Reduce Autoimmunity, with Dr. Alessio Fasano

Welcome to the five Journeys podcast. Live. Like you matter. I am beyond psyched for our guest today because it's 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, this is like 2010, and I said to my husband, this dude's going to get the Nobel Prize for this research. So 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.

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 gonna go see your boyfriend? I'm like, yes, he's talking, he's talking. Not to put you on the spot.

That's right. No point in that.

So I want to talk about Zonulin's because literally when I read that book paper, I was like, this is. 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 to me. Like, how did you. How did you get into zonulence?

So, you know, there are two ways that we can handle this question. The sanitary way, so that, you know, I was smart enough to think about it and I pursued that until I found it. Or the real story. That is always an act of serendipity. You try to do something and you stumble on something else. Which one do you want to hear?

The real story. I was going to say, how'd you stumble on Zonulins? But then I was like, oh, I don't want to offend you if it was in fact a stumble. So, okay, tell us the real story.

So long, long time ago, I was very much interested to how microorganism interact with us, how they can cross talk and what is the outcome of this interaction. At that time, we were looking at one microorganism at a time, not as we do now with this whole Ecosystem that we call the microbiome. My interest was on cholera, believe it or not, because when I went to medical school and I was trying to find a niche to save the world and I was thinking to got in research with cancer or something, my boss at that time that became my mentor said, you don't want to do that. You want to focus on diarrheal diseases, right? Diarrhea, it's not glamorous.

Are you shitting me?

That's right, you shitting me? He said, you know that every year, this was again a while ago, 5 million kids die because diarrhea. And that changed the prospect of the story. And the following few years I studied with him the physiology of the gastrointestinal tract. And again, in my naive kind of approach on life, I told them, I know everything about the host. Now I need to learn about the bug. Where should I go? And he said, well, I think that the best place is in United States, in Maryland, in Baltimore. The place is called center for Vaccine Development. They do this kind of stuff on enteric pathogens, including cholera. You go there and the following two years I was in Baltimore studying this bug and ultimately to develop a vaccine. So in other words, something that eventually can be given to kids that will not die of cholera. And the approach taken was to take the bug and taking out the weapons that he used to make this purging diarrhea that make people dying with color because of dehydration. This was at the beginning that molecular biology allow us to cut and paste genes. So there was very cool stuff. And eventually I was put in charge in doing that on this blog. And after a fair amount of time and a lot of failures, I was able to develop this live attenuate vaccine that did not produce this huge purging of diarrhea in animal models because the bug did not have the weapon anymore. There was this very powerful toxins that is called choler time was ready for prime time. So that we had to give this to volunteers. Volunteers meaning medical students, obviously a fair amount of money.

Wait, wait, wait, Alessio, did you give them cholera and then test the vaccine on them? Or like how did you test that it worked?

Exactly. The way they went was they were paid a huge amount of money, $500 to be locked in. Because of course you don't want to spread color around in a facility at University of Maryland. And you had three chances. One, placebo. So water. So you will take $500 for nothing. Two, my vaccine that will work because I showed in animals that they were not sick or three, the real deal, you shit your pants, but we would take care of you. Two out of three though, was in your favor. So that was the premise. And we did the trial. It did not work. I mean, you know, the placebo didn't get sick. The folks, you know, that, you know, got the real deal end up to have up to 10 gallons of diarrhea. But we took care of them. The ones that they got the color of vaccine had much less diarrhea, but still enough, a couple of gallons of diarrhea that made the vaccine not suitable. So bottom line, two years just flushed in the toilet, literally. So I got drunk for a couple of days and didn't show up in the lab, but in the press. And then, you know, again, typically what distinguishes, you know, somebody that has the intellectual curiosity to do research. I went back to the blackboard and said, what went wrong? How come that, you know, this vaccine did not work and you know, end up to discover another toxin besides, you know, the powerful one that I took out, you know, by genetic engineering, the vaccine that rather than purge water through the cell as the typical tox, they do, they loosen up the space in between cells. These gates that keep the cells tied together. There was a black box at that time because we little knew that this space was dynamic. There was just the beginning. Understanding that you can even increase opening of the space in between cells. Therefore this toxin was a brand new category autopsy with a very different and peculiar mechanism of action. I start to study the mechanism of action. I got more and more insider of what this key open, this gate in between cells do to reach the point in which, gee, this toxin goes after a very sophisticated machinery of these cells. I can't believe that this machine is there just to be the target of a bug that makes us sick. Probably cholera has been smart enough to understand and exploit something that we do for other purposes ourselves. So that led me to think there must be a counterpart molecule that does this job for us to open and close these gates in between cells. And that's how we discover the first member of the zoning family that was in the brain.

