Hi friends, I recently had the privilege of delivering a keynote address at the metabolic Health Summit held in early. May in Santa Barbara the particular circumstance. For this presentation came about directly as a result of dr. Dominic D'Agostino's, invitation, one of the event organizers and my most recent podcast, guest anyone who has heard my recent episode with dom will know exactly why this presented a unique challenge keynoting for a metabolic Health conference, especially when organized by Dom forced me to really reflect on what I could best bring to the event that might be.
Special or unique but still ultimately speak to the theme of the conference metabolism. My resulting presentation describes how intestinal permeability and bacterial products play into chronic disease and inflammation. And through inflammation. Aging in this presentation. I talked about how intestinal permeability promotes, the release of bacterial products from the gut into the bloodstream and how this stimulates the immune response. Sometimes chronically. It's thought that we all have some degree of postprandial inflammation.
Partly as a result of that mechanism, but how that plays out, may depend on our individual gut Integrity as well as the responsiveness or sometimes hyper responsiveness of our individual immune systems inflammation, isn't the only Factor though. It's an important one. The bacterial product lipopolysaccharide. Also interacts directly with LDL particles in a deleterious way, which makes up a second and even more direct mechanism that may promote atherosclerosis. We also discuss how lipopolysaccharide that
region AIDS from the gut, ultimately compromises the blood-brain barrier, leading to neurodegeneration how biomarkers of blood brain barrier breakdown proceed classical. Markers of Alzheimer's disease, like amyloid beta and Tau Tangles. How lipopolysaccharide? Promote inflammation through toll-like receptors, the principal inducer of innate immune response. This over activation of innate, immunity can then go on to affect brain function. Mm, you know, senescence,
Is the immune decline of aging and more. Finally I spent a good amount of time covering different lifestyle factors that regulate intestinal permeability both in a good and bad way. Including alcohol, stress gluten, saturated fat, fiber and omega-3 before we dive into this talk on intestinal permeability. Those of you that are also visual Learners can see. My slides in the accompanying video of this presentation. You can check them out on my
Assad's page on found my fitness.com. Just go to found my fitness.com and click on the episodes, in the toolbar, on the top of the page. Finally, a big special word of thanks to dr. D'Agostino and the metabolic Health Summit. Make sure to check out my podcast with dom, the most recent of which is episode 74. And now onto this episode
A big objective for metabolic Health Summit is really to bridge, the gap from science to implementation. And and as we were as your organizers planning for this event, we had a short list of people who really have the proficiency, the knowledge, the skills to transmit, or translate science to the public and high on that list.
With dr. Rhonda Patrick, so in around this time, dr. Patrick Rhonda. Graciously invited me to be on her podcast. Found my fitness podcast. So she had actually came to our lab, maybe about four, five years ago. And so, you know, I told my co-host Angela and Victoria was like, well, I think I can ask around to patch. I didn't want to do it in an email. I don't think I did. So I asked her in person and she had I'll have to say
She was very task loaded during this time. So I am extremely grateful that she took time out of her busy schedule with a lot of things going on in her life right now, to join us at metabolic Health Summit and I'm going to give a short introduction. She has quite a long, a bio, but dr. Patrick is a scientist and a health educator based in San Diego. She runs a popular website and podcast on YouTube channel. Called found my fitness her areas of focus.
Include micronutrient, deficiencies, the role of aging and the role of genetics and epigenetics. In health status, the benefits of exposing the body to hormetic stress such as sauna is, and heat stress is why I do the hot tub, and various forms of cold, exposure, exercise and fasting, and also plant phytochemicals and the importance of mindfulness, and stress reduction and sleep. So, really take in a holistic approach.
Metabolic Health. But Health in general her work has been published in journals, like experimental neurology, Faz AB, nature cell biology, and Trends in cell biology. Dr. Patrick's talk is titled intestinal permeability and the bacterial link to aging brain barrier, dysfunction, and metabolic disorder. And with that. Let's without further Ado. Let's invite our speaker to stage.
Thank you.
Good evening, everyone. I'm so excited to be here. Thank you. Dom. Thank you to the organizers. Victoria field and Angelo poffo as well. I'm so excited that this finally worked out, you guys have invited me a few times. So just so happy to be here tonight. I am discussing something. I haven't I'm excited actually because this this really pressed me to. There's there's some topics that I've been really interested in lately and diving into doing a lot of research literature reviews on.
So I was like, I need to push myself to learn more about this and what better way to do that than to present on it. Right? So I'm going to be presenting on something a little bit new in terms of things that I've talked about. Generally speaking. I'm going to talk about the role of intestinal permeability. And today we're going to cover. We're going to cover how what intestinal permeability is and how it can lead to the release of a bacterial product called lipopolysaccharide, or LPS, which is a type of
Endotoxin its present in the outer cell membrane of gram-negative bacteria. The bacteria that are inside of our intestines. We're going to talk about how LPS as it's called, for short, buying to lipoproteins and circulation and how this can play a role in atherosclerosis. We're going to talk about how LPS can compromise the blood-brain barrier and also how that plays a role in the development of neurodegenerative disease. We're going to talk about the role of LPS.
In the way we feel in our mood and then finally, we're going to get into what everyone's probably most interested in is what do we know about certain lifestyle factors that can regulate intestinal permeability. So let's start off by talking about what intestinal permeability is. So if you look sort of add a schematic of our intestinal lining we have in Tara sites, these are gut epithelial cells. They are connected to each other by tight junctions.
