The Dr. Hyman Show - How to Fix Your Gut Bacteria to Prevent Heart Attacks with Dr. Stanley Hazen

Episode Date: January 2, 2019

There’s a lot more happening in your gut than you might think. Sure, our digestive system moves food through the body, extracting nutrients and eliminating waste. But there’s actually a significant portion of calories we ingest that don’t get absorbed and instead are used to feed our gut bacteria. This inner microbiome creates its own type of waste: metabolites that can be absorbed into the bloodstream and pumped throughout the rest of the body. We’re finding some of these compounds can impact everything from obesity and diabetes to blood pressure and heart disease—it’s astounding to realize the far-reaching effects on whole-body health that all start within the gut. Today’s guest on The Doctor’s Farmacy is here to explain that connection on a deeper level. Dr. Stanley Hazen is both the chair of the Department of Cellular & Molecular Medicine at the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation at the Heart and Vascular Institute of the Cleveland Clinic. He’s published more than 400 peer-reviewed articles and has over 50 patents from his pioneering discoveries in atherosclerosis and inflammatory disease. Dr. Hazen made the seminal discovery linking microbial pathways to the pathogenesis of cardiovascular disease, which we talk much about in this fascinating episode.

Welcome to the doctor's pharmacy that's F-A-R-M-A-C-Y. I'm Dr. Mark Hyman and we are here with Conversations That Matter. In fact, today we're here at the Cleveland Clinic with Dr. Stan Hazen. A conversation that is going to be, I think, mind-blowing for most of you, talking about the connections between the heart and the gut and so much more. Dr. Hazen is an extraordinary scientist, one of the leading scientists here at Cleveland Clinic. He's an extraordinary doctor who's been trained at the Washington University School of Medicine, one of the best medical schools in the country. He's got a PhD in biophysical chemistry and molecular biology. He's trained in internal medicine, diabetes, endocrinology. He's been at Cleveland Clinic his whole career. He's head of, co-chair of the

prevention, cardiology, and rehabilitation at the Heart and Vascular Institute. And he also is chair of the Department of Cellular and Molecular Medicine. He's got a lot to do. He's published over 400 peer review studies. He is an inventor on 50 patents. He's made one of the most important discoveries in medicine, one of the best innovations at Cleveland Clinic in 2014, which is the discovery that what you eat and your gut bacteria have a huge impact on your risk of having a heart attack and many other things like kidney disease and who knows what else. So we're going to talk about this whole world of the microbiome.

So welcome, Dr. Hazen. Thank you. Thank you for having me. Of course. So first of all, most people might not know what the microbiome is or why it's important or why it would in the world be connected to heart disease or anything else if it's all in the gut. So can you just give us a 30,000 overview of what is the microbiome? What are the implications of this new science and how you got interested in it?

So we all have literally trillions of bacteria that live in our intestines, and we call that the gut microbiome. It has to do with the fact that what we eat is actually our largest environmental exposure. It's a foreign object that we bring into our bodies. Pounds every day. And it's experienced through the filter of this gut microbiome. And that's because a significant portion of the calories that we ingest actually don't get absorbed and make it further down the intestines and gut microbes, which predominantly live in the colon, the distal part of the intestines, will actually use the food

as nutrients also and generate waste products that then get absorbed into our bloodstream. And what we're now finding is that many of these compounds have effects on our bodies. They play a role in control of blood pressure, heart disease, diabetes risks, obesity. It's really astounding over the past decade, the enormous role that gut microbes play has now become appreciated. Yeah, so it's not like what happens in the gut stays in the gut, right? That's true. And this also helps to explain why two different people who both eat the same sort of diet, one may experience increased risk or susceptibility for development of a disease like insulin

resistance or diabetes, or in this case, atherosclerosis and heart attack and stroke. And it's because one individual has a different gut microbial community and therefore is making different levels of metabolites that are in their bloodstream. And that impacts our disease risk and we have evolved always colonized with bugs for the past millions of years yeah and they have evolved inside of us and it's an interplay that is absolutely essential some of our vitamins like vitamin k require gut microbes to actually make them and you know we evolved a need for vitamin k that can only come from bacteria so they're not all bad in fact in majority they're necessary and good yeah it's

amazing so just to take it up a little bit we have about uh 10 times as many bacterial cells in us as our own cells and we have about a hundred times as much bacterial dna we may have 20 000 genes there might be two to four million genes of bugs in there. And they're all making stuff. They're all making these metabolites and proteins that are absorbed. And we were on a panel recently and you were saying that so many of our blood metabolites are not even human. They're microbial and they all have different effects on our biology. So the question is, why if we've evolved for years with these microbes co-evolution why is it that in the last hundred years we see this explosion of heart disease has our gut bacteria changed and how and why that that is an excellent question and it's not totally figured out but what is for certain

is that our gut bacteria are changing as we have changed not only our environment in terms of how we generate food and process food and the whole science of agriculture has changed as well as the prevalence of antibiotics use which is like a nuclear bomb to the gut microbial community and every time a person takes antibiotics the whole community or a big portion of it gets replaced and often it doesn't come back the same way as where it was to start with so there there are differences and what's actually interesting and exciting is that if you look not just at humans but even at squirrels in the park in new york central park central park they are getting obese also oh my god i was in the park

