactly is it working? What are the biochemical pathways that we can then interrogate very deeply? You remove that pathway, you add that pathway, not in people, but at the bench, and really say, this is the pathway, this is the interaction, it's these species with these receptors and these metabolites, that's where we need to get to customize it even more. But even before we get there, which will take a little while, we definitely can start by priming the pump in a way and taking whatever microbes you do have and and making them as happy as we can. That's a great place to start while you're waiting for the scientists to continue to do the work. If you were pressed right now in 2026, would you say the microbiome is directly causing some of these metabolic conditions, is influencing them, modulating them, but perhaps not being the primary cause or is a bystander? If I was pressed, I'd say it's all of the above, so it's quite conceivable that there are some microbial functions and features that can contribute to the pathophysiology of something like obesity or mass old or diabetes. I don't think they'll be the microbiome's going to be the singular cause, because we already know of other causes that start with genetics. So I think that's entirely possible. But then as the person transitions from, let's say, normal glycemic control to type two diabetes, the host is sending signals that could be read by the gut microbiome and the microbiome could change in response to that physiological change. And then sort of the third piece, I'm not sure so much as a bystander, but I think one of the things that was interesting in that review is that maybe the microbes are actually responding to the therapies that are being used for, let's say, type two diabetes, and they specifically mentioned metformin as it's kind of a standard longstanding therapy. So they're changing because of the treatment approach. So I don't think it's going to be either or I don't think that's possible. What I find fascinating about what I call the metabolism show in the colon is that it is a dynamic environment. It is potentially causing, but it's also responding to everything that's happening to us. The air we breathe, the food we eat, all of it. So it's almost like a metabolic fingerprint that's changing as you change. And so it'll be a little harder to wrangle that in a therapeutic capacity unless we can find some very, very fundamental and large effect size types of functions that we say if we target this and we can reduce this inflammatory pathway or this, the hormones that help you feel full, the satiety pathways, then maybe we could make a big impact on the disease. So there's still a lot to tease out in there. Yeah, and I have to imagine that the selection criteria or inclusion criteria is really important there because going back to what you said earlier, it might be that a certain intervention is particularly beneficial, but only for a subset of people with a particular kind of microbiome signature. That's exactly right. And there's definitely a lot of standard things you can do to reduce confounding from disease states or age, various things. One way we got around that in our studies that may work for others who are trying to design studies to really look at causal inference or things that might be sort of more than just a relationship is to do this crossover design where people get both interventions. Sometimes that's possible, sometimes not because then the person becomes their own control and whether, you know, their age, biological sex, race, ethnicity, their DNA, it's all the same on both treatments and you can do specific analyses to look at that within person change. So that's one way to partially get around it. Yeah, and the neat thing with that is that when you are your own control, I mean, then you could go back and analyze the responders versus non-responders and potentially there are some defining characteristics that may be explained why some people responded. Exactly. With a large enough sample size and with an intentional design where you want to look at some of what people bring with them, you know, in their metabolism suitcase, then yes, those questions are very important to address. If that's the question you want to answer and then you have to do certain things in the design to make sure you really can capture those pre-intervention aspects and how they might impact the intervention response. Just while it's top of mind, you mentioned before that met form and may influence the microbiome and I think that statement kind of really underscores and it might have been the authors that were underscoring this in that paper that we really have to be careful with just cross-sectional single-time point data looking at the microbiome and a disease because in that example, you could go out and observe that people with type 2 diabetes have a significantly different microbiome composition or a function without knowing that that was perhaps not the disease that led to that change but it's the medication that that population is exposed to. Yeah, that's exactly right. Humans are so complex and we have so many things that make us unique and being able to learn these things and it's not just that pharmacological agent or medicines impact the microbiome but the microbiome can also affect how well those medicines work so it's a very bi-directional complex puzzle which is what makes it so exciting and I feel like we're at a time today where we have enough of the computational power of the methodologies of the clinical understanding of mechanisms of disease that that word and at an inflection point where if we can bring together the right kind of people around a table that really want to solve a problem we can we can move the needle. Every new year we talk about diets, workouts, habits but the more I learn about health the more I believe the best place to start is with a clear picture of what's happening inside your body. Consider it like a car service but for your body. 