Right? It wasn't in the gut, I think at the beginning.

Well, actually we discovered in the brain the receptor. And there was the brain first, but then we discovered these families that they are everywhere. They are in the gut, they are in the heart, they are in the brain, the kidney, and so on and so forth. And of course, after the discovery, we start to ask what this molecule does for a living. Why we have it. And we realize that's important for some physiological reasons. And that's typically happened when you push physiology to the limits. You get into the disease, you know, territory and, you know, we start asking, you know, what kind of disease may have an issue in which you don't control the trafficking of the junk from the environment into your body that can eventually have, you know, consequences, of course, you know, food allergies, you know, chronic inflammation, they were on, on the list. But I was very much interested, for personal reason in our immunity. And that's how I focus mainly on autoimmune disease, because that's also an issue in which we little knew, you know, that beside the genetic predisposition and disposure something in the environment that makes you sick, there is also the need that this instigator needs to come in our body. And there was no port of entry that we're aware of. You know, these are molecules are very large. These are general proteins that we instigate the immune system to mount an immune response against their own body. And, and they cannot come through unless something goes wrong in these gates. And that's how the rest is history. Cool.

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 believe before, but they have this connection and this very dynamic structure that you may consider as a sort of gates. They are always, almost always closed. Sometimes we open when we need to. Zoning 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 zoloin or to maintain that too high in terms of the system, 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 was deciphering this. So let me tell you 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 genetic.

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 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 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, the receptor that you know, the, the stimuli from the environment and gluten is one of them, but also bacterial component, viral component will instigate the release of zoning, is this CXCR3 receptor. So in other words, if you have something that instigate the release of zoning, there can be many things, but let's say gluten, gluten fragment bind to this receptor and this binding will instigate the release of zonin. And the results only would 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 for listeners, I'm going to. I need a dummy down version of why do we care?

Well, this is again very good.

That's a nice, that's nice all this.

It's very important because you're language, but.

It'S a very important question. You know, we care because there was an inexplicable, you know, epidemiological observation considering, you know, chronic inflammatory diseases 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. So in other words, and the timing for this puts a little bit in jeopardy, 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 Celiac disease. Three, four decades are not enough to have genetic mutation to explain the acceleration. The environmental trigger that we know being gluten for Celiac 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, the way the sun hits. Well, again, we can cover that later if you want to, but anyhow, the point being that this acceleration can only be explained if there is something else other than these two factors, because that didn't change. Yet you have this doubling every 10, 15 years of CD disease, of Crohn's disease, of asthma, of breast cancer, you name it. How you explain that? 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 are compartmentalized, they don't see each other and therefore you should not have an issue. But if you lose that barrier, you know, like the fort, the old west, you know, people that can come in, or you know, the wall around the castle, people will come in because you lost your protection there. So that is an element that seems to be important. The fourth being an immune system that becomes hyper belligerent. After all, we've talked 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 fifth thing, and I was all excited.

Well, actually I was thinking 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.

How about changing epigenetics though?

I'm coming. Okay, Be patient. 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 no 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. That's where we are going after.

So talk to. So can you talk about the status of. Did I get the name right? Lorazatide Estate.

Oh, hold on, wait, wait.

And by the way, don't ever call me belligerent. Not things not to say to women. You're belligerent.

Just let us down the path.

I want to go that path before we go.

Well, the end result of that path is that I could take a drug and maybe eat out and not be a hot mess.

No, I understand, but let's.

Okay, fine. We'll walk deliberately down the path.

So what are the factors in western hemisphere that's different. And what can we do to reverse it? Let's go down that path first because.