yesterday or the other couple last week, and there were these fat, fat squirrels. I'm like, holy cow. Well, we, on an industrial level, are putting things into our food chain, and that works its way through the entire pyramid, the food pyramid. And there was a study that was reported several years ago about the obesity of squirrels in central park and at least the association with gut microbes shift and but obesity has been known to be linked to alterations in microbial community as well yeah we're going to get into the whole link between

your gut bacteria and obesity which i know you focused on which is fascinating and it's like how does your gut flora play a role and even animal studies they found they could swap out gut bacteria from a fat mouse to a thin mouse and the thin mouse gets fat on the same amount or even less calories right so the whole idea that all your weight is dependent on calories in calories out it's kind of an old idea basically is what you're saying well the reason it still requires calories in calories out, but the difference is what we now realize or think about is you don't absorb all of the calories in the food that you eat. Different people may actually have a slightly different efficiency of where their engine runs. absorb an extra 2% of the calories from their food compared to the other because the different constellation of gut microbes they have may make it more efficient for them to extract energy from the same amount of food than the other individual. And while that may only be a dozen,

two dozen, 50 calories a day, when you add that up over time, it really adds up if you say 3 000 or so calories is one pound um you know two three percent difference in energy extraction makes a huge difference over time so what you're saying basically is that we've done a lot of things to mess up our gut we've eaten foods that are processed we're not eating as much plant foods we're having less fiber we're taking antibiotics we're born by c-sections we're taking other drugs and mess up our gut like acid blockers and anti-inflammatories all these things are driving this ecosystem to be out of balance and that seems to be leading to more obesity more disease more chronic illness across the spectrum that's one way to put it i think it's hard i don't like characterizing the

gut is out of balance or good or bad because it's never so easy as a single switch on and off, good, bad. Each particular pathway you look at is everything is different shades of gray. But yes, the shift is happening and it's undeniable. And one of the things that is the most astounding is, as you mentioned, you can take an obese mouse or even human and harvest microbes from the intestine, that's the feces, and transplant it into a recipient and show that you literally transmit the susceptibility for things like changes in blood pressure, changes in susceptibility for clotting risk and atherosclerosis

and changes in obesity. Amazing. So let me try to understand this because you're a preventive cardiologist. You're focused on the heart. How the heck did you kind of even come up with the idea that you should be looking south? That's a good way to put it. Well, we weren't looking for this. My background also, as you mentioned, was in chemistry. And we were looking for chemical signals in the blood that actually tracked with and predicted the future development of disease. So we had collected samples of blood from a large number of subjects who agreed to be followed over time. And at the time we collected them, they did not have a disease,

but in the ensuing three-year period, half had developed a heart attack, stroke, or death, and the other half had not. And so we asked what chemical signatures in their blood predicted the future event. And then basically a large number of those chemical signatures could only have been made by bacteria and that led they weren't human molecules well they are human molecules we didn't realize they were there the vast majority of the compounds in our plasma we're still trying to figure out what the structure is believe it or not yeah and um so when we finally figured out that these compounds in the blood could only be made by at least some point in the lifetime of bacteria to help make

that compound. Then we put two and two together and said, well, the majority of the bacteria in our bodies are actually in our intestines. And then there was kind of a eureka moment where we said, well, wow, everything we eat goes through that filter. And we're able to show that both in animals and in humans, if you gave a cocktail of poorly absorbed antibiotics that really aren't normally given orally, are only given intravenously, but we could show we would virtually almost sterilize the gut. And then the level of all these compounds in the so strongly a person's risk, for example, a heart attack, could only be made by gut bacteria. That's so fascinating. So the idea that you discovered that the gut and the heart are connected was a total serendipitous discovery, right? It wasn't like you were looking for it.

We weren't looking for it. We just saw the, we were looking for compounds that tracked with risk we just had no idea to think that they would involve being made by bacteria so now let's talk about that compound which you're famous for and have won many awards for discovering tmao or trimethylamine n oxide and this is a fancy word but tmao is easy to remember and it's produced by bacteria apparently in response to certain nutrients in the diet specifically choline and carnitine which are high in animal products that's true and fish and meat and eggs and dairy and so you kind of went down this pathway to look at how this is working and how do you change diets? And you did some early studies comparing how diets of vegans affected their microbes in the TMAO versus meat eaters.

And so can you talk about some of that early research and what you found? Sure. So in general, the precursors that give rise to this compound TO, are more abundant in animal products. And in particular, one of the compounds, this thing called carnitine, is almost exclusively found in red meat. Carni. That's where the word comes from. Carnitine. Carnivore.

