The Dr. Hyman Show - Should We All Avoid Gluten? with Dr. Alessio Fasano

Episode Date: September 26, 2018

In this week’s episode, Dr. Fasano discusses the effects of gluten as well as other potential triggers that aggravate the gut. What does it take to heal the gut? How can we prevent leaky gut? Find out more in this episode. Advancing innovation in research, clinical care and education, Alessio Fasano, MD, has dedicated his life to improving the quality of life for people with celiac disease and other gluten-related disorders. He founded the Center for Celiac Research at the University of Maryland School of Medicine in 1996. In 2013, he moved the Center to Massachusetts General Hospital and renamed it the Center for Celiac Research and Treatment. He is chief of the Division of Pediatric Gastroenterology and Nutrition at MassGeneral Hospital for Children and professor of pediatrics at Harvard Medical School.

Welcome to the Doctor's Pharmacy. I'm Dr. Mark Hyman, and that's Doctor's Pharmacy, F-A-R-M-A-C-Y, a place for conversations that matter. And today's guest is an extraordinary scientist and leader in the field of gluten, Dr. Alessio Fasano, who I've known for a number of years and has been a huge contributor to our world of functional medicine, helping us bridge the gap between what we eat, our microbiome, and chronic disease. So he's an extraordinary physician. He's been at the forefront of the field of celiac and gluten research. He's now at Harvard. He's the head of the Division of Pediatric Gastroenterology and Nutrition at Mass General and professor of pediatrics at Harvard

Medical School. And he's basically leading a huge team looking at how do we understand celiac and gluten issues. He's leading a group called the Mucosal Immunology and Biology Research Center, which is over 45 scientists looking at how do we translate the information about what we eat, gluten, our gut, our leaky gut, the microbiome, and chronic disease. It's pretty exciting work and he's written an extraordinary book called Gluten Freedom, which I'd have you all check out. All the proceeds for the book sales go to support celiac research and it's available in seven languages, which is great. So the topics he's doing now are pretty exciting. One of them we're going to talk about, which is this new research study looking at how our genes, our environment,

our microbiome, and our metabolism all interact to create a risk for disease. So welcome, Dr. Fasano. Thank you, Mark, for having me. Now, you're at the forefront of one of the most exciting areas in medicine, which is this connection between what we eat, the microbes in our gut, and chronic disease, particularly autoimmune disease. And I started practicing functional medicine 20 years ago. Nobody even heard of gluten. I was talking about gluten-free diets. They're like, what are you talking about?

People have to eat the worst food. And now it seems like millions of people aspire to be gluten-free. It's like an aspirational diet. I'm gluten-free. It's kind of a badge of honor. And now restaurants have gluten-free menus. And the question is really, there seems to be a lot of noise about it, but where's the signal here? And we've seen a real increase in celiac in the last 50 years.

And we're going to dig into your work a little bit in a minute. But is the world overreacting to this gluten issue? Is it a fad or is there something there? Well, definitely there is something there, but there's also a fad component. No question about that. So it is an interesting journey that i witnessed firsthand as you were saying 20 years ago you know people didn't even know how to spell gluten so much so to find the gluten-free you know this is gluten-free you know menu and again you know the the field really went far in the past 20 years.

Thankfully, I have to say, because it improved the quality of life for people that have to leave gluten-free for medical necessity. And during this journey, also, we learned many lessons. You know, we moved from the concept that the only people that belong on a gluten-free diet are people with celiac disease to the concept that there are people other than celiacs that need to go gluten-free for medical necessity this non celiac gluten sensitivity which you've really helped pioneer the discovery of yeah no celiac gluten sensitivity definitely is the last kid in the block and then with allergy and so on and so forth so really the field expanded and and. And with that, our knowledge what gluten does to us.

Of course, that went more than the medical necessity when people, they started to think that gluten-free is good for everybody because gluten can be toxic for everybody and so on and so forth. So again, I think that there are some elements- So it's more than we thought, but not as much as some people think. Exactly. So that's the noise. So the single is, yeah, there are two major groups. Some people, they need to go gluten-free for medical necessity, either because they have an autoimmune response to gluten, like celiac disease and allergic response, like with allergy, or they have another form of immune response

that we still don't know completely, non-celiac gluten sensitivity. And then the other probably larger group of people that embrace a gluten-free lifestyle that have the freedom to do so, but definitely they don't have the medical necessity like the first group. Well, I've been doing functional medicine for 20 years, and I would say one of the most powerful tools in my toolkit, my tricks in my trick bag, is putting people on a gluten-free diet

if they have any chronic inflammatory disease, even neurologic or psychiatric issues. It's sort of an interesting thing. And sometimes they do have antibodies, sometimes they don't, but it's sort of always a one, two, three on my list for trying something to see if it makes a difference. And it's extraordinary how many people respond positively when they get off gluten.

Yeah, Mark, the major confusion when you go in such a heated debate of believers versus not believers is that, you know, if you don't have the right premise, you clearly fuel a debate that should not be there, to be honest with you. So, you know, believers like you see the light at the end of the tunnel and realize that besides celiac disease, there are other chronic inflammatory conditions that can benefit to go on a gluten-free diet. What is the caveat here? The caveat is the non-believers, they make the assumption that, you know, that is a premise that has to be based on the paradigm of celiac disease, meaning that everybody going gluten-free should feel better because that's the culprit of the autoimmune process celiac disease. What is the misunderstanding here, in my humble opinion,

for both camps, I have to say, is that while the expectation is that 100% of people with celiac disease, they have to respond to the gluten-free diet because we know that this is a fact, there is the misunderstanding that the same applies to all the other chronic inflammatory diseases. My personal opinion, that can be wrong, I haven't been proven wrong as many times,

is that I am in the middle of this kind of two extremes in a sense that I really do believe that there are subgroups of individuals with other chronic inflammatory diseases, including autoimmune diseases, including chronic fatigue, you name it, IBS, that may have gluten as the culprit, but not all. So ideally, and that's what I see this is going to be the future will lie in terms of best case scenario, in terms of best clinical practice, is to identify validated biomarkers

that will identify this subgroup of individuals in these chronic conditions that have gluten as the instigator and place them on a gluten-free diet. So I'll give you an example. A while ago, in collaboration with some colleagues at University of Maryland, we found out there is a subgroup of schizophrenic individuals that react to Goulden. We end up to quantify, but it's still an approximation that probably we're talking about 15, 20%. Yeah, I mean, those people often will have elevated anti-Glyde antibodies. Absolutely.