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Or I mean, I think you said the energy in was held constant, so you were feeding them the same amount of food. But did they report being more hungry? So what we did was you're right during the six days where we were measuring their metabolism all those six days, we kept their energy constant based on what they were burning. So what we did was after we finished those experiments, we did some testing where we allowed people to self-select how much they wanted to eat. And we measured subjective ratings of appetite and satiety, and we also measured a whole panel of satiety hormones. And we saw a lot of variability in the amount of food people chose to eat when they were given sort of a larger amount of food than they would eat normally at a meal. And also in their responses to satiety are my feeling full, you know, could I a whole bunch right now, etc. So we didn't see anything that signaled that those pathways were altered in this particular design. What we did see was an increase in many hormones that help you feel full, like GLP1, which is one that people talk about. That one was a very modest effect and only at certain types of day, but we saw others that were very interesting and quite robustly changed. So if we had done the study for six months instead of 22 days and consistently had these signals telling the person you're full, you're full, you're full. Over time might that have led to less hunger, less cravings, and self-selecting less food possibly. And I think that's a whole another study that we need to do in the future. And that just kind of shows how you can't answer all the questions in one clinical trial. You really have to be very focused. So really and truly there's a whole bunch of directions we want to take this to tease out all those components and see how to really give people the most optimal sort of relationship with food based on how we modulate the gut microbiome. Yeah, I guess I was looking at it almost from the other angle in that if you have a sustained, you know, 116 calories less being absorbed per day, does the body protect against that from a survival mechanism? That's also possible. So the fact that we saw increases in hormones that should help you feel full says that maybe it's not that way, but a lot of these things start one way and over time change. So I think over time the negative energy balance maybe could lead to more hunger. One thing to remember is that generally high fiber diets can help you feel full or longer. So maybe just the foods themselves could combat some of that. But yeah, those are all studies that need to be done. The longer term effects of sort of consistently creating a small negative energy balance and whether that's going to lead to behavior change in either direction, either you're feeling hungerier and you want to eat more or you actually have less feelings of hunger. Does the microbiome appear to influence metabolic health independent of its effect on calorie absorption and body fat? Yeah, there's certainly a lot of relationships like we talked about links or associations of microbes that are important for various different types of pathways that don't directly connect to body weight. So I do think that there's a whole lot that we could learn and implement related to the microbiome. Once we figure out those mechanisms that could potentially lead to let's say when it comes to accumulating fat in the liver, are there some signals that go from the gut to the liver that help the liver then oxidize those fats or export them back out rather than holding them in? Or are they inflammatory signals that could be shifted? Many diseases, especially as they're advancing, including liver disease, there's a huge inflammatory component that precedes progression to more severe disease. So I do think those are all possibilities that need to be studied in a more mechanistic way in humans, which may not always be extremely possible, but I do think with more coordinated efforts between the basic science and the translational science and really figuring out what are those mechanisms that we think could really translate in humans and can we develop a way to reliably measure those mechanisms in humans? Those are the types of studies that will get us there. That's really interesting about liver fat. I had Professor Roy Taylor on my show a while back and I'm not sure if you're familiar with his work, but he's done quite a bit of research looking at type 2 diabetes and he has something called the twin cycle hypothesis, essentially in short, just that once someone kind of goes over what he describes as a personal fat threshold where they're no longer storing fats subcutaneously under the skin, they begin to store fat in the liver and then in the pancreas and this really sets up kind of metabolic dysfunction. And one of the interesting things from his work and that conversation and we see this is that sometimes someone will develop type 2 diabetes at a much lower body weight than someone else and I asked him, you know, what does he hypothesize might be causing that? Why is someone much more predisposed to type 2 diabetes at a lower BMI than the next person? And we see this in Southern Asian populations, for example. And he said that he thinks it's genetically controlled, some people have this lower personal fat threshold, but now I'm thinking here, you know, is it the human genome or is it the human genome and the microob genome that perhaps is affecting influencing where fat is stored? Yeah, and I mean, there's definitely potential also for signaling via both the host and the microbes that could influence that capacity that you just mentioned of the adipose tissue or the fat tissue to take up excess lipids and that could also prevent the inflammation and the scarring that can happen in adipose tissue that then prevents the beneficial effects of having that storage capacity. So I think it definitely could have a human genome layer to it, but the signals from the microbiome could also contribute. And I absolutely agree that the health of the fat tissue organ itself is super critical to what ends up happening in other organs. And is this pretty clinical data suggesting that that the microbiome can affect the health of fat stools? So I'm not recalling any at the moment specifically, but I believe there must be because, in fact, in some of our own data now that I'm going through to my mind, we were looking for a connection