Gut Microbiome & Diet with Dr. Gary Wu | Research Insights

[00:00:00][Music] come to the latest edition of the mind gut conversation today I have the pleasure to talk to Gary Wu who is the Ferdinand Weisberg professor in gastroenterology at the Perelman School of Medicine at the University of Pennsylvania dr. who is the director of the Penn center for nutritional science and medicine and director and chair of the scientific advisory board for the American Gastroenterological Association for gut microbiome research and education dr. whose research focuses on the interactions between the gut microbiota and the host with a particular focus on dietary influences and metabolism he studies how diet impacts upon both the structure and function of the gut microbiota that in turn influences the host in fundamental ways welcome to the show dr. actually my very much Ameren pleasure to be here so let's get right into the questions feel free to expand on any of those if you if you feel that's appropriate so let me start out with kind of a simple question but that's pretty one of the most often asked question that I hear when I talk about this topic in an adult person what role does that play in the composition and function of they got microbiome I think a diet does two things diet can change the composition of the microbiome but it also is a substrate for the microbiota to produce a lot of different small molecules that that we cannot normally produce because we don't have the genes to actually produce the enzymes that produce those small molecules and we'll end up actually absorbing those small molecules it's called the metabolome so metabolites and so it does two different things and I personally believe that in humans the effect of diet is relatively modest on the composition this structure of the microbiota the types of microbes that are there in the gut environment but it can have a pretty big effect on the types of metabolites that are produced but it definitely has an impact on both so in in terms of the effects on the host party the metabolites are the more important anyway so this is not in any way saying that diet doesn't really can't really change much once we have your own microbiome yeah I think it's sort of you know I think about it as sort of spatially localized effects all right so I think about metabolites as being not not only having an effect locally let's say if you're thinking about the gut microbiota in the intestinal tract but some of these are obviously absorbed and if they pass through the liver and make it into the systemic circulation they can circulate widely throughout the body so these metabolites can have wide-ranging effects not just in the intestinal tract but in in in in organs very distinct from the intestine whereas the microbes themselves largely stay in the lumen of the gut there is a notion that you do penetrate a little bit into special types of cells like immune cells but if you're thinking more about diseases where the gut is involved the mucosal surface inflammation in the gut like inflammatory bowel disease or something like that and maybe the microbes themselves are the fundamentally important component of the microbiota where maybe metabolites are not as important alternatively if you're thinking about the brain are you thinking about the heart knowing that unless you're really sick those microbes are not going to be circulating throughout the body that it's more than metabolites that are going to have an impact now the caveat to that is that is that these metabolites could affect the gut and this is Aaron's area of expertise alteration of gut is theology can have an impact on the brain so there are other more indirect ways by which these metabolites or the microbiota could influence distant organs particularly the brain okay another question related to your own studies you have studied the effects of a vegetarian diet and then omnivore diet on the gut microbiome it's very elegant studies what were the main findings in these studies yeah and so the the plant-based I was more vegan so it's vegans versus omnivores and let me just tell you the reason that we did these studies was that we know that individuals living in agrarian cultures like Africa have a very different composition of their microbiota than individuals living in industrialized nations and so we inferred from that well it must be diet because diet is actually very different in those those two different environments so we undertook this study that basically asked well how much of the effect of change in a MicroBot is due to diet in an industrialized setting so vegans and omnivores in the Philadelphia area and what we found was actually quite surprising we found that the composition of the microbiota was not that different between a vegan and an omnivore even though the diets as you would anticipate are extremely different statistically they were different but it was the effect was was actually very very modest we then actually went back and looked at the literature about other types of studies and unless you're on an extreme diet like a ketogenic diet the effects of diet on human gut microbiota the composition of the microbiota is relatively modest so that was sort of a surprise to us I have some thought we could talk about why then is it that people in Africa have a different microbiota than people let's say in an industrialized nation we can follow up on that if you would like but the other thing that we found were that the metabolites in blood and in urine the small molecules extremely different between a vegan and an omnivore so we can we can predict with about 94% accuracy whether or not you're a vegan or an omnivore simply looking at about 30 metabolites and blood it's extremely different and out of those 30 metabolites about five of them from the gut microbiota but those metabolites are not the ones that are actually most predictive so that actually told us another thing that's quite important the biggest effect the biggest difference between a vegan and an omnivore based on the circulating small molecules of blood our direct effect of diet on us with a smaller impact of metabolites that are produced by the microbiota so that's a