Right. Yeah, yeah, absolutely. And that's how we identify them. And they have other antibodies that then been validated later on, like the anti-tissue transglutaminase 6, that is typically a biomarker of neuroinflammation. But anyhow, the bottom line that I'm trying to say is, if we have taken the, you know, bold statement

that all schizophrenic individuals will benefit from a gluten-free diet and do a trial in which you take 100 schizophrenics and put all on a gluten-free diet, and only those 20 out of 100 will respond, we'll call this a failure. Right, right, right. Because the efficiency of 20%, efficacy, you say, I told you so, that doesn't work. If on the other hand, you stratify the population, find the subgroup, and this is the heart of functional medicine, I guess, so in a personalized medicine.

And you say, well, those that have biomarkers, the anti-glider antibodies, the TTG6 antibodies, whatever it is, that tells me that there is a chance that they will respond to the gluten-free diet and put only those 20, you have 100% efficacy. Exactly. Now, I don't think that is a trivial thing considering we're talking about a devastating disease that hopefully very often do not respond to canonical intervention and you give the life back to people and you may jeopardize you know that possibility if you know again you don't approach this in the correct way so this is a long way to say I'm not in the camp of the people that are skeptical

that say it has to be only celiac, otherwise gluten-free diet is not a business you should be interested in. But on the other hand, I have to give a word of caution to not vilify treatment that can be extremely powerful and effective by placing everybody on a gluten-free diet and hope for the best. Yeah, I think that's really important. I want to unpack that for a minute because there's a couple of pearls in there. One is that gluten can cause brain inflammation across a spectrum of different conditions

from schizophrenia, autism, also see a large portion, 20% almost, who have antibodies to gluten, depression, anxiety, ADD. I mean, all these have been linked to gluten in the right person. I know one of the things that you published in 2003 was a seminal article in New England Journal, which I found extremely helpful because it mapped out the fact that gluten and celiac disease can be linked to over 50 different diseases. So it can be linked to schizophrenia, but it doesn't mean that all schizophrenia is a gluten problem or that all colitis is a gluten problem. And I think that's the problem we get into medicine is we think these conditions are uniform, but they're not.

There's no such thing as schizophrenia. They're schizophrenia's. And I think this is an important concept that you kind of elucidating with this personalized approach to identifying who's sensitive. And the biomarker issue I think think, is important too, because we typically, in medicine, we're trained that unless you have a positive biopsy of your small intestine that shows you have celiac, then it's not an issue. And I still see this going on. And then there's the antibody studies. And if it's very elevated, I think people will agree that that's a pretty good marker, if it's TTG or any gliding antibodies. But if they're slightly elevated, if it's very elevated, I think people will agree that that's a pretty good marker if it's TTG or anti-glycan antibodies. But if they're slightly elevated, what's normal, what's optimal, is there any normal?

We've had this conversation before, we said, well, if you have any antibodies, it means you have a leaky gut, it means you've been exposed to gluten, and it means your immune system is pissed off. That's right. So how do you sort of navigate that world of this sort of gray zone? If we take, again, the strong position of debate with right versus wrong, and we keep in the radar screen what should be our focus, so what is the best thing that we can do for our patients to improve their quality of life, common sense would suggest to you that this is all known.

For example, if you look at the best drug on the market, the best of all in terms of efficacy, best case scenario, you talk about 45%, 50% efficacy. That means it doesn't work on half the people and works on half the people. And this is the best drug that we have on the market. So we know already that these are non-homogeneous populations. The placebo's are about 30%. That's right. So that's background noise.

So if you honestly keep this in mind, lesson learned are, number one, we're not made all equal. Number two, we conventionally talk about diseases as final destination that can be common. So your Crohn's disease can be similar to my Crohn's disease, but how we got there can be very different. So imagine... The end result looks the same, but the causes are different. Absolutely.

And imagine that you then on that premise that I believe is not disputable because everybody will agree on that. Then you go to the next step and say, and I have a magic bullet that can fix them all. That doesn't compute. So that's what drug development now is approaching the problem in that sense. So if you accept that these are final destination

and you can get there in different way, you also, as a corollary to that statement, have to accept that eventually treatments needs to be diversified. Right. Which is a radical concept. What you're saying is that all diseases in a category are not the same. So everybody with rheumatoid arthritis or colitis or schizophrenia are not the same. And each one needs a different treatment, even though it looks the same at the end of the day. And that's a functional medicine fundamental principle. Mark, again, I don't want to be philosophical or romantic here, but, you know. You're Italian, you're alive.