Carnivore, right. Yeah. And in fact, carnitine, when it was first identified, was named that because of the connection to red meat. But I will point out that choline is in all of us and we all synthesize plenty and it's actually found in bile. And when we eat even a cucumber, our gallbladder squeezes, dumps a lot of bile in the intestine and actually on a molar basis, choline is more abundant than bile acids. So even the vegan and vegetarian is constantly feeding their gut choline. And so what you do see is that there's a basal amount of TMAO

that gets made in everybody, and that has to do with choline constantly being fed to the gut microbes. And there are many different microbes that do this reaction with choline. However, for people who eat a lot of red meat in their diet, what we have seen is that there can be a very dramatic increase in TMAO level coming from the other nutrient called carnitine. And in fact, the more recent studies looking at what's the impact of diet on TMAO level that were done in very carefully controlled circumstances where every meal was provided to the individual over the course of virtually half a year. And they switched from a red meat diet to a white meat diet to a plant-based or non-meat

containing protein source. And what we see is there's about a threefold increase in TMAO in virtually everybody when they're on a red meat containing diet. But where they started in that factor of three can be highly variable. And some of the individuals, even when they eat a fairly good starting diet uh can have a very high tmao level and it's just because of the different microbial community they have so just like in the same way you have different susceptibility for developing diabetes and having an elevated glucose level we see even vegetarian and vegans can have a high tmao level

but in general it's lower because they're having less of the nutrient precursor. But you did say to me before we got on the show that vegans have high levels of TMAO, so that was confusing to me. They, in general, do not, but the highest levels of TMAO we have actually ever seen happened to have been in a vegan woman, and we were trying to understand what was going on, and finally, I mean, her level was so high we didn't understand had in that closet and eat steak or what it finally we found out that um she would on a weekly basis do a bowel cleanse with a lecithin enema oh and so she was putting choline into her

body but from the other side oh and um but the bottom line is the gut microbes don't care where it comes from, whether it's from food. Isn't lecithin from soy? It is. And soy is a, so if you're a vegan, you're eating a lot of soy. Is that a source of choline? It is a source of choline, but we can't get away from it. It's an essential nutrient also, so you can't like completely.

And so it's carnitine, right? No. Carnitine, we do not need to ingest carnitine at all. Our body makes all that we need. People who have end-stage renal disease who are on hemodialysis are constantly having carnitine sucked out of their system with dialysis. And so they will get carnitine back in during dialysis. It used to be that they got it orally, but now most of the time, I think perhaps in

response to our research, it's given intravenously and bypasses the whole gut during the dialysis procedure. Yeah, fantastic. So the TMAO does a few things. It actually seems to increase the stickiness of platelets and making them more likely to clot and increase the sort of likelihood of having heart attacks. Talk about some of the mechanisms of how this works and why you think it's linked to heart disease. Because it's not just the idea that you've seen it in the blood. You actually understand some of the mechanistic ways in which it actually does its damage. So there are two major pathways where we think it's involved. One involves cholesterol, deposits in tissues, and the other,

as you mentioned, changes your susceptibility for clotting by changing platelet function. With regard to the cholesterol, the way to think of it is it's like the rheostat on a light switch. Cholesterol is to atherosclerosis what electricity is to turning on a light bulb. You can't have plaque development. You can't have atherosclerosis without cholesterol. But your susceptibility to the cholesterol level and how bright a light you get, how much atherosclerosis you get, can be just like a rheostat switch. And TMAO, when the level is high, you're more susceptible to cholesterol. There's an enhanced propensity to deposit the cholesterol in the artery wall, both going in in terms of the cells that collect the cholesterol deposits,

the receptors that are involved in that are upregulated, and less ability to move cholesterol out of the artery wall. That pathway is inhibited. On the other hand, we do know that at the platelet side, and I mean, you can live with cholesterol or atherosclerosis, but you die from clotting events like a heart attack or stroke. And what we do see is that TMAO directly interacts with platelets and makes them more prone to clot. And at a higher TMAO, it's in the normal range, but people's blood will clot faster. And also, if you look at a large scale at the population-based level, over thousands

and thousands of people, you see TMAO tracks with risk for heart attack, stroke, and death quite strongly, independent of traditional risk factors. And we think it's through this mechanism. Fascinating. So going back to the diet part you if you look at some of the vegetables like broccoli or the cruciferous vegetables quinoa you know these often have higher high levels of tmao too right no um they don't have tmao they can have choline oh choline is what i mean they promote uh yeah but the level per gram of food is much lower than the level of the nutrient precursors of what you find in animal products.

So we have to choose something to eat. I like to tell my patients, we're not air ferns. We need to eat something. So it's always a choice. And what we do see is that eating plant-related products is a better choice, perhaps a healthier choice most of the time than animal related products. Although I like to emphasize with my patients that diet is a personal choice. And if they're not really interested in becoming vegetarian to try and emphasize, well, maybe just start with one day a week, you'll do a vegetarian diet. And

then over time you say, well, what about two days a week you'll do a vegetarian diet and then over time you say well what about two days a week and the other thing is is you can actually look at your tma level and see do you need to be more aggressive or not uh in terms of you know it's a commercial test you've developed it is and it's available though broadly across the country as a blood test and it's yet another way to help personalize dietary choices just like we can target cholesterol or triglycerides or glucose this is now another facet of that well it's fascinating because the the dietary implications are massive and you know people might be hearing well i have to cut out meat and eat only vegetables but it's fascinating in your one of your original studies you had vegans

who never ate meat versus meat eaters who were eating regularly eating meat i'm not sure what the rest of their diet was and the meat eaters had higher tmao but the vegetarians or the vegans had low tmao but when you fed them a steak their tMAO didn't really go up because their gut bacteria were the kind that didn't produce a lot of TMAO. So what if you ate a diet that was plant-rich with a little bit of grass-fed meat? Is that a bad thing? I don't think it's a bad thing, but I think that the thing to do is to test in the individual, do they have a high level or not? And if they do, then they might try parsing it down in terms of the frequency, the portion size. Alternatively, if the level, now that's not to say that all, that TMAO is the whole story. This is just the tip of the iceberg.

