Narrator:

Welcoming an internationally recognized pediatric gastroenterologist, expert in gastroenterology and related basic and clinical research. Doctor Fayez Ghishan. Doctor Ghishan has authored over 250 publications and acts as an associate editor for the textbook physiology of the Gastrointestinal Tract. He has received two prestigious merit awards from the NIH, and was the first pediatric gastroenterologist to be awarded the Horace W Davenport Distinguished Lectureship in 2014.

He is currently working at the University of Arizona as a professor and head of the Department of Pediatrics, and director of the Steele Children's Research Center. Please welcome Doctor Ghishan.

Doctor Fayez Ghishan:

Okay. I always start, as I told you yesterday, with a little story. So my story today is as follows. So I've been chairman for 28 years, and I go to the chair's meeting. There are 150 medical school in the United States. Currently they have 150 chairs. And the half life of a chair in the United States of America is between 5 to 7 years.

And the other hand, the half chair, the half life of the deans and the medical school is maybe 2 to 4 years. And in fact, someone said the difference between a dead and a dean is one letter. So I got this Chair’s meeting and then they say, okay, Dr Ghishan Could you please tell us what the hell? How did you last 28 years? And you're still going? Because I signed up another five years. now with the University of Arizona. I said, okay, three things in life you have to do one. You have to have a vision. If you don't have a vision, it doesn't work. But the vision had to be coupled with passion. Passion and vision make you successful.

And my passion and my vision is to create knowledge. And I'm going to show you how I create knowledge through my research. But the important thing is not only creating the knowledge. The next thing is how to propagate that knowledge to the public, to the to your colleagues. Propagation of knowledge. That's what they said. Okay. Well, so that's nice. But what's the second thing? Second thing. Look, I live in Arizona, next door to the National Park, and I walk every morning at 530 with several of my colleagues, not all pediatrician and internist, and one of them actually is another rheumatologist. We walk four miles every morning and they call it Doctor Ghishan Grand rounds, because I tell them what happened last night in science, because before I go, I wake up and I read what happened in in science. And then during the time when I was sleep, they said, okay, well, that's all nice. So what's the third thing? I said, look, the thing is this stress is bad for you. But if I think this is what you need to do, including you, the audience here. I want you to think of stress as clouds in the sky and the clouds is going to go away. So keep your vision on the sky itself. But don't concentrate all the time on the clouds because that's going to affect your brain, affect your gut and you cannot function. So what I'm going to tell you today, how are we going to use the microbiome to enhance our health? I want to make you all sitting in this room healthier than anyone else in the world, by showing you what to do with your gut microbiome.

Okay, so let's start our journey.

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Okay, so I'm going to teach you today through scientifically speaking by showing you data from my lab. The difference between eubiosis and dysbiosis because it's so confusing in the literature to read. What's eubiosis and what’s dysbiosis. Okay. So I'm going to define how microbiome developed early in childhood. And what can we do early on in kids for example born with C-section who will have the hostile microbiome and God forbid the hostile microbiome is bad. The kids will have a bad microbiome. And then I'm going to find the role of diet. Because, look, in the end of the day, this is what I'm going to teach you. Biology. Biology is not your destiny. Your destiny is in your hand. Your destiny is diet and lifestyle dominate over genetic in shaping your future.

Why do I tell you this? Let's say you inherit high cholesterol from your parents. Okay, fine. So what are you going to do? You're going to wait until you get a heart attack? No, you do something. Biology is not your destiny. You take statins, you do diet, you exercise, for example. You basically, you will get healthier and you don't develop heart disease.

So that mean biology is not your destiny. That's for most of the diseases we know of. It's in your hand what you can do to yourself. Finally, I'm going to give you a suggestion how to improve your health by changing your gut microbiome. Okay, so let's start with a couple of definitions. First thing is what is microbiota what is microbiome.

Microbiota is a collection of bacteria in your gut predominantly bacteria in your gut. But all of you you have yeast in your GI tract, right? Because you eat bread, for example. Well, how do you make bread? Saccharomyces survives here. So you do have basically some yeast in your GI tract which is healthiest okay. So what is microbiome. Microbiome is a collection of genes encoded by the bacteria. So we scientists use microbiota and microbiome interchangeably.