between the gut and fat storage in the liver. And we were actually hypothesizing that this phenomenon of microbiome encroachment into the mucosa layer of the gut could be something that distinguishes somebody who has no appreciable fat deposition in the liver versus people who do have it versus people who have progressed to fibrosis. And we actually didn't find encroachment to be related to these three phenotypes within our experimental design. But what we did find, we actually had a colon tissue from these patients or these study participants excuse me. And we did gene expression. And some of the most altered genes in the gut had to do with adipose tissue function, which blew my mind. And it's suggesting a gut adipose tissue axis. One of the most specific pathways we believed was related to that gene expression signature was adipose tissue insulin resistance, which also makes sense because insulin resistance is really at the foundation of progressing from, you know, healthy liver to compromise liver or from pre-diabetes to diabetes. So so our own data has a little glimmer of a hint there that we really weren't expecting. It just when we were looking at the data sort of in a let's see if we group these genes together and how they relate to both the phenotype but also the encroachment. Do we see any relationships and we saw that that was the case. So but I am sure that there are other papers and and many authors that have really looked at the connection to adipose tissue and we certainly are poised to do that we we have a whole team that all they do is focus on adipose tissue biopsies and humans are really looked deep. So that's definitely another area that could be explored. And sometimes these peripheral tissues like the fat tissue, they're they kind of become a mirror into what's happening in other tissues. So you might not have to go get that liver biopsy. You might be able to learn something from the fat tissue that could tell you more about what's really going on in the liver or the pancreas or other organs. Okay, so watch watch that space. As a registered dietitian today, what would your top nutrition recommendations be for someone who's listening that has non-alcoholic fatty liver disease or let's let's the new name metabolic dysfunction associated liver disease? So with that or even diabetes or obesity, I would actually say the same thing. Most of my career or the early part of my career, I only thought about the food and the person. I didn't have any context that the food that we were eating was interacting with the microbial genome and its subsequent functions. So to me, one easy strategy to make positive lifestyle changes that can fit into many different types of dietary patterns is to every day ask yourself one simple question. Have I fed my gut microbiome today? And if the answers know there's four things you can implement with different types of foods that you prefer to eat or that fit into your culture, your beliefs, that you could implement into your dinner tonight. You can take this straight home to your family tonight. The first thing is to eat more fiber soluble and insoluble fiber. So that's your fruits, your veggies, and your whole grains. So that we've heard about for a long time. How much fiber do you need? It's recommended that you consume about 14 grams of fiber for every thousand calories you eat. And we're sort of the 20 to 30 grams a day. And I would say that's a bare minimum. If you can go beyond that, that's even better in our studies. We were feeding people twice that. So 25 grams of fiber per thousand calories. And people did great on these diets. We didn't have adverse events or people not able to adjust to those diets, which is very exciting. The second thing I call this the more interesting cousin of fiber, and that's resistant starch. So it is a type of fiber. It just has a totally different configuration that makes it resistant to digestion in the small intestine. And that's found in beans and legumes. So I tell people throw beans on everything. You're having a salad, throw some beans on there. You're having a burger, beans on top, whatever it is. And people of course always say, well, those maybe make my tummy a little uncomfortable. I promise you, if you rinse them, if you introduce them gradually, you can eat boat loads of beans. That tons of protein also and minerals. But besides beans, if those aren't your jam, it's certain types of whole grains that are a little, some of them are more obscure like quinoa and pharaoh. So sometimes those are called ancient grains. Those have a lot of resistant starch, also barley, rye, and oats. Another way to get more resistant starch in your diet is a neat science trick. So you take certain foods like rice and oats and potatoes and pasta. And after you cook them, you allow them to cool overnight. They develop resistant starch in that cooling process. So something like oats already have resistant starch. And then if you do the overnight oats and you let them cool overnight, you get even more resistance starch. You get a double bonus. Another way to get more resistance starch in your diet is to eat the less ripe versions of certain foods like bananas. Greener bananas have more resistant starch, for example. And yeah, those are the main ways to get more resistance starch. So fiber resistant starch and then these last two steps are really related to one another, but they have different sort of concepts around them. The first is to eat the whole food version of a food, so the apple instead of the juice. And for an example, and part of it is because if you eat something that starts out as a whole food, there's more chance that some of the little particles that you don't completely chew up and don't get digested, make that nice long journey to the colon where the gut microbes have access to them. The second reason whole foods that are minimally or unprocessed or important is because highly processed foods or ultra processed foods are essentially unrecognizable forms of their original selves. So they've been mechanically tortured. So you take the whole wheat and it's been crushed and peeled and whatever. But then there also oftentimes there's additives, different chemicals like emulsifiers or