Well, just because I'm Italian, I have to say that, you know, the old physicians, in other words, the healers of 2,000 years ago, they were focused on individual, trying to put the individual back in balance by different approach, philosophical, religious, a little bit of science. And then we start to really be programmatic and systematic and then look at conditions as diseases. So we shift the focus from the individual to the disease. And conventionally, we went to that path to try to be evidence-based, to find the target,

to find the solution, and so on and so forth. Recently, and not just functional medicine, that probably sealed this before then, evidence-based medicine. But even the classical trained physician like me start to really appreciate that we should shift back to the individual because that's the way that eventually you can have the best efficacy possible. Well, that's what William Ulster said, right? The father of my retina. Exactly. We should treat the person who has the disease,

not the disease that the person has. Absolutely. And if you got in that kind of premise, the debate is over. You know, there is no discussion that, you know, sure, we have to have conventional, you know, approaches. We have to be systematic. We have to be evidence-based. But we also need to accept with humility and an humble approach that the magic bullet is not there. So there is the lesson to be learned here that, again, there is a possibility of a subgroup of individual

in any given category of chronic inflammation that can be treated with a gluten-free diet because maybe there is this possibility. Our challenge now is to find these people, how to identify those people yeah and you know talking about you know gluten in the brain as you were alluding to we knew this for a long time and this is also not debatable even the people the most skeptical people will know because they do know that serial disease is, so the ones that everybody accepted, with neurological symptoms

and behavioral symptoms that underpin the possibility of neuroinflammation. We know that you can have anxiety, depression, mood swings, chronic headache, because neuroinflammation. And to the point that I was telling you, there are markers in your inflammation. The most classical example is gluten ataxia. Nobody would dispute the existence of this entity. That means you can't walk and you're out of balance. There is inflammation of the cerebellum and your equilibrium is affected because of that. By the same token, nobody would dispute that celiac disease can give peripheral neuropathy. So inflammation of the peripheral nervous system.

And again, by the same token, I think that if now you go back and say, what about people with depression but not celiac disease, or anxiety without any celiac disease, or peripheral neuropathy and not celiac disease? Is it such a possibility? Because now, again, everybody seems to accept that you can have probably gluten outside celiac disease yeah by transition you need to accept the possibility that your inflammation central peripheric can affect people other than individual celiac disease so i don't see you know too much of a dichotomy here no but there's there's an interesting distinction here with the non-celiac gluten sensitivity. There's a mechanism he wrote about, which is our ancient immune system called

the innate immune system that can react to gluten. And there's no antibody measurement to there. It just measures just general inflammation. It's sort of a very primitive sense part of your immune system. And then there's the antibody part of your immune system or the adaptive part. And that is where we get celiac antibodies. But the question is, is there a way to measure this non-celiac gluten sensitivity, just looking at ranges of antibodies that aren't, quote, abnormal? Let's say your range is up to 20. What if it's 15 or 16 or 10? Is that a significant factor to look at? Mark, my honest answer is I don't know. And the reason why is because, again, we're still learning the pathogenesis and on celiac gluten

sensitivity. I really am convinced because the cumulative evidence in the literature that we're dealing with an immune response that involves only the innate immune system. As you said, this is the ancestral way that we develop to fight enemies. It's when we deploy our army without thinking who I'm fighting because I need to fight right away. So I can't think about who are you, customize weapons against you,

or antibodies, since I just need to deploy and get rid of you. It's like carpet bombing instead of smart bombing. Exactly. And again, in that sense, you will not find biomarkers, low titer or high titer, that will link this inflammatory process to the disease. As a matter of fact, there are several groups, including ours, that are looking for biomarkers for non-celiac gluten sensitivity.

My sense is there is going to be a multitude. You were alluding to the first generation anti-glide antibodies. They are positive in 50% of people with non-celiac gluten sensitivity, but that's not a biomarker of reaction to gluten as we typically intend for celiac disease where you have autoantibodies.

This is after the fact. So the innate immune response has been activated. You're fighting. You have the inflammation. And now what you see is a biomarker of the consequence of this war, i.e., as you were saying, the individual is eating, the intestine got leaked, gluten fragments comes in, and immune system does its job. It's under attack and something you know, something that is not supposed to be there and build any bodies against it. So I think that's going to be a combination of several biomarkers. It has to do with many of the functions that will

lead to, you know, the inflammatory process. Yeah. All right. So I want to walk back historically a little bit because, you know, hundreds of years ago we were eating gluten, we were eating wheat and we didn't see the levels of autoimmunity, we didn't see the levels of celiac disease that we do now. And you're here at the Annual Conference of Emotional Medicine, you gave a brilliant talk looking at how we kind of got here, what are the factors that changed that actually are driving this level of gluten reaction. And, you know, my wife now is in Sardinia. I wish I was there with her. And she has trouble eating pasta in America because she always gets a stomachache. But she said she's in Italy now and she doesn't. I know they don't allow GMOs in Italy, although wheat is

not GMO, although they spray our wheat here with glyphosate at harvest, which may have an effect on the microbiome. But how do you sort of explain why we all of a sudden got this way? What are the changes that happen that make people more susceptible? Because the gluten has always been there. Is the gluten different in the wheat we have? Is something else changed in our guts and environment? Like what is this driving force? You know, again, you know, first of all, some people believe that this was just an increased awareness, but we know that it's real. And now there are plenty of evidence that these gluten-related disorders are on the

rise. And it's not an isolated phenomenon. Every chronic inflammatory diseases are on the rise. Allergic disease, autoimmune disease, neurodegenerative disease like Alzheimer's. Everybody's inflamed. That's right. Even cancer, heart disease, autoimmune disease, neurodegenerative disease like Alzheimer's. Everybody's inflamed. That's right. Even cancer, heart disease, obesity, diabetes are all inflammatory. And again, epidemiologists will put their hand on the fire and say, we believe that that's the case.