pretty remarkable statement so we all know there's many companies now that that analyze your fecal microbiome and then make predictions and and several of these just look at the composition and then several of these companies I mean I'd see patients almost every week in my clinic they come with these reports they they make predictions about both the the health of the person and recommendations specifically on what kind of diets what kind of personalized diet would be recommendable to this patients so what what you just said is a big effect is really sort of bypassing the the microbes and and having the direct effect on the host and it's pretty interesting well let me give you an example so it is very often that when I give talks because we are very interested in diet to the micro pata and I think that's a very very important area of research there are a lot of fascinating things that we're learning about it but I'm very often asked so what type of diet should sort of person eat to make their microbiota make you healthier and what I'll tell people is that I can actually tell you a really good diet to eat and the effects might involve the microbiota somewhat but most of the effects are independent of the microbiota and that it is a more plant-based diet stay away from a lot of fat and meat and decrease the consumption of calories and you that's that's a healthier diet Mediterranean diet a more of a plant-based diet is definitely known to be healthy so let me that omnivore and vegan study we looked at many different small molecules in the blood as well as proteins and lipids the biggest difference between a vegan and an omnivore and things that we traditionally test are is the cholesterol level total cholesterol level and so it's well known that individuals on a plant-based diet like vegan or vegetarian have a lower risk of metabolic syndrome and cardiovascular disease so my point is essentially if you're thinking about heart disease for example I there is a very interesting and I think fascinating story we contributed a little bit in a small way to the work of Stan Hazen where certain types of foods that you eat certain types of facts or carnitine can be converted by the microbiota into small molecules like tea ma that are converted into another small molecule that accelerates cardiovascular disease in animal models and these small molecules of biomarkers for cardiovascular risk in humans that's a very interesting observation I think potentially profoundly important if you show that there's a cause-and-effect relationship in humans that you show that it's physiologically relevant that humans beyond what you study in months and I think Stan and other people working very hard on that notion if that's really true that's a game-changer however we already know based on decades of research that if you improve your lipid levels increase HDL decrease LDL decrease the amount of fat that you that you consume try to prevent metabolic syndrome and diabetes you're going to reduce the risk of coronary of acid disease and heart attacks and that's why statins are some of the best selling drugs around the world because they're so profoundly effective my notion is that most of those effects have nothing to do with the microbiota that's simply effect of diet and we know that based on decades worth of research and it's borne out by the fact that there are drugs that are highly effective in reducing the risk for the development of cardiovascular disease that our standard of care in medical practice so my notion is that the microbiota field is very important they're fundamentally important things we're finding out and even at heart disease maybe they're good there's going to be a game-changer but it's too early to know for sure yet but we do know based on a lot of research epidemiologic research and large patient populations diet has a profound effect on human health and my current notion is that a lot of that effect is a direct effect of diet on us with some component that's due to micro bottom but we don't know how big that effect actually is right now now so this is a really fascinating statement I'm sure a lot of the keto and paleo people will not necessarily like this this information but it's it's certainly refreshing to hear this from me an international authority on this topic and you know this information stands clearly against many of the the marketing schemes that are going on right now and the promotion's in in best-selling books and all kinds of media channels so I think that's really a really interesting statement that you made well let me ask you and I'll turn it around and I'll ask you right because it's a sort of a dialogue here a ketogenic diet is fascinating alternative fuel utilization right ketone bodies are fundamentally important in brain function it's used as a treatment for refractory epilepsy there's a lot of interest in in ketone bodies and alternative futile ization and congestive heart failure right so in individuals that are that that are really interested in the ketogenic diet there is actually a fair amount of evidence that it reduces weight that it can actually be good in metabolic syndrome why is it that individuals who are really interested in the ketogenic diet would be unhappy with the statement that both of those effects are are not dependent on the microbiota because you still know that it is that that it has profound effects and I would say that when I look at the literature right when you think about alternative fuel utilization and mitochondrial function these things don't even touch upon the micro body yet they're very very effective so why is it the notion that the microbiota has to be involved in order for it to have a health benefit why can't it just have a health benefit because it's changing our own physiology yeah I can't really answer that to that question I just know that you know because the the microbiota are such a popular topic that it's it's kind of you know mixed in with with promotion of the of the ketogenic diet I mean would I my attitude on this is I'm clearly a outspoken fan of the largely plant-based major Raney traditional major Iranian type diet and I sort of look at these alternate alternate