artificial flavors. None of those make your gut microbiome happy. So by doing the larger pieces that also happen to be less processed, you've done four essentially separate things that are fairly easy to do because you just need to find the alternative. You like peanut butter? Go for whole nuts sometimes. So it's not like you can't eat what you love. You just make an upgrade to those versions of those foods that feed your gut. And you'll see long-term benefits to health, things like blood sugar, body weight, and potentially even liver fat. And I haven't done the study, but certainly the Mediterranean diet is one great example of a high fiber whole foods diet that's across the board, across many metabolic diseases, seems to be beneficial and that kind of aligns with feeding your gut microbiome. Wow, beautifully explained. So just to break out, eight more fiber, resistance starch, and then whole food version. So rather than having the juice have the apple. And what was the fourth one? So it's the same thing, but the whole foods give you two advantages. One, it's the larger pieces and two is the lack of the processing elements that are separately not so great for your gut. Perfect. And I loved the description of mechanically tortured. I haven't heard that before, but it's very accurate. Very accurate. If someone follows those bits of advice and changes their diet to start better supporting and then microbiome, how cool. quickly do these microbial and metabolic changes that you're speaking about at take place? - Well, we saw them in 22 days. So could we have seen them sooner? That's possible. Some of the earlier studies where they were doing control diets to see how the composition of the gut microbiome changes suggests that within three days, you have a compositional change. Whether the functional change happens immediately at that point, I don't know. But I would say just based on our own work within a couple of weeks, you'll see some of those changes that we measure like more hormones that help you feel full. And actually when you eat that kind of microbiome enhancing diet, you're gonna go to the bathroom more. That's called bowel movement frequency, which sounds super boring and kind of gross. But actually, there's a lot of diseases that one of the first signs and symptoms is constipation because when you're not moving the stuff out, now you give the gut microbiome almost too much time to ferment and then you start seeing some potentially toxic metabolites coming from the gut microbiome. So you should start seeing changes in your bowel habits that will be very good for you and all those metabolic changes. I would say within a couple of weeks, you'll see similar to what we saw in our studies. Now whether that's going to impact the waistline at that moment or your blood sugar immediately, I can't say, but I would say most studies see benefits with these types of whole foods, high fiber diets within a few months. - While we're on your food recommendations, I'd love to get your perspective on the most recent US dietary guidelines that were released this week. Did you have any initial thoughts there? - Yeah, my first thought with any kind of public health guidance is that those are goal posts that don't know a thing about you. These are just general concepts. So the most important thing with any kind of dietary guideline is make sure you're working with your healthcare team because there are nuances to what you need to be doing that cannot be captured in a public health guidance. I do like the focus on more whole foods, which is what we've just been talking about. So they don't need to tell me that. I've been talking about that forever. I think also the focus on they have a little piece that highlights the importance of the gut microbiome. So that I got super excited about that. So I think there's some nuggets in there that are quite helpful and similar to prior guidance. And then everything else I think really needs to be customized to whatever it is you need. There is a lot of excitement around protein right now because particularly with the advent of these very effective weight loss medications, the more weight you lose, you're going to lose both fat tissue and lean tissue like muscle. So making sure that diets have sufficient protein, we call these nutrient dense diets. So if you're going to take your calories because you're taking this medication that helps you feel full, you're going to change them, let's say, from 2,000 to 1,000 calories. Those 1,000 calories need to count. So not 1,000 calories of pre-packaged, crunchy, salty thing. They need to be calories that really have the protein, the vitamins and minerals, like the things we've talked about, the beans and the lean proteins and things like that. So those are some of the things that I took away from them and as a registered dietitian and working in this health care system, the most important thing for people to do is really work with your health care team and figure out what's really the most optimal for you. And if something in those guidelines makes sense to you, you want to eat more whole foods, try it out, see how you feel, that's great. And that's something else that's super important. I've had people say, well, I'm not sure if probiotics are really good for you, but when I eat yogurt, I feel great. Fantastic. It's got protein, it's got calcium, it's got live and active cultures. You feel great? That's wonderful. So you have to listen to your body, too, because certain things that people eat and they feel great when they eat them, other people eat them, and they don't feel great. So I think it's also listening to your body that's really, really important. Speaking of probiotics, I'm sure there are a lot of people listening that are wondering about your views on the evidence to support certain probiotics or prebiotic supplements, specifically for weight loss and improving metabolic health. Is that something that you've looked at in detail? So I've thought about it a lot. I haven't done any studies myself, but from the studies I have done and the conversation we've had so far, the community is important. And it's hard for me to wrap my mind around that three or four specific species, or even 10 or 12, are going