Reduce Autoimmunity, with Dr. Alessio Fasano

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Welcome to the five Journeys podcast. Live like youe Matter. I am beyond psyched for our guest today because it is Dr. Alessio Fasano. Before I introduce him, I will say I haven't ever told him this, but I have been a groupie for at least 10 years because I was doing research on something for a talk and stumbled on his paper on Zonulins. I read it and this is like 2010. And I said to my husband, this dude's going to get the Nobel Prize for this research. I'm telling you now. This is our guest today. He is the director of the center for Celiac Research and Treatment at Mass General Hospital for Children in Boston, Massachusetts. He's the author of Gluten Freedom, a book for general readers about celiac disease and gluten related disorders, and co author with Susie Flaherty of Gut Feelings, the Microbiome and Our health, published in March 2021 by MIT Press. Welcome, Dr. Fasano.

Thank you, Wendy.

Very welcome.

It's great to have you.

And I can verify Wendy is a true groupie. If we weren't married, I'd be a little worried.

Yeah. He's like, oh, you're going to go see your boyfriend? I'm like, yes.

He's talking.

He's talking. Not to put you on the spot. So I want to talk about Zonulins because literally when I read that paper, I was like, this is the root cause of autoimmune disease. This is why you get brain fog. This is why people get so sick. It's just fascinating.

So I think we need to talk about what zonulins are before we go much further because.

So they are a family of proteins that they have the capability to open this very complex structures between one cell and another. We have this structure everywhere that, you know, in other words, we have this on our skin for skin cells. But you Know the interface with the environment, like the gut is covered by single layer cells and they are not cement with each other as we believed before, but they have this connection and this very dynamic structure and that you may consider as a sort of gates. They are always, almost always closed. Sometimes we open when we need to. Zolin is the key to open these gates. It's supposed to open the gates and close that immediately after whatever you need to do is done. When it's stuck open for a long time. And this may happen because you're genetically predisposed to produce more zonalin or to maintain that too high in terms of the system that, that is that you lose control of this trafficking. And now you open the flood and stuff comes in. And what comes downstream depends who you are genetically speaking.

I mean, when I, when I was deciphering this. So let me, let me tell you my ex. My interpretation and you tell me if I got it right and correct me if I didn't. Okay, so you have zonulins. And if you are someone who, let's take hypothetically speaking, celiac disease or you.

Are genetically nobody in this room, though.

Maybe someone were in the talk. And you then have more receptors called CXCR3 because you're genetically predisposed. And when you eat gluten, you upregulate the receptors that upregulates the zonulins, you open your tight junctions and here you are exposing the external world to, to your internal world, like my internal thoughts that really should stay internal and not external. You're exposing the whole body to all of this because you're genetically predisposed to upregulate opening the tight junctions. Did I get that right?

You did. I tried to make this much simpler than you did, but yeah, I mean, you know, of course every single time that you have pathways that regulate any function, in this case permeability of the gut or the blood brain barrier or, or the kidney, you have to have a molecule that instigate the pathway and you have to have on the receiving end a receptor. So the receptor that you know the stimuli from the environment and gluten is one of them, but also bacterial component, viral component, will instigate the released zone is this Cxcr3 receptor. So in other words, if you have something that instigate the release of zonulin, there can be many things. But let's say gluten, gluten fragment bind to this receptor and this binding will instigate the release of zoning. And the release of zoning will then eventually start the chain of events that leads to the opening of these gates. Very complex.

I'm going to interrupt and I apologize. I need a dummy down version of why do we care?

Well, this is again a very good question. We care because there was an unexplicable, you know, epidemiological observation considering, you know, chronic inflammatory disease in general, particularly autoimmune disease, that now we can explain based on these findings. For the past three, four decades, particularly for people that embrace Western lifestyle, we've seen this surge, huge surge of non infected chronic inflammatory diseases, cancer, autoimmune disease, food allergies, neurodegenerative disease like Alzheimer's or dementia, in other words, and the timing for this puts a little bit in geography. The paradigm that we had until then, that was if you're genetically predisposed to develop any of these diseases and you will be exposed to environmental trigger, whatever that will be, that are necessary and sufficient for you to switch from genetic predisposition to clinical outcome. Now, this acceleration, only three, four decades, made this paradigm not sustainable, not defendable. Let's go back to the example of CD disease. 3, 4 decades are not enough to have genetic mutation to explain the acceleration. The environmental trigger that we know being gluten for cilia disease, did not change in three, four decades. Why this acceleration?