And the evidence is pretty strong. So, you know, this is to say we're not really looking at a weird, isolated phenomenon that relates to gluten. It's more in the context of these epidemics of chronic inflammatory diseases. So why there is these epidemics? What's going on here? First of all, the timeline that this epidemic is materializing is telling us that it's not genetic mutation in humankind that makes us more susceptible because that takes much much longer it takes generation it's not 30 40 years as we've seen in terms of timeline so most likely we're changing the environment way too fast

for us to adapt and the example you were you know mentioning about your wife, and actually I hear this many times. You hear it a lot, right? I hear this all the time with my patients. The patients say, how come did I go to Europe and it looks that I can tolerate stuff that I cannot even look at when I'm in the United States. Definitely I don't think the GMOs is an issue because, you know, of course, Europe in general

have very strict regulation. GMOs are much stricter than us. When you talk about grains like wheat, there is no such a thing. There is no such a thing. But, you know, there are different ways that you can explain why the load of toxic, you know, peptides may be higher here than in Europe. Meaning because of the dwarf wheat we use here, they use a different strain of wheat? No, no, no, not even that,

because the cultivars are the same. But, you know, the way that we manipulate grains can be different. I'll give you an example that can be one of the many that I can give you. To make bread, you take yeast, you take water, you take the flour, and you make your dough.

We, as human beings, we do not have enzymes to completely dismantle gluten in its basic elements amino acids. What we do is a partial digestion, and what is left over is these indigestible fragments that can instigate inflammation. We know that. Most of us can handle that, no big deal unless you go to the extreme so if you eat a slice or two pizzas it's fine but if you eat three pizzas you will be sick no matter who you are and this applies to anything in life of course even turkey that is good for you if you

eat too much you fell asleep and you know why so this process of panification, so when you make the bread and dough, you use yeast. Yeast has those enzymes that can completely dismantle these toxic elements. In Europe, bread is still made the old-fashioned. This is an overnight process. So you have 10, 12 hours that these enzymes can dismantle the load of this you know fragments not here the process takes two hours because now it's accelerated artificially yeah so you give only two hours to these enzymes to decrease the load so the grain is the same the culture is the same uh same story no but but again the way that you prepare pasta is there are processes that you have to go through, the essiccations, the drying of the pasta and so on and so forth. And again, give less time if you speed up the process to make this right. That's one.

The other is, you know, as you were alluding to pesticides, we use pesticides here that are not allowed in Europe. And again, that changed completely the landscape because now you introduce another variable that can affect the way that we, in terms of our immune system, can react to any given product. And it happened to be grain, but it can be any other product that can give you the same kind of reaction. So, and, you know, I can go on with many other elements, you know, the water, the way that it's treated.

So that may explain. You know, the environment, the pollution in the air. I mean, there is so much. And then, of course, the great unknowns that we still don't understand. Because even here in the United States, it's not homogeneous. No. So you have pockets of places in which this phenomenon seems to be much stronger than other pockets of the place. So there's got to be some environmental situation that we still poorly control.

Yeah, so sort of going back to that, the environmental factors have changed. And I think in your lecture, you mentioned a lot of changes that have happened that altered a different thing besides the food. So there's the quality of the food, how we produce the food, all those things in terms of traditional methods that may affect people's sensitivity. But you also talk about the changes in the gut microbiome. And, you know, you originally came into this through your study on cholera. And now you're sort of coming back to it, looking at, wait a minute, why are people so sensitive? It's not, oh, you're sensitive to gluten, let's get you off gluten. It's like, why is this happening? And how is our change in our environment, toxins, stress, diet, antibiotics, C-sections, how has that led to this increase

in autoimmunity, increase in celiac disease and allergic and inflammatory disorders? So if you really want to look systematically, the environmental factors that eventually are fueling this, you know, epidemics, now that, you know, again, we agree that this is where we have to focus our attention and not the human beings, genetically speaking, because again, we didn't mutate in such a short period of time. You start to really question what happened in the past 50, 60 years. It was different from the previous generation where we didn't even have these epidemics.

And, of course, you alluded to some of the factors. So, you know, our lifestyle. You know, mostly we're living a rural lifestyle, you know, one or two generations ago. So living, you know you know vicinity of animals um or expose a lot more microbes that's right a variety of but you name it parasites viruses you know but bacteria but there was a full exchange and then again we make again this other convention that we are isolated xylos in terms of environment. We are in a continuous, secular life.

So soil, animal, human, back to soil. And the waters, you know, we conventionally analyze them separately, but we are a unified ecosystem. Yes. And, you know, again, if you believe that, and you look just at the human beings and make the statement, we didn't change that much. True, but what about our soil?

What about our water? What about our animals? What about living in a crowded environment versus a sparse environment? How this changed the dynamic of what's going on. And again, now that we have tools that we didn't have before, we can understand this continuous ecosystem, what we exchange. So the most important thing that we change are microbes. And microbes are an integral part of what we are. And now we know that, again-

We're only 1% human, right? Most of us- Yeah. I mean, again, genetically speaking, that's definitely the case. And we are whatever we are because we co-evolve with microbes. It's not that we- It's not just waste, right? That's right.

From Mars and then all of a sudden we've been exposed to something we've never seen before. We look and act know are shaped the way that we are because we co-evolve with this ecosystem now again that's you know when when when we ask ourselves what kind of changes we made the the stuff that's visible so the air is polluted now there is fog or the water looks dirty, it's the low-hanging fruit, but probably not the driving force. It's this parallel universe that is instrumental for our health that changed dramatically. The microbiome.

The microbiome. So, in other words, this community that is supposed to come in orderly since we are in the wound and stay with us until we die, that has been completely revolutionized in its composition and function. That, you know, I'm mesmerized how come that we are not making even more dramatic changes that we're seeing. So that means that there is some terms of adaptability. But I can't emphasize enough that changing lifestyle from rural to urban, introducing antibiotics for treatment of infectious diseases, introducing new practice like the C-section. Yeah, which is almost one-third of all births now, right?