fuel diets really as as a as a therapeutic I mean almost like you know if you have a particular problem you may want to take this as you would an antibiotic or some other treatment for a while to normalize the abnormality and then switch back to the to the large you plant-based diet I mean would you would you agree with that statement or you know I I don't know yet so I have to tell you I know increasing numbers of people that are on a ketogenic diet so who are qr-code keto adapted yeah and there's a growing level of evidence that it does provide benefits so I am I think like a well-balanced plant more plant-based lower caloric consumption diet as you're sort of describing I think that that that is probably what I would imagine most people would be able to tolerate a ketogenic diet is more difficult but I do I'm a little bit uncertain yet because I want to see more information in larger populations but I think that I wouldn't fund 'mentally agree with you I think from a population basis you basically say eat less red meat less fat more plants and vegetables decrease decrease caloric intake exercise more that's I think a very sound recommendation to give in the current state of affairs however if you have metabolic syndrome and you don't want to be treated with drugs or you know you have other diseases I do agree with you with the current state of affairs maybe a ketogenic diet makes makes some sense but as a health white policy yes I do agree that probably I wouldn't recommend that wholesale to everybody but you know I think that more studies need to be done because I know and you know and I've seen the literature on the benefits of a ketogenic diet and I think we just need to wait and see more how the science actually evolves in the field okay a question that someone related to what we talked about Amanda goes so if if this is so this notion that and I think it's pretty well substantiated that the the programming of the gut microbiome happens in the first thousand days of life and then pretty much it has a tremendous stability this ecosystem is a tremendous stability throughout life so if somebody goes on on the diet let's say for a year as an adult and then stops that diet does does the microbiome and the metabolites all reverse back to how their person started out with or is any evidence that you can actually permanently changed this early programming yeah I would say that it's not completely well understood so we know that there are changes to the microbiota within 24 hours based on a change of diet we published a paper on this and I think in 2011 that within 24 hours a human microbiota will change and we know in mice it changes in less than 12 hours the effects annamaya a mouse are much larger than a human my notion is that short-term the effects are relatively modest and human and probably reversible or though we haven't directly studied that the longitudinal study where you put people on certain diets asked you change to a different trajectory and then is it ultimately reversible as well its metabolites I think people are starting to do those types of studies we're getting a signal that some of it may be somewhat reversible but I think that the definitive word especially when you think about metabolites are not all that clear my notion however is that the metabolites should be to a certain degree reversible because again the metabolites when you think about diet I think a lot of the metabolites are produced that are dependent upon the type of diet you eat because the diet is the substrate for the microbiota produced these metabolites so if you don't provide your micro body the right types of metabolites they may not fit that the right type of substrate through diet they may not produce the the certain types of metabolites that's what the pre cutted preed the notion that there might the right microbes are there to begin with because if you don't have the might right with the right microbes and you've been you give them the right food and the microbes aren't there you won't make the conversion make those metabolites so it's a bi-directional thing now I know that that things happen in life that will change the trajectory of your micro body so David relman has done studies right with antibiotics so antibiotics and some individuals will change or trajectory or microbiota temporarily you stop the antibiotics and actually comes back it's one of the bigger interventions on a composition of Michael Fatih but then there are individuals that that if they get an antibiotic or they take several rounds of antibiotics they moved into a completely different trajectory and they don't actually return to what they were before even though they stopped their antibiotics then and there are other interventions like if you get the flu or you get the gastroenteritis you're Michael Baden fundamentally changes and to a large extent sometimes it does return to where it was before but but if you take an antibiotic maybe you'd end up in a different place if you get a fecal transplantation you may change the trajectory of your Michael bada and importantly a lot of those organisms may not be yours anymore they may be coming from from your donor a question I and I'm sure you get asked the same question a lot as well what is a healthy gut microbiome can we say that yeah so I think if you were to view it from a micro microbial ecology standpoint you would say that it is a very rich and diverse microbe honest or a lot of different types of organisms you think about it as a rich lon versus a less diverse microbiota which which doesn't have as many things and you think about Allah and it has a lot of holes in it that allows weeds to sort of grow up and take over so I think from a microbial ecology standpoint it's is more the richness of the microbiota is probably at least in my mind from ecology standpoint an indicator quote of how now whether or not quote a healthy microbiota Converse health to the human host there is sort of evidence that well maybe that would be the case because because the rich microbiota tends to be associated again with a more plant-based diet living in an agrarian culture we have lower risk of cardiovascular disease and metabolic syndrome