And finally I create mouse models in my lab I deliver these mice by C-section. They are totally sterile. We call them Gnotobiotic mouse. I'm going to show you the value of using these animal models in our research. Okay. So this is basically a slide which shows you the microbiota which involves the skin microbiome involve the gut microbiome urogenital. I live in Arizona. Arizona in Tucson is the capital of the world in kidney stones. Why? Because thirst is not an efficient mechanism to compensate for water losses. So if you ever come and visit me in Arizona, you have to drink a lot of water. Otherwise you will get kidney stones. So now I work with urologists to define the microbiome of urogenital system, to try to predict why would someone get kidney stones and someone does not get the kidney stones a nd oral microbiome is very important. So remember if you go tonight for example, and kiss your wife, do you know, what do you do to her now 25,000 bacterial colonies will be transmitted to her from your mouth to her mouth. Okay? So just be careful, because if you kiss your wife ten times, you're going to get, like, millions of bacteria transmitted to your wife or vice versa.

Okay. Be careful. Okay. But finally, digestive diseases. Microbiome. Okay. Because that the predominant basically number of bacteria in your gut okay. So the truth is the inner tube of life as shown here on paper in science is your gut microbiome. Okay. So you as a humans, are you humans. Now I'm going to show you that you may not be okay. So you as a human, you are a super organism. Why is that? Because you have another organism living within you. Okay, okay. But the truth is the brain and the gut is connected. Okay? So the fact is, when we say to someone, oh my God, I have a gut feeling that this is really true. Well, that's true because you have enteric nervous system.

You remember you have more nerve tissue in your GI tract, more than your spinal cord. Well, that mean it is true that the basically we have a two brains in our gut and in our brain. Okay. So the first question okay, what consists of brain gut access neurotransmitters C, B cytokines C bacterial metabolites and A all of them above.

Oh okay. Let's say. I know you're going to know that this.

Wow. See, you are so smart. You already learned that you have a brain gut access. Okay, okay. Okay, so this is the truly what I described to you. The brain gut interaction. It's really connected. If you are stressed out here in your brain, it change your gut microbiome. Vice versa. If you basically if you have something called SIBO, small intestinal bacterial overgrowth, people tell me, oh, I have a foggy brain because the metabolites of the bacteria in the gut affect your brain.

So it's clear there is definite connection. Okay. So I'm going to tell you one thing here everyone and few things that Parkinson disease is a brain disease. I beg to differ. Parkinson disease is a GI disease. Why do I know this? If you take a stool sample from a Parkinson patient, put it in this, Gnotobiotic mouse. Next day, they start trembling. So now there is new idea suggesting that nucleus an alpha which is brain made in the gut, transfer all the way through your neurons up to your brain and affect your dopamine mechanisms. Okay. Okay. So the number of bacteria in our gut. Is greater than the number of cells in our body and greater than the stars in our universe. 10 to the 14 power. Okay. We do have approximately over 100 trillion organisms, 500 to 1000 species. 90% of our cells in our body are microbial cells that are 100 fold more genes in our gut than in us. Okay. Next question. How many bacterial genes do you think we have? 1.2 million, 2.4 million, 3.3 million, 4.2 million. How many bacterial genes you have?

A.

Okay. I have so much to teach to you today. 3.3 million. The awesome 3.3 million genes. Okay, okay. Look at this. Okay okay. Let's move now. Next slide please. Okay. Look, you and I we have 23,000 genes but you have 3.3 million bacterial genes. So in fact when you think about it, 10% of our DNA is a human and 90% of our DNA is bacterial.

That means you are only 10% human.

It's a humbling experience to think of it this way. Okay, okay. Where do we get the bacterial in our gut? Well, number one, there are some bacteria from amniotic fluid because in the past you remember we used to call it 20% of the bacteria can be cultured, 80% of bacteria cannot be cultured. You need to sequence that. I'll show you how I do it. Okay. The initial acquisition through the vagina, for example, the feces, the hospital and breastfed babies. I basically disagree with the ESPGHAN and WCPGHAN because they say that in breastfed babies, you know, you can give them probiotics. I think that's wrong. I think this is wrong. Babies with breastfed babies have Bifidobacterium dominate over 90% of the bacteria. That's the best. Basically, probiotics you ever have is in the babies. Probiotics. Okay. And then from solid foods by the age of two it is okay. This is my concept okay. So the reason why I'm showing you this because look the gut and the skin out of the two most highly productive organ in your body, every 5 to 7 days, you renew your epithelial cells. So what I do nowadays, I take the stem cells from here, and I grow organs from it. I make organoids, I make colonoids, I make enteroids, I make organoids just simply from cells of the GI tract. Okay, so this is a cut section. What I did here is I took a cut section of, basically the epithelial cells and cut it.

Look at this. This is the brush border membrane. And I have a reason why I'm showing you this. This is the normal pathway. This is the capillary with red blood cells sitting beneath the lateral membrane to transport nutrients as I mentioned to you yesterday, I cloned many of the genes involved in the brush border membrane and individual membrane.