Well, it depends. Because I just was in mexico for a meeting and i learned an emergency section is 60 of the population 60 92 in brazil so it's staggering 92 absolutely and again i would welcome with c-section option check up abc you know, Mark, the reality of the story is, again, you know, a lot of hundreds of thousands of women died because of, you know, exactly. So C-section has been a tremendously important plan vacations or cash more money in, or the woman decides to go C-section for her own needs but not because of medical necessity, I will suggest to think and think very carefully because, again, the plan of engrafting and growing the proper, friendly microbiome has been planned for two million years to be done through vaginal delivery.

Yeah. Because the baby absorbs through its mouth all the vaginal flora, which colonizes its gut. Absolutely. And that is a flora that has been highly selected by mom to be genetically compatible with her and therefore with her baby. The skin microbiome is not selected. They are all comers.

So the operator in the operating room or the nurse or the anesthesiologist, their microbiome come in there and may not be that friendly for the new baby there. And that's why you see more allergic diseases asthma absolutely because no matter no matter if you talk about prenatal factors mom's lifestyle mom's environment or perinatal like the c-section or antibiotic exposure or the way that you feed the baby, breastfeeding, feeding, or bottle-feeding, or postnatal. All these things binge on the composition and function of the microbiome. Why I'm so obsessed with this?

First because as you said, that's where I start. My science from the very beginning was totally focused on understanding how microbes, they cross-talk with us. At the beginning, my focus was on a single pathogen to understand how they can make us sick. And then that knowledge moved to the community and now the ecosystem that now we call microbiome. But again, we were studying this 20 years ago with tools that were ridiculous compared to the ones that we have right now that now clarify the complexity of the matter

yeah and we're just really at the infancy of this discovery most definitely but again it's giving us the opportunity even more to appreciate how singularly we are how different we are from each other, how eventually, you know, losing tolerance to develop an inflammatory process can be so different from one individual to another, even if, again, we end up with the same disease. You know, it's interesting. I treat a lot of patients with gluten issues and celiac disease. And often I find they don't get completely better when you remove the gluten. And then when I put them on a gut restoration program,

really getting rid of the bad bugs and putting in good bugs, just simple functional medicine principles, which are not really that well-established scientifically, but we've been using for decades to just help normalize gut function, then they get better. Have you seen that? So we and others have published that even if you're strictly gluten-free, 20% of kids and up to 40% of adults, they still have inflamed gut. Not because they cheat, but because, again, there is no repair.

I don't know why. Most of the time it's because inadvertent exposure to cross-contamination. Other times, because again, there are situations in which the immune system is hyperbelligerent. So if I have to say, you know, clearly I understand what's going on, the answer is no. But again, I would be dismissive if I would not consider this hyperbelligerent in this individual that are not able to repair the inflammatory process to be totally unrelated to microbiome composition function. Well, it's also interesting, you know, the way I think about it is that the sort of the gluten is sort of the gatekeeper. It sort of opens the gate and creates this leaky gut. And then all these other food antigens can leak in and start to

aggravate the immune system so the body begins to start to react to other things and i've seen this over and over over the decades is this something you're noticing yeah i mean again i i'm quoted all the time about this because you know our group was the one that discovered the molecular mechanism by which gluten can really make your intestine leak through the release of zonulin, this molecule that has been now linked to a variety of chronic inflammation. You should get the Nobel Prize for discovery. I know, but people are still very skeptical. But anyhow, the bottom line is that you put two together and say, well, if gluten is capable through some of these indigestible

peptides to engage in a specific receptor that instigates the cells to release zonulin and make the intestine leak, then this can be detrimental and harmful to everybody. The answer is it depends. Actually, the vast majority of people would not have consequences if you have a balanced diet and can even be useful to help what we call antigen sampling to bring very small amount of antigen so that immune system will be more robust trained in case that the storm will come, the real deal will come. The problem arises when you exceed the amount of gluten, for example, so that this continues all the time. Or even if you have,

you know, not a huge amount of gluten that you eat, you are genetically predisposed that when you increase the gut permeability on the other side of the fence, you find an immune system that is ready to fight against gluten. And these are the people that have gluten-related disorders. So all this to say, I would not categorize gluten as the villain of the 21st century necessarily. After all, if you and I were here, rather than jump from one tree to another, we have to thank agriculture that predicted the amount of food that gluten can be an issue for, you know, a variety of individuals outside celiac disease, that will be also to not see what is becoming more and more obvious. Yeah, it's pretty extraordinary to see how this whole field is opening up. And, you know, one of the things we often were made fun of for decades is this idea of a leaky gut. That basically the belief was that if you had a leaky gut, you'd have sepsis and you'd die, basically, which means you'd have overwhelming infection.

But this sort of intermediate zone of sort of slightly leaky gut leading to inflammatory diseases is seemingly connected to everything from obesity and type 2 diabetes to heart disease to autoimmune diseases, neurologic diseases, autism. I mean, it's sort of like almost this unifying theory of how we get inflammation. So I'm fascinated how historical memory is lost during generations. For example, you know... Amnesia.

Yeah, I've called that amnesia, whatever. But, you know, at the beginning of the 90s, we were convinced that celiac disease was a big deal in the United States. The establishment really came after us big time and said, you know, you really missed the boat here. We looked for celiac disease and we didn't find it. So, you know, you are not, you know, in the right direction. And this is to put that very mildly

because the criticisms were much more harsh than that. And again, and their premise was on a state of mind that was fixed on what was at that time the definition of serial disease. Young kids with a big belly, diarrhea. And that's true. We don't see that. We don't see that.

We see other stuff. And you don't have to have any digestive systems. Well, zero. And that's true. We don't see that. We don't see that. We see other stuff. And you don't have to have any digestive systems. Zero. You can be obese. But that was not clear at that time. And that's the reason why we were highly criticized. Now in 2018, if you ask anybody, nobody will question that celiac disease is as frequent in the United States than in Europe. But if you ask, has it been always like this? The answer, most likely, is yeah, of course. We always thought so. Even the ones that were hypercritical.