diseases like inflammatory bowel disease metabolic syndrome are associated with decreased richness so they are sort of associated with each other is their cause and effect relationship between decreased richness and disease or increased richness and how there is some indication that on certain circumstances like clustered of the facility that that there is a cause-and-effect relationship there is he even a little bit of evidence in inflammatory bowel disease based on two controlled studies where fecal transplant was actually performed maybe a little bit of evidence in metabolic syndrome but I don't think that I'm absolutely convinced yet I'd like to actually see more data that the healthy MicroBot a richer microbiota is plays a cause-and-effect role in maintaining health I think we're sort of headed in that direction but I'm not absolutely convinced yeah well from what you said earlier it could easily be like an alternative explanation that this particular diet is healthy has direct health effects on the host as well as on the the health of the of the microbial ecosystem even though the to them are not necessarily related they it's possible as they're related but they could at the same time we really operate independently there two different channels that food accesses oh I totally agree with you III have this diagram that I often show in talks and it's basically a triangle with with diet at the apex on the top and MicroBot on the left lower hand corner and the the human host on the right lower hand corner and the biggest arrow is between diet and the host the direct effective diet but then there's a smaller arrow that goes from diet to the microbiota and then the microbiota has an arrow to the host and it's a composition and metabolites so I again believe that the biggest effect of diet on human health and disease is probably a direct effect of diet on the host but there is a component that works through the microbiota either its composition or the metabolites that produce that does have an effect on the host but my notion right now based on current evidence is that that effect is smaller than the direct effect of diet on the host another question I mean don't sort of relate it to each other but it's it's said that our ancestors consumed an average of 100 grams of dietary fiber per day while the typical North American diet provides about 20 grams a day would it be healthy if people increase their daily fiber consumption - the amount of our ancestors or not necessarily I think that in general fiber is is a good thing there are numbers of studies suggesting again diets in these are more plant-based diets tend to be healthier there are many reasons for that if you're if you really if you believe in the functionality of the microbiota is that fiber increase in fiber release and production of increased metabolites like short chain fatty acids that have been shown to activate certain types of receptors and the in the mammalian host that could also play a role and a lot of good functions in immune function and brain function and you know beastly so there's that component of it but there's another way to think about the high-fiber diet and that is to maintain a diet that's isocaloric meaning that you're eating the same amount of energy if you eat more fiber in plants that means that you're reducing the consumption of other things right and so the the one of the challenges I think in thinking about diet studies is that you can't just change one thing and make it icicle or the same amount of energy if you change one thing you have to change something else so in general people who eat higher fiber diets are eating less fat and less meat for example and and is it because you're eating more fiber or is it because you're eating less fat and meat right and so it's difficult sometimes to separate those two so I do believe that eating more fiber intrinsically may provide some benefits but I think a significant proportion of those benefits is that you're not eating something else that could be more deleterious than than just eating a more plant-based diet okay a Marty blazer has written a very interesting book missing microbes and when you listen to his talks he emphasizes the progressive decline in the microbial diversity and abundance of organisms and it seems that suddenly listen to his presentations there's a whole series of bacterial or microbial taxa that is is slowly disappearing just like declining number of species in our external environment do you think a dietary regimen for example going to the 100 gram of fiber day nutrition would that potentially reverse or get us back on track to the same microbial diversity and abundance of organisms that our ancestors said or still some people in Africa or on the Orinoco River in South America have yeah you know it's a very interesting question and that's the sort of the reversibility my notion is that if you don't have the organisms in your gut already and your environment is not going to provide those organisms into your gut then increasing the amount of fiber is only going to have a limited ability to increase the diversity or increase the numbers of different types of organisms and you're cut because they have to come from somewhere right so Justin Sonnenberg did a really interesting study again in mice but I believe it probably will translate to humans that if you eat a diet if you have a mice must eat a diet that's low and what it calls Michael bot associated carbohydrates that that fermentable fiber that the the microbiota of a mouse will begin to lose organisms and it's actually passed on from generation to generation and if you feed the mouse that it's lost those organisms again a lot more fiber it's it's it has limited ability to route to reverse things and that's because the organisms are no longer there so you and if you give it something that would allow those organisms that grow back if they're not there in the first place it's hard to get them to come back what does reverse it is speak-o transplantation so if you wholesale provide those organisms back and they engraft then you provide the favourable diet and they will again bloom it's sort of like if you don't have a seed there