How to transport these nutrients across the G.I track. Okay. Why I'm showing this okay. So this is my work okay. This is to define eubiosis and dysbiosis or what I did here I took samples of ulcerative colitis patients and control biopsy samples okay. Look at this. This epithelial layer. Here is your lining of your gut. The mucus is green and the bacteria as red I tag it with red color.

Look at this space. That's beautiful space. This brush border membrane I showed you. It should have to be separated from the mucus layer on the bacteria in your gut. Okay. So this is eubiosis. This is clear eubiosis. This is a patient with ulcerative colitis treated with Remicade. And look at this. Absolutely beautiful. Now this is the problem.

This is a patient with moderative ulcerative colitis. You see the bacteria and the mucus layer in top of the lining of the gut. This is severe ulcerative colitis. And you see the distance on top of each other. I measured these distances in my lab okay. So it's clear that when you have someone like this that's at dysbiotic state, dysbiotic state, okay, that's really bad for you to have.

But what my aim of showing you with this is the following. I want to teach you how to eat food, which move you from dysbiotech state to this type. That's the idea. The idea is use diet to regulate your microbiome and separate your lining of your gut from your bacteria.

Okay, so this is what I do for research okay. This has not been published. We've just submitted for publications okay. So this is I took 160 patients with Crohn's disease and Crohn's disease. I took stool sample from these patients. I put these basically the stool sample. I put an FMT fecal microbiota transfer into the mouse I told you, which has no bacteria.

This is healthy control. I put it in this germ-free mice. There is no inflammation is here tagged with red color. This is called correlation. See this is blue color. There's very little red if any. Now this is a patient with ulcers with Crohn's disease. Look at this. When I transfer this bacteria to this mouse the poor guy has even developed Crohn's disease.

This is the first time ever someone is showing. The fact is that the dysbiotech state can be transferred into animals. And you can create animal models. Like this way. This is the number of bacteria which we have identified so far. We are pinning down the number of bacteria to really one bacteria, which can cause this problem. Okay the NIS, just give me $3.5 million to study this phenomenon because had never been published before.

Okay, so you may ask me, say, oh Dr Ghishan, you know, you showing us animal model. What the hell is this? I'm going to show you now what I do, basically to prove it for you in humans. Look at this. So this is cell culture, okay. Gut cells. All what I did here, I took a metabolite of the stool sample and the healthy control blue color, Crohn's disease, red color, all inflammatory state.

Then I make organoids like basically organoids from the colon. I make this three dimensional, or I can make it monolayer. And look at this when I added look at the red color. Okay. This is what we call part one, which is the medium or inflammation and whitish color is highly expressed in Crohn's fecal transfer. This is merged with E-cadherin.

Okay. So what I'm showing you that actually you can take the microbes from the gut of dysbiotic  patients and transfer it and create a new model of a disease. Why I'm telling you this because, look, the future is if I can identify a single bacterium, for example, causing this problem, I can cure these patient by giving them a viral phage to bind and the kill the bacteria.

And maybe I can cure patients like this. Second, I can develop new models, for example, of treatment for example. So now I have patent a new drug basically with a pharmacist school in our place to inhibit this parallelization business, which I showed you the inflammatory state. So the beauty of this system is that you can really develop new drugs for treatment of IBD.

Okay. So what I showed you so far is this you and I, if we are in a healthy state we live in harmony and tolerance with our microbiota. This that's how eubiosis space is wide open. This is disease state. You the host have a breakdown and tolerance. You make antibodies against normal bacterial flora okay. So you think of the microbiome of your gut is foreign. You attack it. That's what happened with Crohn's disease. You make antibodies against yeast. You make antibodies against your E-coli. So we need to move us from dysbiosis to eubiosis. But I'm going to show you on the end of the slides that dysbiotic state can be induced by diet. Okay.

Okay. This is my lab. This is what we do. We have 16A Amplicon RNA. We Next Seq 550. We can basically do all these things. 80% of the bacteria cannot be cultured. We need to use this sequencing equipment okay. That's what we do in our lab okay. But this is the future. This is my gift.

Someone gave me this gift, $1.3 million to buy this Novaseq 6000. I can do 48 samples. Like if you give me your blood, I can do basically all of you within. Literally one day, I can sequence your entire human genome. One day I can sequence. Your entire human genome. You know, that's the power of sequencing. This is the ultimate sequencing equipment available in the world.