Same phenomenon with this leaky gut story. You know, again, it's not that I was like a functional medicine doctor always tuning in this i came to this by you know chance by again doing this cholera vaccine and learning the cholera can make your life got leak and then try to understand how that does and see that there is a very sophisticated machinery to loosen up the to increase the impermeability of tight junction in the intestine. And then- Because of the little connections that-

Yeah, these are the little gates in between cells that we thought that were cemented so that no things can come through. And then we learned- Everything goes through the cells, not between the cells. That's right. Everything that we negotiate with environment, we thought that has to come through the cell.

And then we learned, no, actually, there is a space in between cells that can be modulated in its permeability and you know when we studied the mechanism of this toxin and we saw this very complicated machinery the reasoning that i made there i said it can't be that we evolved to this machinery they are just to get sick with this toxin from vibrio choleraibrio probably learned physiology from us and exploited that possibility for its own return. Yeah. And that's how we end up to, you know, this choroid zonulin.

And I have to say, you know, with the story of the leaky gut are now half away compared to the story of celiac disease is over, it goes to the discussion over. I say half away because even the establishment now of evidence-based medicine, the hypercritical to our work that has been coming right here,

the general vein, when we discovered Zonuli. You're on the right track when you're... Well, you know, again, Mark, again, I am an individual that, not only I'm open-minded, but I am an individual that not only I'm open-minded, but I am the individual that, you know, I admit that, you know, science is a constellation of failures with very few successes.

And you live for those. But I also admit that science is not a perfect, you know, path. Most of the time you're wrong. And there is nothing worse as a scientist to not admit when you're wrong. What you do is... They're going to attach their ideology. That's right. Because what is true today, it will be garbage in three years.

We know that. It's that dynamic. So as a good scientist, you formulate a hypothesis. You design an experiment to challenge the hypothesis, and you perform the experiments. And then you evaluate the outcome. The nine out of ten times is different to what you anticipated with your formulated hypothesis.

This brings to two kinds of science. The incremental science. I want to go from point A to B to C to D to get to my final destination. I know where I am. I see my sights where I'm going. That's the one in which your peers will follow you, will understand what you're doing, and eventually will accept the approach that you're taking

because everything is clear. Sometimes you want to go from point A to point B and you end up to point Z. So in a place where nobody's been before. Most of the time it's dead end. So it's something that leads to nothing. Very few times you got in what we call transformational science. It is not something that you

intend, but you end up to be in something that changed completely the paradigm of way of thinking. The unintended consequences of your... And that's what the song and the story was all about. When you got there, to understand if you're in a dead hand or you do something, transformation,

the only thing that you need to do is to sit and see if your peers can validate and reproduce what you've done or this was not reproducible. The zoning story now is highly reproduced. As a matter of fact, I don't, you know, alter the vast majority of what is the science and zoning nowadays. We contribute a minuscule component of the hundreds of papers that are out there.

All this to say that not only the zoning story, but the story of the modulation of gut permeability with the identification of genes that can modulate the junctions, the identification that lost a barrier function is the core of many chronic inflammatory diseases. People are coming around. It is so powerful, yet it's a sort of a discipline. Medicine is not really thought about how do we then address that? How do we fix a leaky gut? How do we normalize the function in there? What do we do to fix that problem? Well, we can't because we don't know yet, you know, why the mechanism that leads to that. Because this is a very complex machinery with very sophisticated functions.

And I was mentioned during the lecture that the structure of these tie junctions is extremely redundant. That means it's a function that's dear to us. Because where the redundancy means that you have backups. You have a lot of backup systems to make sure you don't get a leak. In case something goes wrong. I can tell you with great level of confidence that the two key elements that makes your intestine leak is one, gluten, as we said, because it's really zone through this mechanism, and an unbalanced microbiome, what we call dysbiosis.

That can be either because the function and the composition is unbalanced or because the microbiome is established in the place where it's not supposed to be. Small intestine bacterial growth, SIBO, is one of the most powerful ways to release insulin and make the intestine big. We see this all the time. I call it the food baby. They get bloating after eating and extended. And that often means that there's bacteria in there producing gas.

That's right. So I think that, you know, it's going to take another few years for people to accept completely this idea of the importance of the intestine barrier in a variety of chronic inflammatory diseases. So the hard soul of immunologists, traditional immunologists will never come around this. They will never come around to the idea that autoimmune diseases can be treated as I believe that they can because if you stop this- By fixing the gut. Of course. Which is how we do it in functional medicine, without even knowing what we're doing.

These conditions, including autoimmune disease, are based on five pillars. The genetics, so who you are, your environment, including what you eat, an increased gut permeability, an immune system that becomes hyperbelligerent, and a microbiome that is not doing what it's supposed to because epigenetically will make your genes to be either expressed or repressed

so that you switch from genetic predisposition to kidney cartilagy. And when I say chronic inflammation, I mean anything. Yeah. You know, cardiological issues. Even arthritis. Microbiome. Anything. Anything.

Which I think is fascinating. So any of these five pillars are fair targets to try to ameliorate inflammation. Again, genetic editing, I don't think that's a possibility because the complex is way too much. There are too many genes involved. I don't think that's going to happen. Modulate the environment. That's something that we should really focus on. So we have to deal with all those pillars.

Absolutely. And then in medicine, we just try to find the one drug to fix the one thing. No, no. It's not going to work that way. So if you will continue to have an environment that is really conducive of inflammation, food, pollution, chemicals, you can fix whatever you want in terms of immunosuppressors or change the microbiome. Everything will go back where it's supposed to be.