I want to know what we do wrong. Well, again, this is a work in progress. If you got a chance to read Susie's and mine book. Everything is spelled out in there. 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, you know, until the recent past, if you got an infection, you would die because, you know, it was only recently that we develop antibiotics, vaccines, and so on and so forth. And COVID 19 dodged. So see what happened? Even if we have this, you know, 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 13, 14 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. It's too hot, there are chemicals that would 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. It's a good thing, we want it, okay? And if we have a microbiome that is imbalanced because the main enemy is to create inflammation, are microorganisms that balance microbiome that is engrafted 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 barrier 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 which is killing the microbiome by itself? Like what's, 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.

It doesn't matter. You know, this is very factual. For 2 million years we've been engineering a very sophisticated machine, a Ferrari that will require high octane, you know, gasoline in the tank. And we put that gasoline in the tank until the recent past. Now we put, you know, water or Coca Cola in there and we wonder why the car is not performing. I mean, you know 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, 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 gutter Santos, 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, right? So the food and the proportion is being completely reverted. Who embrace the junk food lifestyle. This is a long way to answer your question. It's 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 kettles 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 macromanure 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. So.

Has there been studies actually showing a significant reversal in terms of. For the good if, if the diet changes? Has there been actually, I mean in clinical practice I can thousand percent say that. But has there been good scientific studies showing that reversal will change your microbiome and therefore your health status?

Yes, There are plenty of studies in animal, preclinical animal studies, plenty of evidence in preclinical animal studies. There are also evidence in some very well controlled clinical studies done in humans. There is a problem though. It's a cultural problem and there is a social problem and there is an economical problem. Sure. These are very difficult roadblocks to change the status quo. Let me elaborate on that. If my daughter has the idea that food is to go to the frozen section of supermarket and take the trail and put in the microwave for five minutes and that's dinner, that's a problem. If my culture is telling me the more obese the better, because this means that you're healthy, that's a problem. If to eat the right way, the way that we discuss being more expensive than eat junk food and I Am a single mother of three kids and I have $5 a day to dedicated to food supply in my household. What do I buy? Fruits and vegetables that will not fill the belly of my kids. Or the pasta. That's right. Or you know, that kind of sandwich from that chain that will eventually fill the bell on my kids. So you see how complicated is the story. Now I give you an n =1 example because this is all this. I'm not saying that this generation is lost, but it's going to be very difficult to do what you just proposed. Change the attitude of the people because it's culturally now embracing these people. This is n =1. So don't know what that means. My grandchild was born during the pandemic. My daughter and son in law were super busy as we were, but my wife and I took over and said we would take care of this kid while you guys keep doing what you're doing. And we fed this fellow the Mediterranean diet. He never saw a French fry, he never ate a fast food sandwich. And unnamed what he ate was the real Mediterranean diet. This guy absolutely adore fruits, vegetables to the wazoo. He has taste for it. He developed that kind of taste. Now he's two and a half. He doesn't know what this junk food is all about, nor is asking for it. Why? Because he does not have the taste for it. And when he will grow up and would become at the age that he start to cook, by definition he wants to cook that way because that's his taste. And when he's become a father, will eventually provide that kind of food to his kids and the chain of events will change the status quo. I mean, you know, if we don't do that and we want impose, people say, you know, so far you eat this way, from now on you have to eat this other way because otherwise you're going to die of cardiovascular problems, you know, and your life expectancy would be shorter. It's like to say somebody that is a smoker, you got to stop because otherwise you'll have lung cancer. They know it. But stopping is very, very difficult because now it's entrenched in their, you know.

And their friends and everybody else is doing it. So it's a cultural thing like you said.

And yeah, there was a social issue, there was peer pressure now. But you know, did we make a change to smoking? Big time. When I was growing up, 90% of people smoke now. It's rare, so can be done. But we take that cultural shift that I hope, you know, will be A no brainer given what we see that's happening here. You know, this generation for the first time have a life expectancy lower than the previous generation. And we can blame like, you know, global warming and you know, unsettled situation that we're facing the world, just ourselves. This doesn't come from external factors. These are the consequence of our poor choices. Like we choose to go to war rather than settle reasonably differences or that we decided that people that emigrate from Africa needs to die in the Mediterranean Sea rather than open up and make sure that they will have a shot in Europe. These are choices that we make. Or a wallet between Mexico and United States. I don't want to be too political, but the reality of the story is we can blame only ourselves for the consequences of an unsettled world that can live in much better shape if we make more savvy decisions, starting with nutrition.