It's the first of many, many, many pathways that we now are recognizing gut microbes are linking to various aspects of our astounding is you can transplant the microbes and show a difference in how fast a mouse can solve a maze yeah or whether or not it wants to bury marbles and save them for a rainy day that kind of behavior it's fascinating has been linked to microbial transplants and showing shifts in behavior that's fascinating just change the poop out in people and you can give them brain damage or heart damage or autoimmune disease. So what are the implications for medicine? Because all of a sudden, all the silos are breaking down, all the barriers between what

we thought was true. I mean, cardiologists never learn about gut microbiology in cardiology fellowship, but maybe they need to now. And same thing for neurocognitive diseases or immune diseases and what are the implications for how you have to rethink uh health care and medicine and education what what are your thought about that well i think one of the major consequences of this is it really has opened people's eyes uh to how important as you mentioned food is as a medicine if you will and to our health because

that is the clearest most obvious direct connection that we can impact in terms of chronic dietary patterns shift the composition of the microbes in our intestine and um and so that is actually the single biggest influence initially that we can do. But I would say beyond that, we will be developing targeted therapies that actually go after microbial pathways and try to curb them or inhibit them, much in the same way you inhibit cholesterol synthesis with a drug called a statin. As you know, we're now in the process of developing drugs that instead target the bacterial enzyme pathways

and have shown, at least in animal models, we haven't transitioned it to humans yet, that we have drugs that can block the formation of TMA and TMAO and therefore have shown inhibition in diet-dependent atherosclerosis and diet-influenced thrombotic event rates in animal models. So you can have your steak and eat it too. Actually, my favorite study you did, I want to know if this is really valid or not, was that if you have red wine and extra virgin olive oil and balsamic vinegar, you can mitigate the effects of TMO. So if you have your steak with a glass of red wine, a nice salad with olive oil and vinegar, does that work?

It's hard to say, but what we did see is that— You published it, didn't you? Yeah, well, what we saw is that we developed—the first drug that we developed for this pathway to block it turned out also, because of its structure, we thought it was a natural product. And so we screened in our pantries, and then we're surprised to find that this natural product was actually didn't realize it was a natural product but found it in extra virgin olive oil and balsamic vinegar and grapeseed oil and and so again there's another aha moment and you say oh maybe some of the benefits of a Mediterranean diet may might be derived from uh these kind of

compounds that are in these you know in a mediterranean diet at higher level one of the things that's interesting is the compound that we initially were working on uh it's not very potent you need to take it in large amounts so you need a lot of extra virgin olive oil but in uh the mediterranean countries they do it's a lot? Like a tablespoon? Like four to eight tablespoons. A day. A day. But that's actually approximately what they do consume.

And the other thing we found is that if you cooked the olive oil, you lost the compound because like alcohol, it was a small alcohol, it was cooked out. And what's interesting is here in the United States, we often try to have this obsession with heating our oil and putting things in it and you know frying and so um actually using the extra virgin olive oil after the cooking is done and drizzling it on top uh like preserved the the compound in in it so don't cook with olive oil that's what i always say yeah all right so i want to i want to sort of dig into this before we get into the drug you're developing and

some of the dietary implications on how to fix TMAO and help your gut bacteria. I want to talk about some of the controversies in the science around nutrition and diet. Because you can look at the vegan community and they can produce a whole lot of studies that show the vegan lifestyle is healthier and other studies are showing the opposite. And it's very confusing for consumers. It's confusing for doctors. It's confusing for me who spent 40 years studying nutrition. And I'd love to hear your perspective on it because you've got, you know, large recent

studies, for example, the pure study, which was, you know, 135,000 people, I think 95 continents or something looking at, and this was an observational study looking at patterns of diet and health. And they found that animal products and animal fat weren't really correlated with heart disease as much as, for example, cereal grains and potatoes. So it was a huge food consumption study, 42 countries in Europe looking at dietary patterns, same thing. They found that cereal grains were higher risk for cardiovascular disease, whereas animal

products and fat were not you've got other large vegan vegetarian omnivore study looking at whether there's differences in risk and there really wasn't you've got studies looking at 11,000 people who shopped in health food stores who are vegetarians or meat eaters and they both had their risk of health dropped in half of disease dropped in half so from the perspective and some other studies, for older studies looking at meat consumption, showed that there was an increased risk. And those may have been confounded by many things,

like in the era when they did those meat studies, they found that, for example, people were eating meat, didn't care about their health, and they ate more, and they didn't exercise and eat vegetables because people at that time were told meat was bad. So people ate meat, didn't care about their health. so how do you make sense of all that given you know these observational studies with your molecular studies and the gut bacteria it's very confusing so one thing is i think to recognize is that observational studies um are hypothesis generating um because if

you just by observation epidemiologic studies only, you'd think that, for example, aspirin use would be associated with the development of heart disease because it associates with the development of heart disease. People take aspirin to prevent heart disease. But we know that taking aspirin doesn't cause heart disease. And similarly, I would say that on the whole, the majority of the epidemiology studies do suggest that an animal product red meat rich diet is associated with higher risk.