But if you start to think more, I would not say holistic, but comprehensive, let's start with lifestyle. What really is a common sense? Of course, we can't go back and live in a cave. That's not feasible. But can we avoid some know, avoid some chemicals that can instigate inflammation? Can we eventually, you know, decide to feed our kids food

and not the junk that we feed so that eventually they have the same chance that we had? Can we promote local production of produce rather than massive production that, of course, comes with the price? That's, you know… It's changing our agricultural system, our food processing and production system. It's all of that. And again, you know, this is an uphill battle because you go against major interests, of course.

But if you do that, then you can tackle how can I fix a leaky gut? What is the problem? Is the dysbiosis? Can I then use prebiotics, postbiotics, probiotics, symbiotics, whatever it is? Fecal transplant. Whatever it is. And then, you know, that got also to the point of dysbiosis. Because, again, these factors, they all interacted.

Well, you said something very powerful in your talk, which is that the single biggest thing we can do to change our microbiome is change the food we eat and the quality of the food we eat and get off the processed food and eat more plant-rich foods and good quality foods, right? Yeah, if you think about these five pillars that I just told you, they highly interact. So if you affect foods, you affect the composition microbiome. If you put the microbiome back in balance where it's supposed to be based on our evolutionary plans,

the immune system will defend us rather than be belligerent against us and will unleash inflammation only when it's definitely needed. If you have a balanced microbiome, you also will have a gut permeability that will go back to the way they're supposed to be. And a good gut permeability will make the immune system to be less belligerent. So it's all interconnected. It's all connected. So you said something to me about a year and a half ago that has just resonated in my head, and I don't know if I got it right, which is that in your work, you discovered that

anybody eating gluten has some change in their permeability, even if they have no symptoms. And to me, in my simple-mindedness, that means that anybody eating gluten is going to generate some level of chronic inflammation. Did I get that right or wrong? No, I don't think so. Again, as I was telling you, actually, the vast majority of people that will have this increased permeability followed by, again, a very tightly controlled inflammation that is good for us.

I mean, you know, I'm a gastroenterologist, and if you do— So a little bit of a poison is good because it helps you. Absolutely. But if you look at the gut of anybody— Yeah. So I've been in this business a long time. I've never seen, in a biopsy of a human being, a gut with no inflammation. He saw inflammation there all the time.

And, you know, what we define inflammation in the terms of a critical mass of immune cells, they are really there, ready to fight. So it's not colitis, it's just a low-grade... No, absolutely. It's a low-grade... It's like you've got your military and they're ready in the front lines. It's like that you have athletes that are training for the Olympics. They don't train just the day before to the Olympics. They train for the four years before the Olympics.

So that when is the time, they're really in the best shape possible. So the gut is in the entire gut and not just the colon is in a chronic state of tidally controlled, healthy, low inflammation that is local, goes nowhere, but it creates that condition in which you have a baseline situation that is ready for the fight. Like a training camp. That's right. It's a training camp. Exactly.

The problem arises when this inflammation goes to the next level and spill out the gut and go somewhere else. That's where it's the problem. And that is when that tightly controlled gut permeability, because again, if you have a gate, this will be open and closed all the time. Gluten is one of the many reasons why we can open and close this gate. It's useful for us to do that. If it was not useful, mother nature would have put a wall and not a gate. So the fact that gluten increased

permeability to everybody, it doesn't mean that everybody will be in trouble. There is a subgroup of individuals definitely got in trouble and other that would not. That's the reason why I would not demonize gluten necessarily, but at the same token, I would not dismiss the possibility that outside celiac disease, as we've been saying for almost the entire podcast here, there is the possibility that there are people that don't have celiac disease and they got in trouble because of gluten that increased the, you know, upregulated, you know, um, upregulates the zoning pathway, creates a shortcut for other junk to come through,

and creates a syndicate. That's right. So one of the things I read, I don't know if it's true, is that in the effort to increase food production, we hybridize and bread wheat to contain more starch and to be shorter and drought resistant and grow better and produce more carbohydrates, which is a dwarf wheat. And in the process, we combined the genes of different wheat strains, which led to more gliadin proteins in the dwarf wheat. And that

those gliadin proteins seem to be more of the ones that trigger inflammation. Is that part of why we've seen this increase? I'm not an agronomer, so I speak secondhand for what I learned. Mainly, there was a meeting that the National Academy of Science actually convened in Washington, D.C. a couple of years ago to which I was invited. So I had the opportunity to hear the agronomers. There's been such a change, no question about that. So Romans and Greeks, they used to eat, you know, a very tall, you know, very different wheat wheat.

Um, um, you know, we eat is not the wheat we ate. No, no, absolutely. But you know, was it told plant, um, you know, only 5% of the top had seeds. Um, 4% of the dry weight was gluten at that time. And then later on during the Renaissance, we increased the heel to make more producible and useful wheat by doubling the amount of gluten in there. So from 4% to 8%. And then the last reiteration was during the agricultural revolution that we had this dwarf wheat. So one third of the plant now is seeds.

So the efficiency is much higher. And now we're talking about 12% rather than 4% as we started a thousand years ago. The epidemics that we have seen materialize after this event. So I don't think that is the cultivars that have been pretty much fueled by farmers to heal. That's what is fueling the epidemics. I really do believe that it's more the way that we handle the products. And what your wife is experiencing in