Well, hold on, Alessia, we have to explain the listeners. There's been an acceleration, isn't it fourfold? The incidence of celiac is fourfold over what it was in World War II from the stored samples.

So this applies to all autoimmune disease, including CK disease, doubling every 10, 15 years, and only for those that live in the Western hemisphere. Clearly there is something that has to do with the way that we live. This acceleration can only be explained if there is something else other than these two factors, because they didn't change. And yet you have this doubling every 10, 15 years of CD disease, or Crohn's disease, of asthma, of breast cancer, you name it. How you explain that. And again, the answer is that now the recipe is made at least by five ingredients. The two that we knew already, genetic and environment trigger, but other three, the third is indeed the loss of this barrier function. That's the reason why we need to care. So if the barrier works well, these two worlds, genes that live in our body and these instigators that again are large molecules, they're compartmentalized, they don't see each other, and therefore you should not have any issue. But if you lose that barrier, you know, like the Fourth, you know, the old west, you know, people that can come in or the wall around the castle, people will come in because you lost your protection there. That is an element that seems to be important. The fourth being an immune system that becomes hyper belligerent. After all, we're talking about chronic inflammation. The fifth, and probably one of the most impactful is the change of this ecosystem. The microbiome that has a lot to do to switch from genetic predisposition to clinical outcome.

I was convinced you were going to say toxins as the fif thing and I was all excited.

But you know, toxins, it's a reductive issue. Toxins are part of the second element, that is the environment. But the last three, they are very interconnected. So if you have an increased gut permeability and therefore increase antigen trafficking, the immune system will be facing more enemies that will become belligerent and vice versa. If you have an hyper belligerent pro inflammatory status, some of the chemicals produced, I.e. cytokines will increase your gut permeability. If you have the gut permeability, you put your microbiome off balance. If you have dysbiosis, it's one of the strongest stimulus to release zoline, therefore to make the intestine leak. They're all interconnected. But the key element that you just mentioned is that the microbiome is able to influence if, when, why and how our genes are put in motion. We co evolve with the microbiome, they talk with each other and epigenetically, the microbiome is the one that will make you to start the march from genetic predisposition to clinical outcome. Because turning on and off genes that eventually you do put in motion. That's the reason why you can develop CD disease when you're 80 years old. You're born with these genes. You've been eating gluten for 79 years, you've been tolerating it. Why? Because the genes are necessary to break tolerance to gluten and not put in motion yet. Then epigenetically this changes the dysbiosis will increase zolin and therefore the antigen trafficking genes controlling your immune system being turned on gluten comes through and that's it and you develop the problem. If this is true, then that means that there must be, if we understand what we did wrong and that we're doing wrong in the western hemisphere, must be a way to slow down, if not revert this phenomenon. And that's where we are going after.

So what are the, what are the factors in Western Hemisphere. That's different. And what, what can we do to reverse it?