to work well for everyone, because there's a lot of inter-individual variability. There is also, of course, whether these species make it all the way to the colon. And if they do, how long do they stay there? And that goes right back to that neighborhood concept. If you don't have any friends in that neighborhood, you can take the probiotic. It gets there, and it just doesn't survive, because it's a hostile kind of neighborhood. And then it's what you're eating, because you can take these probiotics, and then you starve them. And then they don't survive. So I think I don't have any issue with yogurt, fermented foods. If your doctor says you just had a colonoscopy, you've wiped out your microbes, here's take a probiotic. That's all good. But would I spend hundreds of dollars a month on a probiotic at this point in time? I don't think so. I really think at some point in time, we need to get to the point where we can customize those a little bit more, and there's just more science that needs to be done before we confidently get there. So if you want to do something, do the prebiotics, which is the food. Do the healthy food that's going to feed what you have. And then if you supplement some of that in a modest way, I think it's fine. And again, go by how you feel. You take it, you feel good. But you don't see any adverse events and your doctor's OK with it. I really don't have an issue with that. 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And right now momentous is offering our listeners up to 35% off your first order with PromoCode The Proof. Go to livemomentus.com and use PromoCode The Proof for up to 35% off your first order. That's livemomentus.com PromoCode The Proof. I think a lot of folks have heard that the first thousand days of our life is really critical for the development of our microbiome and things like the way you're delivered. So C-section versus vaginal birth comes up whether you're breastfed or formula fed, whether you're exposed to antibiotics early in life, like all of these come up. And I think often people feel a little disheartened because maybe they would deliver through C-section, were fed through with infant formulae, et cetera. And they're left in this place now, perhaps struggling with losing weight or perhaps they have a chronic condition. And they're wondering if this conversation applies to them. If these recommendations that you've walked through apply to them. So my question to you is, how fixed is our microbiome from the first three years of life versus being kind of pliable and modifiable based on changing our dietary habits? I love this question because it was actually my biggest fear with the study that we've talked about throughout this conversation that we did because there are some really intriguing mouse studies that showed if over generations, you fed a Western type of diet that starved the microbes. And then, you know, I don't know how many generations in. Let's say four generations in, you switched to a microbiome friendly diet. Those mice couldn't populate the microbes they needed to populate. So one of my personal biggest fears is that through many decades, of very much across the board, most of us don't get enough of those microbiome friendly foods. So generations of that, plus lots of antibiotics, I thought, oh my goodness, we're not going to see a response in our endpoint of changing this energy balance. But not only did we get a response, it was almost perfectly consistent, only one participant didn't actually respond in the direction you would expect. So I have some hope that there's some resiliency to some of the species and that the diet approach will have some benefits. However, there are studies looking at populations that have been in situations where the diets haven't been so infiltrated by the highly processed types of foods. And they have some species in those communities that are pretty much absent in more modern societies. So there might be some things that are depleted to such an extent that they won't have their optimal response. And the question is, what are those? And then do we need to find a way to replete those? I think something else, people don't think about is another way you get your microbes is that they travel in from your food. So the soil and how we grow things and how we take care of our earth and our planet is so critical for actually having nutritious foods. So there are a lot of things that can make you discourage. But at the end of the day, time and time again, high fiber whole foods diets, whether they're interacting with your genome or your microbiomes genome, there's plethora of evidence that there will be some health benefits. So don't give up and don't be discouraged about trying to make some of these changes. You mentioned JLP one agonist, Julia. And I just wanted to quickly get your your view on this. Clearly there's strong and growing evidence that these pharmaceutical agents can be really effective for treating obesity and type 2 diabetes, accumulating evidence for fatty liver disease. But I have seen mixed reports on how these drugs may affect the gut microbiome. Is that something that you've looked at and based on what we understand so far? Would you say that they appear to have a positive, a neutral or a negative effect on the microbiome? And if someone's taking a JLP one agonist, is that even greater reason to make these dietary changes that you're recommending? So I don't know that the studies have really been done to look at this deeply in well controlled studies in humans. But what we do know is that when you take JLP one receptor agonist, a loner in combination with some of the other things like glucagon receptor agonist or GIP receptor agonist, there's a change in transit time. So how fast stuff moves through the intestine? There's a change in bowel habits. So I'm nearly 100% sure there's going to be some change in the microbial community because it's biochemistry down there and reaction time and all, you know, how fast the actual foods get down there is going to have an impact. So I think we need to fund and do those studies. I do know we study these medications at Advent Health, particularly looking at metabolic mechanisms. And most of the studies we do involve