Sardinia, it's testimonial that it's not that the genetics and the, the load of wheat, um, a load of gluten in wheat is the culprit. So it's not like they grow more ancient strains there. No, no. Or well, you know, of course there's gonna be less gluten in there and ancient grains can be beneficial. For example, where people would not see the gluten sensitivity like corn wheat that's right you know to decrease the the load

of gluten would not be beneficial for celiacs because no matter if it's four percent or twelve percent it's it's it's way too much yeah yeah fascinating so one of the things i think people who are listening were wonder about is is when do you introduce gluten? Because there are a lot of women who have children and we're fearful that if we introduce too early, it'll cause a problem. If we introduce too late, it might cause a problem. What's the Goldilocks rule here? And should we be avoiding wheat in kids completely? You know, we ask this question, you know, when we're trying to understand what is fueling these epidemics

and a matter of fact we did this by first of all doing a what is called a retrospective cochlear analysis so looking at all the studies in the literature and trying to find out you know is there any hint there and the hint where maybe you know the breastfeeding practice are decreasing is the culprit or the C-section is the problem or the introduction of gluten at a large amount too early in life. And that was the premise that seems to suggest these are the kind of reaction that we have to look at. It was out of the question and it still applies that if you introduce gluten way too early before the three months of life, you

increase the chance. No question about that. No cream of wheat for your baby. That's right. But what was not clear for these retrospective studies is if we follow the current recommendation in the American Academy of Pediatrics, so between four to six months, are we really increase the chance of having probably celiac disease? What about if we postpone, let's say a year of OH?

So we allow the immune system to mature and be able to handle this better. And we did such a study. We've prospective full of 700 neonates at risk for a Citi disease because some of the family had Citi disease for 10 years. So it was a long excruciating journey that we took. That was published a couple of years ago in New England Journal of Medicine. The lesson that we learned was, you know, a very hard one, I have to say. Nothing pin out to be right based on the retrospective studies.

I mean, you couldn't find a pattern that connected it. So if you delay 12 months of age, you delay the onset of disease, but the final destination, so the frequency was the same. The incidence was exactly the same. Now, you can argue that delaying the onset of disease allows very important organ like the brain to develop better and be protected against this heat of inflammation. But it's not a preventive approach. C-section of vaginal delivery makes no difference. Breastfeeding or bottle feeding makes no difference.

Am I saying that these are not important factors? Absolutely not. But it's teaching me another much important lesson. You know, again, as we have to deal with, you know, patients and not diseases, you cannot deal with individual factors, not them as a whole. You have to look at the entire situation. And presentation dr leonard of some of the data of the next generation studies this cd disease gem study and you know that is the ones that we are doing to try to find out why some people are risked with cd disease keep straight yeah and stay healthy

and some take the wrong turn yeah It's teaching us that lesson. It's the combination of the above. It's not the single one. It can be C-section and bottle fitting, or it can be antibiotics treatment and exposure to whatever environment factors. But again, all this to say that the single element

and change the single practice by, say, postponing is not going to work of other interventions that should be as important. Amazing. So, Dr. Fasano, you were appointed king for a day and you could change anything in healthcare, science, medicine, food. What would you do to make the world a better place? Well, I would take the Manhattan approach. When we were... The Manhattan approach.

When we were, you know... The Manhattan Project. That's right. So when we were during World War II, at the critical moment, you know, of the war, you know... The Germans were building a nuclear bomb. The Germans were at the verge of the nuclear bomb. And they, you know, the leadership of the allies realized that this would have been the tilting point. So they established the Manhattan Project and said, take the best of the best.

Lock in the room. Tell them what is the problem. And don't let them out until they come up with a solution. I think that we need a Manhattan Project here. So President Obama did something like this. let them out until they come up with a solution. Figure it out, yeah. I didn't need that. We need a Manhattan Project here. So President Obama did something like this, called 100 people in Washington, D.C. just before wrapping up his presidency. Obama.

Yep. Scientists, you know, leaders in industry, nonprofit organization like, you know, the Gates Foundation, the Robert Wood Johnson Foundation, major thinkers, government officials from the Food and Drug Administration, USDA, the NIH. And he locked us in this building and say, we invest a huge amount of money, taxpayers' money, to do the human genome project, not the human microbiome project, but the healthcare is broken.

We need a solution here. You need to tell us how we can capitalize all the investments so that we can really improve the quality of people. What is needed? And again, if you continue to approach healthcare as a business, so that lobbyists go to Washington D.C. and push one direction or another, and not as a social service, we will never solve the problem. So no king can be able to fix anything here, because it takes a village. You can just convene.

In my book, the civilization of a country is measured by two metrics, the way that you educate your population and the way that you take care of it, healthy-wise. And we do a miserable job here. So I'm afraid so. So I take out the education piece because it's not my expertise, but in terms of healthcare, it would take a Manhattan Project. I love that idea. Convene the best minds in the world to solve the problem of healthcare and food and the food system and change the way we do things. I love that. Absolutely. Because, again, if you will be from another planet,

if you'll be a Martian and you have a Zoom and you'll slide down here, you will be very puzzled. So because you will see on the left, you know, the industrialized countries, they spent, you know... 20% of their GDP. No, well, they spent $40 billion to eat more than they are supposed to. Another $20 billion to advertise to eat more.

Yes. Another $60 billion to lose weight going to the gym or the slim fast or whatever it is. Yeah, it's a pretty screwed up system. And on the other side, the right-hand side, you have people that die of starvation, and still they do. And he said it would take a fraction of what you're spending there. That, by the way, I didn't compute the cost of treating, you know, obesity type 2 diabetes, arteriosclerosis, heart attack, neurodegeneration, and so on and so forth.

Take a fraction of that price, put over there, and everybody will be much better off. And Manhattan Project should look at the global aspect of the story. That's actually great. I mean, actually, I'm trying to convene a commission to do just that, to look at our entire health and food system and how we got here and how we get out of it and bring all the key stakeholders together. Because without that, I don't know how we're going to work on this. And it's true, we got to get the money and the egos out of the system and figure out how to solve this for humanity. Well, that is a beautiful goal. Thank you, Dr. Fasano. And thank you for being on The Doctor's Pharmacy, a place for conversations that matter. If you like this podcast, please subscribe to it and

leave a comment and share with your friends on Facebook and Twitter. And we'll see you next time on The Doctor's Pharmacy. Thank you.