Sure. What we do wrong? Well, again, this is a work in progress. And if you got a chance to read Susie's and mine book, everything is spelled out in the air. For what is the evidence what we have been doing radically differently in the Western Hemisphere compared to the way that we used to live before. And the way that some population developing countries are still living? Well, we used to be born mostly exclusively, I should say by vaginal delivery, because we didn't have the C section. We used to feed real food and not junk to our kids. There were foil infections because until the recent past, if you got an infection, you would die. Because it was only recently that we develop antibiotics, vaccines and so on and so forth. And COVID 19 doshed. So see what happened? Even if we have this weapons, you still pay a price. Okay, so all this to say that this was the way that we evolved for the past 2 million years. That was our evolution. There is a crucial time, the first thousand days of our lives, from conception till two years of age, in which the immune system needs to be programmed to decide when unleash inflammation. Remember, 2 million years ago, our ancestors average life expectancy 1314 years would die either because a dinosaur will eat you, or you will die of infection. No time to develop autoimmunity or cardiovascular diseases or cancer. And therefore inflammation. It's nothing else that create a very hostile environment for microorganisms to grow. Is too hot. There are chemicals that will kill you, the tissue will die, but the organism as a whole will survive. So a control inflammation that is unleashed when we under attack has turned off, when we have defeated the enemy is a good thing. We want it, okay? And if we have a microbiome that is imbalance, because the main enemy is to create inflammation, are microorganisms that balance microbiome that is engrafted in the right way, without deregulance on its composition and function and so on and so forth. Will program the immune system to put the bar for inflammation extremely high. Now, if you live in the Western hemisphere, you're much more frequently born by C section. You feed junk to your kids, you use an abuse of antibiotics infection to the wazoo. This brings the microbiome off balance. And the programming of the immune system to unleash inflammation is such that the bar is very, very low. So you unleash inflammation for trivial, non necessary reasons. And it's a matter of time that doing this over and over again on a specific genetic Background will put you over the edge and switch from genetic predisposition to clinical outcome. Of all the elements that I told you, you're born once you take antibiotics. Occasionally you eat three times a day. Nutrition by far is the most impact reason why we in the Western hemisphere are paying a dear price in terms of chronic inflammatory diseases. That's my personal. I don't know if correct, but that's my personal reading of what's going on. What.

What fits the category for junk, you know, like where's the line? Is it all sugar? Is it anything processed? Not just gluten. Right. Because you can eat crappy gluten free food and it's still junk.

Well, it's also what. What are the food sprayed with? Are you having a lot of glyphosate? Back to talking, which is killing the microbiome by itself. What's your line then? Sand. We know what our line is, which is pretty high.

We're pretty far. We're pretty far to the. Whichever side it is in terms of no crap. I don't know if. Is that left or right? I'm not really sure.

We're just, you know, it doesn't matter, you know, if this is very factual. For 2 million years we've been engineering a very sophisticated machine, a Ferrari that will require high octane gasoline in the tank. And we put that gasoline in the tank until the recent past. Now we put water or Coca Cola in there and we wonder why the car is not performing. My generation, and therefore I remember and I come from an humble family, so the poor diet was the only way that we knew how. We were eating a lot of fruits, a lot of vegetables. Very cheap, you can grow by yourself. Particularly in the blessing country like, you know, Italy, where I was from. Legumes, you know, olive oil, tubers, nuts, fish. Because, you know, we had a very, you know, a rich fish, you know, array possibility in the Mediterranean Sea. Meat way too expensive. Maybe once every two weeks. If that's. And that was the proportion of the gutters Anders, because like me in the, you know, ages in which I was growing in Italy, they had plenty of fruits and vegetable. They don't run. They are there. You just pick. You have to go a good hunter to get an animal. And if you do, it's once in a while. So the food and the proportion is being completely reverted. Who embrace the junk food lifestyle. So this is a long way to answer your question. Is not just to eat fast food, junk food. Is the proportion wrong if you eat red meat every day? You will not be well, because back to the microbiome. Let me make another comparison here. Let's say the microbiome is a farm with different animals. And I developed my farm because it has to be mainly a dairy farm. So I want a thousand cows, but also I want, you know, pigs, horses, chicken, you know, rabbits, I want them all, they eat different things. But again, I buy the food to sustain a thousand cattles and 10, you know, chicken because I just need the eggs for myself. Why do with the cows? I need to make the eventually the milk to be a dairy farm. Now I change the food chain supply because now I buy much more food for the chicken and not enough for the cows. What's going to happen? I have a surplus of eggs, I don't know what to do with that. And definitely I cannot be a dairy farm. That's what happened to us. By changing the diet and favoring some food, let's say red meat, you feed the part of the microbiome that is prone to create inflammation because the microbiome itself may generate a micromanure of inflammation and you starving the protective component of microbiome, what we call the probiotics, because there's not enough food. What is the best probiotic food for a good bacteria? For probiotics, in other words, what is the best prebiotic fibers? In the Western hemisphere, particularly in the United States, the percentage of fiber intake is 4, 4 less below the minimum recommendation. So why wonder why we're in trouble? It's under our nose.

As you're talking. One thing that I realized that we diagnosed clinically, we diagnosed dysbiosis all the time. And when you were talking, I'm thinking scientifically, is there a clear cross point where what makes it. I don't know what makes a good microbiome and what makes a dysbiotic? Is there like a line in the sand that says what is that? Because scientifically you have to define that.