So where on this? I mean, I think you nailed it when you said obviously if you're on $5 a day, these aren't the conversations. It's like Maslow's hierarchy of actualization that when you're in survival, you are, you're just focusing on safety and next meal you are not focusing on optimal, you're focusing on survival. So you can't thrive until you get out of survival. So let's.

What is like nothing? No, I mean even the, I was just going to add. Even with the $5 a day, I think if we had $5 a day, we could grow, we know how to grow vegetables. We, we can provide and think about that, but there's no culture of that.

Well, I mean, you're an immigrant and I love gardening, so that goes well together. But yeah, obviously if you live in a tenement and you have no outdoor space, that's not the kind. You're just not in that conversation. It's a different one. So let's set the survival to the side. Even just getting through the day, I mean, we have four kids, they're all in a million directions. We cook every meal and it's really hard. Like it's hard.

Yeah, when it is hard. But you know, I paraphrase my grandmother saying that so a good meal needs 20 minutes to be cooked. If it takes more, with the exception of a few things, that's not a good meal. I am a very busy man. My wife is a busy woman. We are not back home or we don't have freedom to start cooking before 8 o' clock at night. But 8:30, food is on the, on the table.

Wow.

And it's made it real good quality food. It's a matter to organize yourself.

Come on, Alessia. I'm going to take issue with this because we feed like nine to ten people every night and just making a salad takes a half hour for that many people. It's just. There's just a lot of food prep.

You know, like I take a counterargument to this. If there's nine people that you feed and only one person that prepare, it would take half an hour. But if all nine will pitch in.

Nope, it'll be faster.

Absolutely. You and it's a family matter. That's part of the cultural shift that you have to have. The kids cannot be just on the receiving end. They need to take ownership because they will become parents at some point and they need to learn how to go shopping for the rights, you know, produce. If you have the possibility to have gardening experience, to plant your, you know, your, your plant. I back to my grandchild on my bulk. I don't have a land. I have a balcony with two, three pots. One has tomatoes, the other one has basil and the third one have strawberries. Why? Because, you know, he likes, you know to.

He likes strawberries.

Strawberries. So we don't pick it, he picked it directly from there. But is the culture and of course we don't survive on these three parts. But it's the example of what the stuff comes from and what you can do if you put yourself together to be self sustained. You know, the $5 a day in which, you know, I live in Boston and there are pots in Boston like in the third world country are in that kind of situation. And there are initiatives from very important foundation like the Shah foundation with this project is called My Way Cafe, for example, to change the status quo. There are many schools in the intercity of Boston in which the cafeteria is made by microwave and package can come God knows from where that they put in there. And it's just disgusting just to look at these people. They came in and school by school change the cafeteria, invested $60,000 to do a buffet, you know, buy a real kitchen and put somebody that will cook in there. And these kids now, they have fruits, vegetables, you know, and cooked meal on real, you know, meal. And this is the only meal that may have every day because they don't have enough. Now if indeed we will be able to implement some of the obvious policies that will make this affordable for everybody, you know, even if they are not expensive, but you know, again can be used wisely, then everything changes example, 1/3 of the produce that Walmart stop and shop market basket they have goes in trash because they reach the lifespan on the shelves and 24 hours before they're rotten, they have to be pulled out and flashed. So you have to pay for this produce. You have to pay for somebody for.

Waste.

Pay for disposal. You take a fraction of the cost to do that. Take a truck and go to East Boston and deliver for free stuff that have another 24 hours life solves to all these families. You pay less. You do PR for your company because you do a community service and everybody will be happy. Now we have the initiative like the bracket basket initiative or the food bank initiative that partially they do that this big corporation that keep losing their money that way can reinvest their money again, no big deal. You know, you give that for free.