You have to basically call Illumina, and you put your name on the list to be able to get this equipment. Why I'm showing you this equipment. Because the future is not only DNA sequencing. I can sequence your DNA. That's no problem. Literally 19 hours, I can sequence your DNA. The problem is this DNA goes to RNA. RNA goes to protein. I want to find out what's your protein levels in every disease state. That's the future. It's called RNA seq. That's the future. I do this in my lab. This equipment can do basically cancer genomics. I can think cancer genomics figured out what what chemotherapy I need to give my patients. I can do sequencing of Covid 19. All the mutations I can do it with this is with this equipment within a short period of time.

That's the future. Okay. So the next question is your microbiome similar to my microbiome? Maybe yes. Maybe no maybe not. Yeah. When I go to Italy, even for example, I said, okay, is your fresh fresh maybe maybe fresh, maybe not fresh. I said what do you mean what's the problem?

Okay, that should be quick.

Oh my God. Some people think it. I can't believe it. Look, I tell you what, the FBI, I'm going to tell you secrets now, but don't tell the American government. The FBI is using microbiome to define whether a killer is present in the room or not. So e all every every one of us. Microbiome is like our fingerprint fingerprinting.

Okay, so I tell you what I'm going to do now to make money. I'm going to basically do a matching male and female, like a dating service, by checking the microbiome of the woman to see if she wants to marry a guy who will have similar microbiome like and, well, for 100 bucks, I can do that. Yeah, I think that would be good.

Okay, well.

Okay. So look, so you basically babies when they are breast fed this the reason why I'm saying Bifidobacterium dominant basically in breastfed babies okay. Why would I give them probiotics I don't know makes no sense. This is God made probiotics because it's driven by HMO human milk oligosaccharide okay. So but then diversity occurs by the age of 2 or 3 years okay.

So we're talking about 1000 days. I'm going to emphasize to you what I do with this 1000 days, but nonetheless, okay, okay. So where do we get basically our interaction. What do we get. Microbiome okay. So basically here it says mother offspring is the best. And basically that's better than within household for example or other twins or within a village.

There's no interaction basically in a in a population that's usually why each one of us have a separate mechanism, okay. Vaginal delivery, very good bacteria. Okay. Can you imagine what God, how he made us that the mother change her areola skin microbiome in anticipation of the baby latching on the breast? Change her gut microbiome. Change her vaginal microbiome in anticipation of the babies being delivered. Okay, but C-section is bad idea. So what we're going to do with this? Well, this is vaginal swabbing. Okay, so this is the idea being propagated that you take a vaginal swab and you swab the baby. Does this work? Okay, I'm going to show you this data. This data just going to actually just about maybe last week okay.

So this data suggest that it's clear you can do a vaginal swabbing, an infant transplant with maternal fecal material or with vaginal. Don't do this. I'm going to assure you don't do that. This will be messy. But you can do this, for example. That works. Okay, I'll tell you why it works. Okay. This paper just came out and basically host cell microbes last week on what it says if you're doing this vaginal swabbing, you actually can change the microbiome to lactobacillus. Just like vaginal delivery and decrease the metabolites will be changing for example. So the microbes will become vaginal this, similar to basically, these patients, to their mom vaginal microbiome. So it's clear that this thing, this is a triple basically blinded study. And then they looked at actually what happened with those kids in regard to neurodevelopment. And it is definitely better. So this works okay. So it looks like we do I have like one kilogram for example, of microbes in our gut. Okay. So the problem is what happens now if we eat certain foods I'm going to show you like emulsifiers. Every salad dressing in the US I don't know about you here, but every salad dressing uses emulsifiers.

Soy lecithin, soy lecithin is emulsifier. Okay, polysorbate 80, for example, emulsifier. But the most common one is soy lecithin. Look, this is what happens. See this study basically, you remember the space. I told you the mucus is green, the bacteria is red, and this is the lining of the rat. Look, this is what happens. The space is almost gone with sorbitol. So you should stay away from basically emulsifier. Don't put salad dressing, use olive oil as well as lemon juice. That's the best dressing you have. Don't use emulsifiers. What about maltodextrin? Look at this. This is maltodextrin for example. Look at the space here. And control. This is basically with the addition of maltodextrin. And the space goes down. Okay. So I know last night that was meat as well. Red meat I want to assure you that I want you to start cutting down on red meat. You can eat some red meat but not extensively. Why is that? Well, it looks like meat has basically choline and carnitine. And your bacterial flora changes to basically it's different bacteria TMA lyases change carnitine carotene to TMA, trimethylamine trimethylamine. If I injected into animals in my lab within two weeks, I created coronary heart disease as well as chronic kidney disease. So cut down on red meat intake okay. So last question here. What country has the best source of cold pressed olive oil for your health? Italy, USA, Tunisia or Jordan?

That's a tricky question. I know what you're going to say, but I'm going to tell you.