But you are correct that there are many studies that have come up and questioned that. When you look at interventional dietary studies, they fall in two categories. One is they look at a surrogate endpoint. A true experiment, not just tracking people over time. Right, where you're actually providing them with the meals or meeting with them frequently and trying to confirm compliance because actually the epidemiology studies that look at how good the data is for nutrition studies, historically we know that it's not very close.

Like a lot of people kind of fib a little bit when they pull out those forms that are maybe 20 pages long. It's true. There was a recent study on carbohydrates at Harvard, and they were missing 800, I think, calories a day. Yeah. So what were those calories? Yeah.

But what we do see is that in interventional studies, such as the PREDIMED trial, which was a very large prospective intervention trial where subjects were asked to go on a Mediterranean diet versus what was a low-fat, low-chol low cholesterol diet what was seen was about a 30 percent reduction in future heart attack stroke death and development of cardiovascular disease i was having a bottle of olive oil a week or a handful of nuts every day right exactly and and so we know those kind of studies are much i think i interpret them to be more powerful evidence than epidemiology uh studies that's not to say that uh being on a you know the epidemiology studies aren't worthwhile they are but we have to rank their quality of the evidence yeah um some of the more recent uh intervention studies are

what they do is they don't look at actual hard endpoints, but they've looked at biomarkers or interim or surrogate markers like a person's cholesterol level or glucose level or blood pressure. doesn't necessarily mean that if you eat a diet that slightly changes to a very, very small extent, one of these surrogate markers, it has a substantial long-term impact on your health. I mean, it stands to reason, but it's not always the case. So the intervention trials with hard endpoints are really what we need to do. And surprisingly, there are very few diet. Do it. You got to lock thousands of people up in a room for a year and feed them different diets more than a year.

And instead, and we're not millions of dollars. Yeah, it is. It's that's what people have to really realize. So I think that, you know, I, and it's not just diet. The other aspect is the lifestyle change is exercise. And they are intertwined and they both feed on each other. It turns out as you change your exercise pattern, your gut motility changes, your metabolism changes, your microbiome changes. And so I tell my patients all the time that a routine exercise program is the cornerstone to all lifestyle

changes because it's it's what actually is the biggest thing that helps show compliance with a diet change is if they're maintaining a routine exercise regimen yeah because i mean if you're going to exercise if you pig out you're not going to feel like exercising so they just have to find the time i mean i know that's true if i know i'm going to exercise i'm not going to eat a whole lot before because i don't want to get sick if i exercise so it does limit you find the time i mean i know that's true if i know i'm going to exercise i'm not going to eat a whole lot before because i don't get sick if i exercise so it does limit you know the choices i make and and in the end people feel healthier and it's additive when you actually look at what the health benefits are of an exercise program they're additive to the diet and the diet health benefits are additive to i mean so diet exercise are additive to controlling blood

pressure controlling lipids and the other preventive so we all know we're supposed to eat right and exercise and sleep and deal with stress but now we have something else to do which is tend to our inner garden and try to figure out how to get a healthy gut microbiome which nobody has a clue how to do so it's a lot of the work you're doing you're taking really two approaches one is looking at dietary inputs and and what changes we should make and two you know you're developing drugs that can help change the pathways but i wonder if it's like whack-a-mole though if you you get tma or maybe there's 4 000 other things you didn't study and maybe three of those are far more important or connected i mean it's kind of a little bit confusing but tell us about uh diet first if

you for you what do you eat and how and how do you actually look at a way to advise people? Is it cut out all meat and animal products? Is it to eat way more plant foods and fiber and things that are going to fertilize the good bucks? How do you tell people to eat as a preventive cardiologist? So I recommend to decrease red meat in their diet. Some people actually eat red meat every single day. And I think back over a decade ago, I used to eat red meat most of the days.

And so I recommend that they try cutting it in half and then after a few months, cut it in half again and slowly over time, decrease it and increase, as you say, the plant-based related, you know, the vegetable component. I think a Mediterranean diet has some of the best clinical data now associated with reduction in the development of cardiovascular disease into the future, but that's only because probably it has been studied now. Yeah, right. Compared to what? And so, I mean, those are the recommendations that I make. The other thing is I do recommend monitoring the TMAO level

and seeing if it is high in an individual, then we become much more aggressive. We also try to cut out supplements that actually might have inadvertently things in them that raise TMAO. So, for example, many energy drinks or protein supplements can have carnitine in it in terms of the energy drinks or have choline or lecithin in it, especially for some protein shakes. And I say that, you know know just let's get it natural the roots in the vegetable right yeah don't uh usually when we try to take something in a pill form we mess things up yeah and it's better to you know make our own gardens and become