That's right. This is really the crossroad where the entire scientific community is this.

Way to go, Ed.

And I believe that finally we're at the verge of transformational changes. And before that I go there, I have a question for you both. What is the normal length of air or the normal color or ice?

Right.

Is such a thing? No, no, There is no such thing as the normal healthy microbiome. There is no such a thing. What we did so far said take our three microbiome, there will be different, mine will be different today from tomorrow. So it's a moving target. And then we statistics say well maybe rather than three, we analyze 300, we will find the normal microbiome. We did, we did not find anything. They said, well let's go three to three thousand now we are the million people to find the microbiome. So I have to define first of all healthy individuals. And definition of health is already challenging. I need to find a million of them and then eventually I know already that it's going to be a million different microbiomes. There is no such a thing. What is important is to appreciate the symbiotic relationship between the host and this ecosystem. We genetically are all different. Even identical twins are different because epigenetically they have genes that they function differently. If indeed the symbiotic relationship has to be personalized. The corollary is that we all have a different microbiome. What is not changing between me, you, Andy, you is the outcome of this interplay. The metabolic pathways, they are controlled by this. We all need to have blood pressure certain limits. We all need to have glucose level in our blood at certain limits. That is achieved thanks to this interaction between these two worlds. They are very different from each other, but the outcome is standard. That would define a human being as we all have one nose, two eyes and two legs. We all have to have metabolic pathway that works in a certain way that's achieved this perfect symbiotic relationship between these two and microbiome. You change one the microbiome, you can influence the other epigenetically. And the outcome is that you switch from being healthy to have a disease. If you take the fruit fly and you Drosophila exactly and try to predict when they die, the stronger predictors is when the intestines start to leak. That is the biological clock. That said the fruit fly is going to die within a certain period of time. They found the mechanism why they start losing that barrier. Meaning stuff comes in, there is much more inflammation, I don't keep up with repair and I die. They stop that genetically and by doing that they double the life expectancy that the Drosophila. It's like the right 80 years, you live 106 years. And all this is associated to change the microbiome and so on and so forth for it. You know, if you're lucky enough to be born with long telomeres, you will have a longer life expectancy because they naturally they tend to get shorter and shorter over time. And, and the the shorter is all depends on your lifestyle genetically. Again you, you can born with if you have a family ultracentenary you have long telomeres that protected the DNA from damage. That's what they do for living and therefore the process of aging. And if you born by people that have a lower lifespan, they're a little bit shorter. But even if I got the short telomere to start with, and I have a good lifestyle, that you know, process of getting shorter short is much slower if I don't have a very healthy lifestyle. And what we're talking with accelerates, you know, telomeres shortening infections, inflammations, dysbiosis, gut.

Barrier, gut barrier, gut barrier, sonulins.

Absolutely.

It all ties in. Unfortunately we gotta actually I could legit.

Chat with you all day. See, I've been. I told you. This is why I'm raving about them. So okay, so Alyssa, where we'll put everything in the show notes. Is there something in particular you want people to follow you on or find you or like which? Both books. Like what do you want to tell people as we sort of close down?

I think that again most of the stuff that we discuss is in the book that Susan and I put together. There was a work of love and sweat and pain because we're writing on the microbiome. When you write a chapter and then you move to the next and the previous chapter already obsolete because you know the literature, I've never seen anything like this. It's still hot. 700 papers a day comes out. I don't have any comparison any other filled in the past. And that, yeah, you know, again we, we try to really put some fundamental pillars that would not change in the discussion there so that the book will not become obsolete. As a matter of fact, we finished the book wrapped up given to the editor that Covid came. So we had to write that part. I mean that was so.

Okay, so go read the book. Go get the book. Gut Feelings, the Microbiome and our Health.

I think that would be a good resource to rationalize why you need to do some changes or lifestyle choices to be capable to make full use of your potential, of whatever mother nature gave you genetically and play your genetic cards well so that you can win the big game no matter what.

Awesome. Dr. Fasano, thank you for joining us for another episode of the Five Journeys podcast. Live like youe Matter. If this made a difference for you, pay it forward. Write a five star review so other people can discover it and tell your friends, have a great day. Don't go it alone.

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