Oh, I who said. Jordan, you are absolutely right. That's my country. I'll tell you why. Because they. Oh, thank you. So if this is the thing, olive oil started in the Fertile Crescent in the Middle East and migrated to Europe when the Romans basically occupied the entire Middle East. So the one in Italy, for example, is originated from my hometown.

Okay, okay. Okay. So are we going to use probiotics? Okay. So I believe if you want to use probiotic it has to be the strain level Lactobacillus Rhamnosus GG. That's will be probably because this you see this is all dogs, not probiotics. It's same. Don't ever go to Walgreens or CVS pharmacy and buy whatever you see on the shelf. That's does not work. Okay. So what's the difference between prebiotic and probiotics. This is the substrate for this for the probiotics okay. So the best probiotics here is basically a human milk oligosaccharide and 2'-fucosyllactose has been added recently to infant formulas as a synthetic HMO okay okay. So now I'm going to show you data. This is a data generated by, me and my colleague at Vanderbilt University.

We collaborate on LGG lactobacillus GG. So we discover two things. One is that immediate effect related to epidermal growth factor through ADAM17 transcription factor. But there is a sustained effect of LGG for the long term by upregulating TGF-beta transform a growth factor, whether through genetic epigenetic manipulation okay. So this is what we've done okay. So look there is a critical window 1000 days in humans in animals is very short. If I give algae for example at 1 to 5 days postnatally to animals, basically I can decrease the DSS colitis dextran sodium sulfate colitis in other mice, however, if you give them basically this LGG at one month of age and you give them this insert, nothing happens. So it's clear critical window is very relevant in early life. And I believe the critical window on humans. We have not proved it in humans, but I think it's the first 1000 days. Okay. This is my paper in JCI. What I basically describe that cytokines, for example. Okay. Cytokines get upregulate basically, this epithelial barrier, you'll get leaky gut. And it would take LGG because of P40 protein, which is expressed in the LGG, tighten the membrane through epidermal growth factor receptor.

Like I told you.

Okay. So now I'm going to summarize for you okay. Gastrointestinal tract colonized by a large number of bacteria in your gut. Colonization occur very early composition heavily influenced by diet, microbioata essential signal to ensure basically your gut microbiome and immunologically dysbiosis is bad for you eubiosis is the best thing. So what I'm going to suggest to you is this I want to optimize your gut microbiome.

One modified Mediterranean diet with extra virgin olive. What's modified? Modified meaning white meat. You eat more white meat. White fish. White chicken meat, white turkey, for example. Okay. Use extra virgin cold pressed olive oil because it have T- TMA lyases inhibitor. So you cut down carnitine and becoming TMA decrease red meat consumption. Why is it you know once a while that's fine.

But not every day okay. No emulsifier cut down emulsifier in your diet no artificial sweetener. I didn't have time to show you. But there's evidence that artificial sweetener is bad for you. Maltodextrin is not good for you. Decrease caloric intake. Moderate moderate intake of daily exercise. That's the best thing for you. Increase fruit and vegetable I managed yesterday.

Fruit and vegetables are the best thing for you because it does generate butyrate in your gut. The fiber when you eat the whole five. All fruits don't drink a lot of juices, just eat the fruit itself because it has the fiber, reaches your colon bacteria, ferments it, make moderate. That's how your colon functions. Otherwise you can get constipated.

Okay, pre and probiotics. However, remember this fact probiotics like you and me like to live in a nice environment. There is a place in Arizona called Scottsdale. Highest concentration of richest people united states. That's the reason why I go there. I suck their money. They don't like to live in Nogales down on the border. That's a harsh environment. So probiotics. Now when you. I want to teach you one thing. I'm sorry I've taken your time, but look, 25 hydroxy vitamin D3 is a marker of inflammation. Don't zap those patient with vitamin D if they have Crohn's disease or autoimmune disease. Because one alpha hydroxylase is upregulated, change 25 to 125 25 is always low. You give the more I publish this work, it makes them worse. Induce they’re remission first and then you give them vitamin D, okay. Spice your life with little curcumin. Curcumin inhibit NF-κB. I published this work decrease your stress level. That's a very important and finally feel good by helping others. How are you going to help others?

When I give this lecture to my donor, donate money to the Steele Children Research Center, which I direct, that would be good for you. And finally, look, you need to enjoy life. Don't drink cheap wine, for God's sake. spend your money. Don't hold the money. You're going to take it to your grave. Spend it on a good wine, good Spanish wine or good Italian wine.

Okay, and the end of the day, the road to good health is paved with good intestines. So take care of your intestine. Okay? And thank you very much.