20 tax write off.

Absolutely. Rather than to put this in a big can of garbage, put in a truck, just deliver.

So I think you're highlighting. There are a lot of layers that need to be addressed in order to circle back to the. My favorite topic of zonulence, which is keeping the gut healthy.

Because I believe that we departed from what we discussed by saying this is the common sense. Is this a society? Common sense? No. So this is a poor parlay. Why? If this was a society of common sense, we would not have this weapons of mass destruction on the street and kill people. And we are still discussing if this is self defense, if we have a pistol that can shoot 25,000 bullets every second or it's insanity.

Right. People are not. There is no.

How do we solve this problem. We just. We took poor. Probably. Yeah.

So I want to go back to the work that you're doing because we're not going to solve that one. But I think you make really good points. So are you allowed to talk? Can I go back to the medicine now?

You're okay with that?

Go back now.

So does your wife bust your chops, by the way, or does she just. You mentioned your wife. Is she gonna bust your chops like I bust his chops?

What do you think?

Okay. She's Italian.

I mean. Yes. Okay. I should just say a general rule in any family who runs this show, I don't know, at least in my circle of any family which the men run show, when something happened, it's not gonna happen, period.

All right. So going back to. What I was asking is can you talk medicine? Because I never want to eat gluten and it's gotten 95% better. But I. You Know I'll still get a headache, I'll still have some brain fog and my gut still reacts like Tiny, tiny.

Amount of cross contamination.

Oh yeah, tiny cross contamination. So, so, so can you talk about the medicine you're developing and when's it going to come to market? No pressure Alessio, but I've really been waiting for years.

You know the medicine that you're alluding to, this Larazidide is an inhibitor of this zonolin. In other words, it binds to receptor and doesn't allow zoning to signal the cell to open these gates and has been developed enough for a while, is now in the phase three trial for celiac disease. We end up to have the possibility to use the same molecule because zoning is involved also in the pathogenic some long Covid complications, particularly in kids. What we call the multi organ inflammatory system or MIS C syndrome. MIS C and now it's in phase two trial there. What this molecule does is stop this trafficking for city disease of gluten, for mis C of this spike protein from COVID 19 from the gut into the bloodstream that caused the cytokine storm that makes this fog six and so on and so forth. You know, drug development is a very long and inefficient route. You know, now we talk about phase three for CD disease. The phase three is still ongoing, may fail anytime or may be successful anytime. So when you say how long it takes, I don't know. The only thing that I know for the little that I've been involved, I work in academia. But you know, I helped to set up this company that you know, now it's non existent anymore. That it was in charge of this molecule is when you bring this molecule from the doorsteps of science to clinical applicability. The success of failure depends not on the science anymore, but business choice, study design, how you cut corners so you do this right. Economic crisis like we had in 2008 so there was no money to do any trials. A pandemic that makes recruiting impossible. So there are so many things that can derail the process. So I cannot answer the question if and when this molecule will be on the market. But the idea is indeed, as your beloved husband was saying, a safety net. So that you know that all the time, particularly when you're outside of your household because home, you know what you're doing, there is a chance that somebody will not do the job right. Taking the pill that will allow you to have that peace of mind that you will be protected in case of cross contamination. You know Makes a world of difference. Foresee the disease for which we know the triggers. Imagine all the autoimmune disease for which we don't know the trigger. So we don't have the option to take anything out that will protect eventually if works also for these other immune diseases to have this trafficking of God knows what that makes these people sick.

What are the downsides? Out of curiosity for the drug? Any major.

The downsides is that you have to take this every single time that you eat. Because there can be a good thing or bad thing because it's like for two, three hours and therefore you have to take this often. But on the other hand, the fact that the short lived, avoid complication and blocking the system that must be there because we need that right and acts in the gut so it doesn't go systemically. So in general side effects are due to the presence of something that doesn't belong to your body in your bloodstream. And this doesn't go there. So these are the features. You have to take that for life because there is not a cure, it's a treatment. So that's. That's the other downside to this.

So when are we getting the CRISPR change gene change to fix all the celiacs?