you know urban growers and whether it be uh with our own uh you know in the ground or in containers it doesn't really matter that's amazing now let's talk about other approaches because this drug approach is fascinating and what you essentially have done is figured out a pathway in the bacteria an enzyme that produces tmao and created sort of a non-antibiotic antibiotic in a sense it's blocking a pathway like you's blocking a pathway, like you said, with a statin. Tell us about that and where are we at in the trajectory of that and what does it actually do and what can we look forward to with this? Okay, so what the compound does is it blocks the bacteria essentially from being able to eat the nutrient precursors that

give rise to TMAO. So think of bacteria as dumpster diving. They can eat anything they want in the gut. But you're saying you cannot eat this particular precursor, choline in this case, is the pathway that we initially have gone after. and so the initial inhibitor was developed at and published at the end of 2015 more recently we've just come out with something that was about 10 000 fold more potent something that is potent enough that we can put in a capsule because the first drug was not potent enough to like put in a capsule and take enough and so now what we're in the process of doing are trying to finish those studies so that we can transition this into human interventions. We're not at that stage yet, but we're moving close to that.

We do see that this pathway is linked not only to atherosclerosis and clogging of the arteries and clotting risk, like heart attack and stroke, but it also is linked to chronic kidney disease development and heart failure development and obesity too um well there's a question it might be linked to obesity uh we see that very strongly in animal models the story in humans with that is a little harder to figure out and um and that that's because we don't animals can be put in a cage and put on the exact same diet, but it's hard for us to do that in humans.

And so there is some data that other groups have reported that shows a striking relationship between this pathway and visceral fat, the fat that's like in your gut, in the omenta. Yeah, belly fat. Belly fat. That the belly fat actually can help make TMAO. There's dataa yeah that belly fat belly fat that the belly fat actually can help make tmao there's data the actual fat makes it not just the bacteria well the the it's

a tmao gets made in two steps the first step is the bacteria make a precursor called tma and then our bodies uh historically we've said the liver was responsible for actually making the TMAO from that precursor. But now we see that second reaction happens not only by the liver, but also by belly fat or omental, you know, visceral fat. All right. So we have something to look forward to now. Your other hat, you're a preventive cardiologist. You co-direct the center here for preventive cardiology. And, you you know there's a lot of emerging thinking about cardiology i think in the last few decades we went from this low fat diet craze to you know focus on lipids and cholesterol and now there seems to be a shift

to understanding it's more complex and the role of insulin resistance and pre-diabetes and you know i read some recent studies one One was looking at everybody who had a heart attack who went to the emergency room in like a five-year period. And I think they got lipid numbers on about 60% of those. It was like 130,000 people. And then 50% had normal LDL cholesterol. I think 17% even had optimal, like under 70 LDL. And yet when you looked at other studies, which looked at people who came to emergency room with a heart attack and they did glucose tolerance tests, two thirds had either undiagnosed or diagnosed prediabetes or type two diabetes. So is it the sugar? Is it the cholesterol? Like what's the dynamic there? You talked about visceral fat

and belly fat and heart disease. It seems to me that we're shifting our thinking to being more related to this insulin resistance process and particle size and particle number can you share what the thinking is about that well they the the complication of this whole system is that they're all interconnected and they all co-associate with each other so metabolic syndrome or what we initially used to call syndrome x and then metabolic syndrome it's it's the same thing but keeps get reincarnated yeah each decade and that is is that increased visceral or belly fat is associated with high blood pressure diabetes and abnormal lipids and

they all connect and also something called called inflammation, like vascular inflammation. And so it looks like I don't think we can really say, you mentioned the word whack-a-mole, and as we pound on one, the other ones become maybe perhaps as or more important. They're all equally important to go after, I think. It's not uh curing heart disease is not going to end up being a single bullet it's going to end up taking i think

multiple bullets on multiple targets including uh the uh addressing although i will say that maintaining a person's weight is probably one of the single biggest things one can try to do to influence all of these different facets. Even though when we actually look at statistically and predictive models, weight drops out because it's the increased weight causes the high blood pressure, causes the insulin resistance. And it's only those who show insulin resistance or high blood pressure or dyslipidemia high cholesterol that exhibit the enhanced risk but that central piece in the middle uh is the enhanced obesity that touches on all of those pathways well it's interesting this guy uh named david lodewig at harvard has done a lot of

work on this and it's actually sort of challenging our traditional hypothesis which is the weight comes first and then we get obese then we get all these cardiovascular risk factors. He's saying that the diet, which is high-starred sugar diet, drives the pathways of prediabetes or insulin resistance. That leads to the weight gain. So it's not the traditional way we think about it. And challenging the paradigm, which may be the quality of our diet is so poor that you're not overweight at the beginning, but as you start to eat these foods,

you actually start to have this low-grade belly fat and changes in your biology and that leads to this hunger and weight gain and slow metabolism that that's true and also we see that uh the amount of simple carbs uh has a significant impact on your microbial community as well versus resistant uh resistant starch versus you know more whole grains and so they're all interconnected and i i i agree with you that this is the it's not just single cholesterol only although i will say you need to have cholesterol to make atherosclerotic plaque but your susceptibility to develop coronary artery disease hardening of the arteries varies from person to person um you know and with higher cholesterol they'll be at higher susceptibility but whether or not you know someone who has