a registered dietitian so that the participants can eat those high nutrient density diets. And over time is the adjust to both the medication and healthier eating, which they're very much appreciative to learn how to do some of those side effects and some of those challenges go away. So yes, I think it is almost 100% for sure. There'll be some impact. The question is, you know, what is the impact and how do we modulate it beyond diet, which I think it is definitely a crucial part of it, especially as people are getting adjusted to the medication. Sometimes, you know, if you're having different GIs side effects, that might not be the time to put a bunch of beans on everything. So it has to be something you work on with your healthcare team to figure out how to adjust the diet to kind of travel with you as you are using these very beneficial medications. And if I just say one more thing, no medication for diabetes or obesity is ever intended to be a replacement for lifestyle. It's always a partnership. So the better your lifestyle, the better the medications are going to work. So, you know, as much as I think these medications are very beneficial game changers for persons with obesity, I just encourage folks to work with your healthcare team to make sure that the lifestyle piece is also being addressed. Before we switch gears to the microbiome and brain health, was there anything that we didn't cover related to your randomized controlled trial or some of your other research looking at energy balance that you wanted to kind of cover before we move on? Yeah, one thing I can think of right off the bat probably because I'm headed to Canada next week to talk about this. So it's top of mind is that one other thing that we measured that wasn't published in that first paper that Daria Goudisman from my group just led the publication that came out this year was we looked at the metabolites or the basically the end products of the metabolism of both human cells and microbial cells. And so we looked at metabolomic profiles, which is just looking at the global profile of metabolites in stool samples 24-hour year-ins, which means they were captured, you know, perfectly in a 24-hour period and blood samples. And I wanted to make this the very next paper we published because the metabolites give you some insight into function. And you might have one microbiome and I might have a different microbiome, but we might get a similar functional readout, which is kind of shows you the why it's important to look at function. But what we found in that study was that because we already knew these diets were very well controlled, people were eating them at home for 11 days and while they lived with us in our metabolic center for 11 days. So the food was being consumed, which is a huge thing. It seems so silly, but a lot of studies are based on self-reported dietary intake, which has limitations. So in this paradigm, we changed energy balance, we changed some host characteristics, we changed the microbiome, we wanted to see what happened in the metabolites and we wanted to do it in blood as well as the fecal samples because a lot of diet studies don't have the fecal samples available and but they might have the blood samples. So we felt like we could potentially find a signature of metabolites that could essentially characterize a fed and happy microbiome versus a starved and hang Greek microbiome. And that's exactly what we found the metabolic metabolite profiles were quite distinct and they hinted at a couple of things. Some of the metabolites that were changed by the diet and the remodeling of the microbiome have been previously connected to obesity phenotypes. So we believe that's important because we're kind of validating prior metabolic associations. Interestingly, we found that some of the functions that changed were made a lot of sense and implied an important role for the microbiome, for example, on the healthier microbiome enhancer diet. There were less protein fermentation metabolites that are toxic and there were more of these plant polyphenol type of metabolites that are also quite protective. And then the final kind of interesting point, oh, and the other thing before I get to the blood my metabolome is that we on the Western diet, we saw higher levels of certain metabolites that have been previously seen by Kevin Hall and his group to be associated with high ultra-process diets. So we've sort of validated what you could potentially be seeing in the blood in your studies if people are following a high ultra-processed food diet. So I think I thought those were all really good. But the other cool thing was that there were 24 metabolites that were changed significantly in both the stool samples and in the blood. So the directionality was consistent in 22 or 24 of them and you know you don't expect perfect directionality in these two sample types. But this means that if you have a study where you've fed kind of a high fiber or low fiber type of paradigm, you could use these metabolites as signatures. You could look for for them in your own blood samples for those studies to see if you might have impacted the gut microbiome in a positive or negative way. So I think that's just scratching the surface of what we can learn about metabolites, but it's a nice beginning of the story. - And those metabolites just to be clear could be used to kind of determine adherence to a diet intervention in a free living experiment? - Or an observational study, or even another type of feeding study, they could be, they could, the scientists could attempt to look at those and see if they replicate what we saw under these very controlled conditions to start looking for kind of across larger populations, what could be some biomarkers that could indicate fed and happy microbes versus hangry starved microbes? - Interesting. Okay, so let's switch gears now. And talk about the microbiome and brain health, particularly long-term brain health. When you and I spoke a couple of days ago, you mentioned to me that you're involved in some interesting research that's looking at how the microbiome may play a role in the development of Alzheimer's and Parkinson's disease. What's the background story here? - At Advent