You know, I don't know if genetic editing would be the solution actually. You know, personally, you know, if you're born with the genes and we talk about CD disease, but we can talk about again anything else. Alzheimer's, breast cancer, insomnia. So worth the gene editing. It's such a difficult path to follow. But I believe that learning what kind of mistakes that made us to accelerate the incidence of this stuff will allow us to do what I believe will be much easier. Prevention, primary prevention, try to intercept that rather than fix one is already broken. So we want.

Don't do as I did for Bottle of Life.

My dream is to be the Jeff Lube of the situation so that you come to me to change your oil rather than the mechanic of the situation that you. Because I'm the mechanic now you come when your engine is broken and I have to fix your engine. You know, it's much more complicated, it's much more costly to do that. And in that sense we have two big projects ongoing that one is on CT disease and the other one is on autism to try to understand on a specific genetic background of risk because these are neonates that they have somebody in the family with either disease. How come some of these kids will eventually derail and develop serious disease or autism and others stay put and would not we do what we call now this multiomics. We look at their genes, we look at the microbiome, we look at the zolins, we look at their patients, proteomics, the metabolomic profiling and trying to see any sign that will suggest me that they are making that turn that will lead to that final destination. That's wrong one. And now we start to see that there are particularly derailment in the microbiome that epigenetically will make motionsome genes that will influence gut permeability or permeability because as I told you, dysbiosis will increase zoning that eventually will start the march from genetic predisposition to clinical outcome. And this require huge amount of data that needs to be modeled through artificial intelligence to do prediction model. So that if I know that when they shift the microbiome in a certain way, and the model is telling me that because of that, in 10 years her chance to develop Alzheimer is 75%. You know, I have a way to bring her back and say I changed the microbiome so I epigenetically turn off what has been turned on. And this is not going to happen. Prevention again is much cheaper than treatment. And by the way, because the goal is quality of life and containing the health care expenses, it's a win win situation for everybody, for the patients, for the health insurance, for who cares about our population in terms of political, social issues and so on.

All right, that's a pretty tall building to climb, but I think we're up for it.

As you're talking. One thing that I realized that we diagnosed clinically, we diagnosed dysbiosis all the time when you were talking, I'm thinking scientifically, is there a clear cross point where, what, what makes it, I don't know what makes a good microbiome and what makes a dysbiotic like, is there like a, 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, you know, community is this.

Way to go, Ed.

And you know, 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 spectrum healthy microbiome. There is no such a thing. And we, what we've been trying, what we did so far said, you know, take our tree microbiome, there Will be difference. Mine will be different today from tomorrow. So it's a moving target. And then, you know, 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 through 3,000. Now we're at 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, Wendy, 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 will define a human being. So as we all have one nose, two eyes, you know, and two legs, we all have to have metabolic pathway that works in a certain way. And that's achieved that 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. Yeah.

I love that. And leads to so many profound processing like, I mean, what you're saying is quote, unquote, healthy microbiome can only be defined by how is the person healthy or not, because the signals in the end will be the same. But the actual composition of the microbiome varies wildly depending on the microbiome and the genetics and the interactions.

So I see this as a future. You know, your office, for example, somebody goes to Wendy's office, and that would be me. I give her my genomic chip that I have on my chain here. She looks into the computer with 23,000 genes and she will eventually receive also the stool samples that I brought with me because she told me to do so. And she's going to put in the back of our office in the machine that would analyze the microbiome while we talk. And you know, we'll also do some epigenetic analysis. And by the time that she finished her physical exam on me, she has all this data in the computer that is now comparing this data to gaddillions of similar data that model what will be the outcome when all these pieces they come together. And she would tell me, yeah, Alessio, you are fine. You will live healthy until age 72.5, after which you have 92% chance to develop Parkinson's. And we need to change this by manipulating what I can. That is your microbiome and this is what you need to do. Come back in six months and let's see if we made this happening. I come back in six months, we go through the same routine. She do the modeling and say, oh, that risk for 92% now is 5%. I think that that's stay put there. And she can give me probiotics, symbiotics, prebiotics, a diet. Because I'm pretty sure that the future is most of the diseases can be handled with the diet because of what I'm telling you that the microbiome is so influential for so many reasons, why we develop diseases that, you know, as we derail. By changing the microbiome, we can bring this back. And when I say microbiome, I intend, you know, the zone and the antigen traffic and all night yards, because they all influence each other. As I was telling you before, it would be much better to do that way.