essentially what we call a normal cholesterol level because of other issues they can be more sensitive to it in terms of developing so now we don't have to worry about the microbiome. We'll worry about the connectome. Everything's connected to everything, right? It is. And so that's why when we see patients in our preventive program, we kind of take a global approach. We will work on diet-influent changes, lifestyle changes,

exercise programs, smoking cessation, but then also work on the cholesterol levels, the triglyceride levels, the blood pressure, diabetes issues. They all, I mean, you literally have to go after multiple different facets. What we have seen, for example, in very large scale genetic studies that have included literally millions of patients is that genetic causes of cardiovascular disease, for example, can only account for 10% of the attributable risk. So that means the other 90%, if it's not coming from genetics, is coming from our environment. And it gets us back to the largest environmental exposure is what we eat. And so I still think that the primary preventive

efforts fundamentally initially need to begin with diet and exercise and then on top of that we you know the medications if necessary to help control things that we can't control with lifestyle alone and diet alone efforts it must be complicated being a preventive cardiologist now because you've got to be not only a cardiologist but you have to be an endocrinologist to deal with the insulin issues. You have to be an inflammologist to deal with all the inflammation issues. I've got microbiologists. But this is going to be true for all diseases. There's nothing unique about cardiology or preventive cardiology.

This whole idea that the gut microbiome participates in multiple facets of human health and disease, it's going to, I think, be changing the way we think of medicine in the future and look at things more holistically. Yeah, you absolutely are right. I mean, this is radically changing the paradigm of silos and medicine and specialties is all breaking down. And it's really what functional medicine is about.

It's systems thinking, how do these things connect? How do they relate? How do we begin to challenge those you know i i was at a lecture recently of a cancer specialist who was talking about immunotherapy and which patients it worked on and which patients it didn't work on and he found that if there was this low population of a particular bacteria called acromantia that the people didn't respond to immunotherapy whereas the ones who had lots of this bacteria actually did respond which is fascinating to think that a cancer therapy't respond to immunotherapy, whereas the ones who had lots of this bacteria actually did respond, which is fascinating to think that a cancer therapy is going to be dependent

on what bugs you got growing in your gut. Not only that, but there was a series of three different studies that were published back-to-back in High Impact Journal and really focused on this idea in the case of, this was malignant melanoma that was looked at but there's no reason to think that other cancers wouldn't behave similarly that certain types of chemotherapeutic drugs called checkpoint inhibitors where those who responded

to them it was completely or in large part dependent on their gut microbiome as you're saying and what was interesting with the acromantia studies is they even took pasteurized acromantia so it was dead yeah and showed that taking that enhanced the therapeutic response um and and so can you take it as a probiotic are we going to be able to use but that's not a probiotic see a probiotic has to be a live culture, a live thing. So what that tells us, it's the bacteria themselves aren't doing it. It's they're making metabolites or compounds that then get into the host, and that is what's influencing our physiology. So I think we have to shift away from specific bacteria

and towards what are the bacteria making and um and how do we harness that information so that we can leverage it for therapies because um the bacterial world is enormous as you mentioned at the very start of this it's the amount of genes alone is 10 to 100 times as many as we have because there are so many different bacteria and um and there's a lot of overlap if you push down and suppress one set of bugs other ones will come up that may have the exact same garden with the weeds you know yeah so what we really need to do is it's like figuring out a whole new chemical braille system and understanding what the signaling pathways are. In many ways, I think of the gut microbiome as our largest endocrine organ.

We're now trying to figure out what are all these new hormones. And we're back a century ago, we were just figuring out what insulin and glucagon, the major hormones that regulate glucose level. We have to think of things at that level, but for virtually everything now, what influences all the different host pathways and try to understand what those compounds are. So acromantia itself wasn't doing it as much as it was making. And in fact, there have been studies that have identified a specific protein in acromantia, at least in animal models, that can be given orally to the animals it would educate the immune system which by the way there are more white blood cells in the gut than any other place in our body and so a huge part of our immune system

and and 60 percent of our immune system hides there that's correct yeah why because it's where you're exposed to the outside world through bugs and food. That's why it's like having the front line of the defense system. Yeah. Yeah, it's amazing. So just when we thought we had it all figured out in medicine, we're like starting over, it sounds like, trying to figure out this whole new world of the microbiome

and its implications and what it's making and how to work with it. Fascinating. I don't want to give the impression that, you know, this means that everything has been done in the past is not valid it is valid it's just that we now have this new incremental knowledge of these are rheostats that are on that light switch that we have to now figure out oh there's a whole new rheost out there that we have to start working on first discovering the rheostat and then figure

out what it tweaks and how to actually manipulate it up or down in the direction that we want for helping to bring about a better outcome. So right now in the whole world of microbiome, it seems like the wild west. There's all these companies making fancy probiotics or poop pills and this and that product or coming up with different ideas about how to fix it. And then we have this sort of parallel world of big data and artificial intelligence, machine learning, things that we never had in medicine to help us understand. I mean, how do you even think about studying 2 million genes and all the products they make and all the metabolites? I mean, it's like how they all interact and what they do. So how far are we given these convergence of these trends? How far are we from really having practical applications? Are we a year, five years, 20 years, 50 years? Where are we in this convergence of these trends how far are we from really having practical

applications are we a year five years 20 years 50 years where are we in this trajectory can you tell we're multiple places across the spectrum in many different areas so um you sound like a politician i hate to say it that way though um with regard to TMAO, we now know the compound. We can measure it. We can actually make some decisions or move someone in terms of their risk category based on that. But with so many other things, we just don't know. And we're still not even at a point where beyond diet or exercise interventions, having a drug that is used in humans yet. So it's just the very beginning.