Health, we have a wonderful neuroscience institute that has an amazing clinical component and scientists led by Kirk Erickson and Lauren Oberlin. And we're sort of like besties, the neuroscience and the metabolism institute were very closely tied because as we've alluded to earlier, metabolism, energy balance, energy metabolism is all very crucial to a lot of disease states. So one of the things that we are thinking about and hope to be able to study is the fact that there's a hypothesis that Parkinson's disease could start in the brain first and the plaques that build up in the neurons in the brain. Those are made by something called alpha-synucleon. And interestingly, although most people that starts in the brain, they have found some cases where those alpha-synucleon plaques are in the neurons in the gut first, leading to a hypothesis that Parkinson's could start in the gut for some people. It's not fully proven and there's more to learn. But as I mentioned earlier, constipation is actually one of the earliest signs of Parkinson's disease. So I would not be surprised if this was true. And the question is, what can we do beyond the cataloging that's done consistently? And I'll tell you what that is in a minute. The area that we are actively writing a grant on is we have a study already ongoing that's called Lambda. And that study we're following 500 people over two years and measuring a whole battery of cognitive tests of things in the blood that newer biomarkers that are very robustly associated, not just with clinical presentation of Alzheimer's, but the progression of Alzheimer's. And then our amazing neuroscientists also have very capabilities for very deep phenotyping of the brain itself with imaging. So having these very deep phenotypes just opens the door to also collecting data on these study participants related to the gut microbiome. And what we want to do is move a little further ahead than just taxonomy or just who's in the neighborhood. But one of the things that's very important is in these metabolites that I just talked to you about that we measured most platforms that measure metabolites, mostly measure human metabolites. They only measure a teeny proportion of microbial metabolites. So we have a collaborator who's an expert at identifying bona fide, novel microbial edelripe metabolites. So we want to cross sexually start by seeing can we see differences in these novel bona fide microbial metabolites. The other thing that we would like to do, we will look at who lives in the neighborhood. That's just a foundational piece of evidence. But the other thing that we can learn from the stool samples, remember how we've been talking about the food travels all the way down the garden and ends up in the colon. Well, the food leaves some DNA in the colon and you can actually sequence the food DNA in the colon and through computational biology techniques, you can figure out with someone eight. Not exactly like you had 10 french fries and eight grapes, but proportionally figure out dietary composition in an objective way. That's the key is objective. Not self-report, we're actually measuring this. And so I had collaborated with a scientist from the Institute for Systems Biology where they used that technique on the samples from our study that we've been talking about over and over again. And they did not have our menus like every single food or anything, that was by design, that's called blinding. So we just gave them samples, they measured the stuff and they said, boy on this microbiome enhancer diet, we saw these eight foods that were completely absent on the Western diet, like strawberries and quinoa and barley oats. So let me look at the menus. And so I went down all our menus and they were 100% right, those eight foods were completely absent on the Western diet and only present on the microbiome enhancer diet. So given how in this observational cohort we're not controlling the diet, having an objective measure of diet and how that interacts with all these biomarkers and these microbes could be very beneficial. So that's our initial flora ray into this, but I do think Gut Brain is something that is still plagued by that general diversity, composition, focus. And this is one step towards getting some hypotheses that then we could test, in a randomized control study where maybe we alter the diet and look to see if we can shift some of these paradigms. - Right, so bringing that back to the practical component for people listening. Again, it's about determining, is there differences in the taxonomy or the composition of the microbiome is there differences in the microbial metabolites. So the compounds that the microbes are producing between someone with Parkinson's, pathophysiology and a control. And then if so, can you intervene on those things and influence the pathophysiology is that what we're talking about here? - Yes, in general, this is basically the inclusion criteria is pretty broad and that's by design because with that, we'll be able to find some people that have normal cognition, mild cognitive impairment or actually have, we're mostly focusing on this one on Alzheimer's, but that doesn't mean we couldn't measure Parkinson's metabolites or biomarkers as well. So the idea being, it's longitudinal. So not just cross sectional one time point, we'll be able to look at changes over time and say, oh, this person started out, mild cognitive impairment at two years that had biomarkers of Alzheimer's disease, what happened to these features? So it's getting, it's not quite as mechanistic as the controlled intervention, but it will give us some hints of more robust metabolites that are actually made by the microbes and seeing if any of those features in association with how we know they're eating objectively, how those change over time, then we would have some hypotheses to put forth and say, we think these are potentially important mechanisms, operative in humans and we need to do a clinical trial to see if we can move the needle on these mechanisms. So it's early studies, but you have to sometimes do those observational studies before you can really have the right hypothesis to test. - So it would be, those early studies would kind of provide the basis rationale