to begin with the plants just not going to grow right and so the notion I think is and and I actually sort of I believe that there's there's an element of truth in this that that in an industrialized nations because we're living in a much more sanitized environment that our food supply is different we're using antibiotics we are we do have a less rich microbiota and the microbiota is it's different and then infants born into an industrialized nation they develop a different type of immune system than individuals and infants born in a less industrialized nation where the microbiota and the environment is richer in microbes and because that's the time where your immune system is actually being programmed that that might have consequences not only immediately but later on in life so I use the example very often of atopic disease because I think and thanks in my mind development of asthma for us as gastroenterologist eosinophils esophagitis are some of the best examples of environmental factors that program immune response is that either cause or prevent disease so corollary to the rich microbiota which is associated with a decreased risk of atopic disease you know this is individuals children living in an Amish home which is azor has a different type of microbiota than Hutterite home where genetically they're very similar but they're household dust is actually very different than their Amish dust prevents asthma in a mouse model where's the Hutterite dust home dust actually doesn't prevent asthma I use as an example of this peanut allergies right so so peanut allergies if you're predisposed to development of peanut allergies the worst thing you can do is you keep peanuts out of the diet of your infant and so you never tolerate your immune system your immune system doesn't get used to the presence of peanuts and then as you grow older you develop anaphylactic reactions to peanuts you become hypersensitive to peanuts and now there are recommendations that if you are allergic to peanuts what you want to do is you want to sensitize people in a state way or tolerance people in a safe way by giving them small amounts of peanuts your immune system now sees peanuts and it becomes less reactive to peanuts that's the whole notion that if you are living in a real sanitized environment you don't have the panoply of microbes the rich microbial environment maybe you don't develop the type of immune tolerance to prevent immune meted disease in a way that you would if you were born into much richer microbial environment I mean this also would imply that the the biggest the biggest impact on on these new problems that we have with autoimmune diseases and allergies and hypersensitivities would really be interventions early on in life I mean ideally these first thousand days that you know the people have identified as a as a major programming phase I mean you agree with this and what what kind of what kind of interventions you I mean you can expose you know children to peanuts but what about all the other things that that are missing from our environment in terms of you know microbial sources that that could prevent this this false programming or incomplete programming of the immune system I you know I think it's early days now I mean there's really interesting epidemiologic evidence and marty has been sort of marty places sort of been a leader in this notion that early life exposure to antibiotics in a mouse model predisposes development of disease like metabolic syndrome on obesity we do know that in humans the use of antibiotics early on in age it predisposes to ours associated in epidemiologic studies with more childhood obesity more atopic disease breastfeeding is protective against certain types of diseases compared to formula-feeding there are all these epidemiologic associations in large cohort studies secre c-section versus vaginal birth right all of these sort of pointing to maybe environmental factors that help to program your immune system so that it may increase or decrease the risk of disease later on in life now I I have to caution my people about my comments in this and that is so I was on a talk show once and we're talking about early life advanced c-section versus vaginal birth would be an example and the the person that called in was really actually very upset because she had had a c-section and her daughter has really bad atopic disease right and she was sort of blaming herself for having a c-section my point is that these associations are epidemiologic associations used studying thousands very large cohorts of individuals in any individual case you can say for certainty that just because you had a c-section that that's the reason for your child's asthma or atopic disease right it is one of many factors genetics being another factor environment is an important factor but genetics are it's also an important factor and other factors that we don't even know about that in combination can increase or reduce or reduce your risk of disease so I'm you know people have to understand that you can't blame yourself because see here it's the reasons that people will have a c-section and this is the physician side of me speaking there are practical considerations that you think in in medical care that are actually important that you have to take into account the other notion is that you know people living in agrarian cultures they have a richer microbiota a less metabolic syndrome and obesity but you also have to remember that our lifespan is actually much longer now than it was a century ago or two centuries ago right so people living in these very agrarian cultures they don't live as long as we do so the you know machine you have to look at the entire spectrum of health and disease and I think proper perspective on this and this is the physician side of me that's sort of speaking about this antibiotics are you know we we do have to be cautious antibiotic resistance there is a notion that early life antibiotics poacher may predispose development in disease but we also have to remember antibiotics were transformative in the treatment of this right pre-antibiotic era i died of horrendous diseases right so I think proper perspective is actually very