Yeah, I mean that requires quantum computing, my guess.

Well, Genova Diagnostics is doing that now on the stool samples. It's a report that drives me nuts. And we said to them, this report drives us nuts. It drives the patients nuts. Put it towards the end because people would get stuck on. People with your similar microbiome often have these different things. It's still there where they go the up and the down. It's so hard to look at the.

Genoa principle, it's correct. It's not much work though for prime time. We don't have all this data. We don't have that mathematical modeling that's been building. That's what we're doing now. But we have to before running you need to learn walking and before walking you need to learn crawling. We are barely sitting and not standing yet.

I don't even think we're pushing up. You know, we're flat. Just try to turn your head exactly right.

But we will be able to to at some point. So. But you know, again, of course there are some. It's not, I'm not saying this is the Genova's case, but there are some companies that are trying to really exploit the potentials running what we don't know how to run yet and we may take misstep so to speak, you know and again because I know what kind of healthcare business you guys involved. Ultimately our goal as healthcare professional is to improve the quality of life for people. That's what it is. No more, no less, no matter what it takes. And you know, for me, you know, when I got pushed back and said geez, you know, you're saying that we're you know, doing some so many things wrong right now but you know, life expectancy now is eight years, it's now 14 years like was, you know, 2 million years ago. And that's true. But how we achieve the goals major milestones. We were spending 95% for procurement and 5% appropriation. That's what we're doing 2 million years ago with the event of agriculture, domesticated food and crops. There was a major milestone 10,000 years ago. Now we free up time to build Eiffel Tower, the Colosseum because now we can unleash the creativity. We have more time but you know, when we reach the point in which you ask yourself it's better to live up to 60 but self sufficient, healthy or up to 80 but on a wheelchair with the tube of your nose and you know, pull ups because you shit your pants.

Quality over quantity.

Well it's health span versus lifespan.

That's right. I believe that both can be achieved if we made the right choices that are not that hard to, you know, put on a piece of paper but extremely hard to implement. To go back to the dominance for example my friend, longevity, yeah, it's mostly related to a state of inflammation. Matter of fact, you know, this called inflammation. All our cells in our body, they are destroyed and resupplied with new cells with a few exceptions. When we start to have an increased destruction and not the capability to resupply, that's when we tilt the point in our return and we start that process of aging that will bring us down to a point of no return and we die. Unless again intervening disease will speed up the process. If you look at ultracentenaria, their level of zoneline is extremely low compared to people in the 40s or the 50s with cardiovascular diseases. If you take the fruit fly and you Drosophila, You 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. But why they start losing that barrier. Meaning stuff comes in, there's 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 80 years, you live 160 years. And all this is associated to change the microbiome and so on and so on.

Are you going to talk about this at the A4M longevity conference in December? Maybe this, this is the talk, right?

Yep.

I'm talking on telomeres and mitochondria triad of interdependence. But you need to talk about. About zonulins. Yeah, well, you know the doorway to longevity. That's right.

And the guts and the software is.

Not a fascinating story there. And I don't have to teach you that. 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 rhythm of that 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 a living and therefore the process of aging. And if you born by people that have a lower lifestyle, they're a little bit shorter. But even if I got the short telomere to start with and I have a good lifestyle, that process of cutting shorter short is much slower if I don't have a very healthy lifestyle. And what we're talking with accelerates telomeres, shortening infections, inflammations, dysbiosis, 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, I know.

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 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 the literature I've never seen anything like this. It's still hot. 700 papers a day comes up. I don't have any comparison any other field 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 the editor Covid came so we have to write that part. I mean that was.

Yeah.

But anyway.

Okay, so go read the book.

Go get the book.

Gut Feelings the Microbiome and our health.

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

Awesome.

Me, you.

Dr. Fasano, thank you for joining us for another episode of the Five Journeys podcast. Live like you 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.

Sam.