for the clinical trials and then the clinical trial would help you potentially shift from an association to a kind of causal model. - Yes, exactly. - Okay, so that's another watch this space. This seems like this space, there's a lot happening and over the next five to 10 years, you know, really a space and area of science, nutrition science for people to keep an eye on. - Absolutely. - Where do you think this area of science, I mean, you've described some of it there, but generally speaking over the next five or 10 years, where do you think this area of science, everything we've been discussing today is going? - I see a lot of shifts in the use of computational tools to model metabolism and integrating those tools with well controlled clinical trials can really enhance our ability to predict certain pathophysiological pathways or predict how an intervention might change them. So I think, the bioinformatics and computational biology pieces are really moving forward, even in this area of objective biomarkers of dietary intake. There are multiple groups working on this because it's so important. If we really exactly knew what people were eating, we could much better understand both health and points, but also the microbiome. So I think that's one. And in my opinion, I think that more collaboration and synergy is really, really essential. And that was really highlighted in that review we discussed earlier. So I cannot learn a thing about the microbiome without collaborators that are experts in the microbiology and the computational biology. And on the same token, computational biologists and microbiologists might have a great idea of a human phenotype to test, but they need someone like us at Advent Health to help them design the trial the right way because the design is everything. So I think more synergy and partnerships aimed at solving common problems is where the field can and should go in the next five or 10 years. And finally, there's, I mentioned earlier, the whole idea of community dynamics and sort of moving away from just seeing who's there. And those techniques are under development were very fortunate to be able to be applying those to some of our samples, but to really get at beyond composition and towards community dynamics and function partially through different types of sequencing approaches, but also partially by figuring out how to integrate multiple data sets. So you have the microbiome taxonomy, you have the metabolites, you might have the human genome, other clinical characteristics. It seems like you just could go like this and put them together and figure out how they talk to each other, but it's actually much more complex than that. So the computational power to truly allow those data sets to inform each other and allow us to learn much more than we could from looking at each one individually is another critical path forward. - Is that the future that you see that someone will kind of walk into, say they're a physician, you'll be able to order a test that looks at taxonomy, so a composition of the microbiome, you'll be able to look at what the microbiome is doing by looking at metabolites, what's being produced and perhaps what's not being produced. And you'll be able to look at their kind of, I guess, more traditional biomarkers lab work, like blood lipids, blood glucose, and then from there create a personalized nutrition approach. - That would be ideal is figuring out how to create robust diagnostics that are feasible to implement in the clinic. In my opinion, although there's more ways to do this at home, stool collection is not something people do on command and it's harder to kind of manage in a clinical office. So that's why I'm so interested in other things like blood and urine where we might be able to not necessarily need the fecal sample, maybe we can learn enough from an easier to access sample that can easily be implemented, not just in a clinic, but even in remote areas through little cards where you put a drop of blood and you are able to preserve it there. So yes, I think we have to get to knowing what the, what's wrong with the microbiome and its function? We had to be able to quantify and define that and then that would be the diagnostic piece and then we would need to be able to intervene to see if we've actually reversed that. That would be a dream come true basically. - And for you personally, if we would sit down, let's say in three or five years from now, what are the top two or three questions that you would personally like to answer with your contribution to this area of science? - So our team at Evan Health is laser focused on how do we capitalize on the microbiomes impact on metabolism? So if we can at least make a ton of progress on the obesity front as a starting point to see could we in a targeted way feed people certain things that would optimize the gut microbiome and thus optimize energy balance? That would be an amazing thing to be a part of and that would have downstream benefits for brain health, for diabetes, for every other organ. And then I think the second thing would be then to move into another disease area like metabolic dysfunction associated liver disease and see if we could find some unique things in that space. And at the foundation of all of this is really figuring out how do we identify those causal mechanisms that can be intervened upon. So not sure if that's all accomplishable in five years, but I hope that by the next time we chat in three to five years that will have made enough progress to have some really sound testable hypotheses that we can continue to explore. - Well, I look forward to having you back on and getting a bit of an update at some time in the future when it makes sense. Thank you so much for being with me today. You clearly very high level thinker and you have a really deep understanding of this space. So appreciate all the work you're doing, your contributions to science and joining me today to help translate this to our audience here. We really appreciate everything you're doing and taking the time to be with us today. - Thank you Simon, I enjoyed the conversation so much. Thank you for having me. - There you have it friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.