important in this yeah so this is um let me ask you want one one more question and and it's related talked about this several times not before so the context or the environment in which people live obviously plays an important role as well so people living in the Arctic or in northern Scandinavia have less access to a varied plant-based diet as people having more southern latitudes like in the Mediterranean area and could it could it simply be that and this is not necessarily reflected in in differences in lifespan or or disease could it be I mean this is not this wouldn't be a sort of a good statement for people that are fascinated by the microbiome and its implication for human health but could it simply be that the differences that you see in the microbiome is just an adaptive response to the environment these individuals live in and there's not necessarily related to you know if they're healthier they have a healthy microbiome so if you have to break down more fiber from multiple sources of plants you need a different repertoire of microbes to do that as opposed to you know if you have a really small intake of these plant-based foods and eat a lot of flubber and and fish and you know other types of non-client dietary components I mean do you think that's conceivable or is it too far fetched no I mean I think that if I if I understand your question amaura and it is so I'll use the example that dysbiosis right so in disease let's choose inflammatory bowel disease the microbiota is dysbiotic it has less different types of organisms and see more types of Proteobacteria why is that is it primarily because that that dysbiosis is somehow causing the disease and somehow you acquired dysbiosis and and that's a primary drive disease or is it that you have inflammatory bowel disease and intestinal inflammation is actually causing that dysbiosis what's cause and effect if I understand your question correctly and then you're bringing in from terms of diet but I'm just using a IBD as an example my notion is it can be both cause and effect there is abundance of information that the reason that dysbiosis or abnormal or different configuration or microbiota is associated with a lot of diseases is that it's simply the response of a complex microbial community to an environmental stress so in inflammatory bowel disease your environmental stress is inflammation of the hosts intestinal inflammation the test no inflammation leads to a more oxidative environment it leads production of alternative electron acceptors both of those factors would favor the outgrowth of what we call facultative anaerobic organisms Enterobacteriaceae a and that's exactly what we see in dysbiosis an IBD i think the big question we cause that dysbiosis it's just your MicroBot is just responding to the environment that's like if you don't eat enough fiber your MicroBot is not seeing it the organisms that are primarily ferment ativ that use these fibers for energy because they have a high compilation of glycoside hydrolases they may reduce in an abundance because you're not giving them the right amount of substrate so you're simply responding to the environment the fundamental question is that change in the configuration or microbiota having effect on the host is it bi-directional and I would say that there is emerging evidence that in certain circumstances it probably does so I use as an example people transplantation and inflammatory bowel disease were there now two really good studies showing that there is an effect and improvement and also the colitis with fecal transplantation so changing the microbiota fundamentally has has a positive effect I will also say that there are diseases that we treat its positions well we already know the microbiota is in for it right and so hepatic encephalopathy is an example so recurrent strategies for treating hepatic encephalopathy are lactulose and antibiotics so we know that microbes are already important in those circumstances so when I think about diseases as proof of concept I think that think focusing on disease is well you already know microbes are very important either in by themselves or because of the metabolites they produce that that that's proof of concept that that alter microbiota is important also in disease so I think it's bi-directional okay last last question personal question what do you personally would do you do anything personally in your diet in your lifestyle that is aim to improve or be good for your gut microbiome i I do things yeah so that personally I exercise more because it makes me feel better I just because I sit a lot and then my computer and do work so I feel healthier and exercise has been proven to have many many health benefits I'm trying to improve my diet decrease the amount of carbohydrates I am NOT doing it primarily because I'm thinking I'm changing my MicroBot I'm doing it primarily because I feel better and I know the literature supports that these interventions are actually good for human health again I think that the microbiota is fascinating and it requires a lot of attention I think it has enormous potential but there are a lot of things we can do in terms of our diet our physical activity we know provides a lot of benefit already and how much of that it's just a direct effect on us versus through the microbiota I think it's still not entirely clear at least in my mind I think Michael bottom does have an input besides of that input is unclear to me yet I think it requires more work in specifically in humans because not everything that you study in the mouse is relevant to human biology a lot of it is but some of it is not so I think you have to do human subjects studies and and but we do know exercise a lot don't need a lot of fat eat less simple carbohydrates and I think you're gonna live longer and you're gonna feel better so that's what I do like the golden rule well thanks Gary for this fascinating conversation I'm sure listeners will really enjoy this and get new ideas anyway so we've come to the end of this and thanks again look forward to interacting scientifically and intellectually in the future as we have done in the past thank you very much Cameron take care now bye bye [Music]