And what I would caution is just because you hear the word probiotic or prebiotic, there is not control over, there's no FDA oversight over these things. They still fall under food. And we have been fermenting cheeses and wines and products for centuries and and consequently if you there are certain bacteria that are used in these processes that have been grandfathered in and have nothing to do with and aren't considered in the health side but are considered food and so there's no supervision and i will say that when we actually analyze some of the probiotics that are sold the majority don't either don't have what's on the label or they have many other things that are not on the label and so it is the wild west and i caution patients not to

actually go down that route rather to eat the fruits and the vegetables and the prebiotic foods prebiotic well resistant starches lots of fermented foods right no well i'm not sure about fermented foods a sauerkraut fan well if people like sauerkraut it's fine um but i i think that uh at this point it's um i think going with going with either a Mediterranean diet or a vegetarian diet chronically will actually help shift and tend that microbial garden and shift it into one. You have to till the soil and feed it the same thing over and over and over. The other thing to keep in mind is it doesn't take a little bit. I mean, just a little indiscretion, if you will, can then last for a while. So it's like water in the corner of the shower stall, the

black mold or whatever, a little bit of moisture periodically can keep the mold there a long time. So bacteria are really good at kind of hunkering down and and going into a quiescent mode and so and then waiting until the the food they're looking for kind of becomes available so it's a chronic think of a diet as a permanent shift in eating pattern not as a something i'm going to do temporarily for a few week period and then get back to what i was doing beforehand and now we have tools like you can change your diet and check your TMAO and there are other companies out there doing things like uBiome and Biome that are testing people's microbiome and all the metabolites.

I don't know what you think of those, but it's fascinating. Human Longevity Institute and the Human Nucleus Project, they're all doing this. Are they way ahead of the curve in terms of where they should be? Realistically, it's very hard, I think, to look at the metabolites that they make in our blood, just like a blood test or a urine test or something in the future. I think that, well, I don't recommend them at this time in general, but I think that they may be there. That's not to say that that direction couldn't be useful yeah um but it's it's hard to know at this point and i've seen guys who were really geeky i figured what the name of the

project like a human microbiome project or something where he basically decides to change his diet extremely he goes vegan or he goes paleo or high fat or low carb whatever and he measures his microbiome all along the way and sees the changes and so you really can change your microbiome by what you eat hugely and in fact each meal literally does result in measurable changes acutely because the bacteria that for example if you ate a candy bar bacteria that like simple sugar will you know have a selective advantage and they will for briefly you know start to multiply more now there's a core 90 that it only shifts after very long and chronic changes in your diet but then on top of that there's a a smaller component that actually is quite

dynamically changed by the the meals that we eat on a more acute basis. Well, this has been an extraordinary conversation. I think it really matters to the future of our health and what we're doing as we understand the complexity of biology, the microbiome. You've just given us such amazing things to think about. I'm a little sort of swimming with all the information, but I think if you were in charge for a day, if you were king for

a day and you could make changes in healthcare and medicine, science, what would you focus on to make the most difference for humanity? I would do two things. One is I would try to make healthcare more affordable and available to everybody. And second is I would, eating healthy costs a lot of money and it also costs a lot of time. And so I would try to make it more available to everyone because it's hard. I mean, eating the fruits and the vegetables is both costly and eating healthy takes more preparedness.

You have to plan your meals and not... It's a little bit of investment. Yeah, so if there was a way to increase the availability of both healthy foods and health care, I would try to do that. I think those are doable. Although I guess if you can actually just snap your fingers in a magic wand or whatever and make something happen, you might just say, okay, let's eliminate heart disease.

Questions. How would you do that? Yeah, I think you're on the right track. I think rethinking healthcare and healthcare delivery and access and two is rethinking our food because if we don't do that, we're screwed. And I think you brought up some really important issues. There's a lot of the food we're eating that's, quote, healthy, costs more because the government subsidizes the other stuff, and we don't actually pay the true cost of food. What is the true cost of growing industrial processed food on our health, on the environment, on climate, on the economy, on our social systems?

I mean, that is a real issue. In fact, that's what I'm working on in my next book called Food Fix, saving our health, our economy, our climate, and our communities, because it's all connected. Just like health, the whole system's connected. And I think you're right on that. So thank you, Dr. Hazen, for joining us from Cleveland Clinic. It's been great having you.

You've been listening to Doctors Pharmacy, Conversations That Matter. If you love this conversation, please leave review uh on on wherever you listen to your podcasts and uh share with your friends and family and we'll see you next time on the doctor's pharmacy