These are groups of proteins that are basically connecting our gut epithelial cells together, so that they're forming a tight barrier. Basically, it's one component of the gut barrier. Another component would be the mucin secreted by our goblet cells in the gut.
So intestinal permeability refers to most most of it. What's understood with intestinal permeability has to do with the some disintegration or disassembly of tight junctions, which allows bacterial products. Like lipopolysaccharide at allows bacteria. It allows food, antigens to leak into circulation. So we're going to talk about what happens when this, you know, when LPS specifically is able to leak into circulation.
So what effect does LPS in circulation have on cardiovascular health? So lipoproteins? Everyone here is familiar with what lipoproteins are there a mixture of lipids and proteins? There. They originate in the liver. Their main role is to transport triglycerides and other goodies other lipids and cholesterol as well to other tissues. Mostly they're transporting triglycerides. Are our tissues are
Cannot make triglycerides. Most of our cells can make their own cholesterol. So it's really important to have triglycerides being transport around because they're a really important source of energy. There are various shapes and sizes of lipoproteins from vldl or very low. Density lipoprotein to low density lipoprotein, LDL to small dense LDL or some small dense low density lipoprotein. And as these lipoproteins start to
Transport around our circulation and donate triglycerides. For example, to other tissues, they beget, they get smaller in size and also they become more dense. Well, LPS, binds to lipoproteins. It actually binds to all of them and through a lipid lipid interaction. And it's actually thought that this is one of the protective mechanisms that our body has to prevent lipopolysaccharide from causing. For example, sepsis.
We know that that lipoproteins play a role in actually lowering LPS levels in from in our circulation and this happens because the LPS is bound to for example, the LDL molecule. So lipoproteins are recycled. There. There cycled through the liver. There is a protein present on my proteins called apob apob interacts with the LDL receptor in the liver and is absorbed taken up. And that's how
Recycled well, because LPS is attached to lipoproteins. The LPS also gets lowered or decrease in circulation. And this has been shown in a variety of mechanistic studies. For example, using statins which lower LDL through a variety of different mechanisms. One of many includes increasing the number of LDL receptors and therefore increasing the recycling of these lipoproteins and subsequently LPS has been shown to be lowered in
Ation after Statin use for example. So again, this, this really seems to be a protective mechanism lipoproteins buying this lipopolysaccharide to help, you know, prevent our bodies from having massive inflammation and and basic steps undergoing separate sepsis. And so one of the ways it does that is by increasing like a protein production. When basically when LPS levels become elevated and then the lipoproteins then recycle the
Yes, through for the liver.
But not all lipoproteins are getting recycled as most people here, know, there are a variety sizes of lipoproteins. We've now had increasing evidence that the smaller and denser LDL particles. Don't get taken up into the liver as well and mechanisms have been worked out on this including because as the LDL particle gets smaller in size the apob protein that is interacting with the LDL receptor becomes somewhat obscured. And so when this
Toby is supposed to bind to the LDL receptor. It's not binding as well. And therefore, it's not getting taken up and it's not receiving recycled as well. And subsequently, that means that the LPS particle bound to the LDL is saying in circulation. So what consequence, what's the consequence of this? If we have a small dense, LDL particle, that's not getting recycled. It's actually in circulation longer and there's been evidence that these small dense LDL particles.
We will insert themselves into the arterial lining, the arterial wall. And of course, the LPS is a signal to our immune cells resident macrophages sense, the LPS signal and it's like, oh, I've got to get rid of that bacteria because it's a threat. So it comes and try to try to engulf through phases phagocytosis, what it thinks is a bacteria, but which actually is a small dense LDL particle.
With an LPS bound to it through a lipid lipid, interaction inserted into the arterial wall. And so it phagocytosis that entire lipoprotein and you get the formation of what's called a foam cell, sort of a soft black. And this is stuck in our arterial wall, the the lining of Our arteries and as it's sitting there for, you know, more and more time, and undergoes more inflammatory and oxidative Transformations, which then causes the foam cell to become.
Um, you know, stiffer and more plaque like. So, this is the beginning of atherosclerosis. There's been a variety of animal studies nicely documenting, this as well with the small dense, LDL particle, and LPS. And in fact, even showing, if you, for example, increase the production of butyrate producing bacteria in the gut, which can help prevent LPS, leakage that can sort of reverse, some of these effects, quite interesting. So, so that's sort of
One aspect of what LPS can do when it's in circulation to cardiovascular health. The next question is what about the brain? What effect can LPS in circulation have on brain health? So the blood-brain barrier much like the gut barrier is made up of a series of endothelial cells that are that are bound to each other and held together through tight junctions. Again, these proteins that are group of proteins that are that are holding the endothelial cells together.
On the basement membrane side of the blood-brain barrier. We have a variety of different cell types, sort of all interacting together, parasites and microglial cells, which are the brains resident, immune cell as well as astrocytes and together. They're making up the blood-brain barrier. So LPS again originating from intestinal permeability can actually break down some of the tight junctions itself, and it binds directly to receptors present on microglial cells.
They're called toll-like receptors for like for receptors and we're going to talk a little bit about that in more detail in a moment. But when that happens, it actually shifts. The microglial cells in the brain from a protective mode to an attack mode. And so they kind of, you know, change their their their phenotype and this sort of results in the debt. The Astra astrocytes moving away from the parasites and the basement membrane.
And so, you end up getting then even further breakdown of the blood-brain barrier becomes more permeable. And this is sort of the beginning of this vicious cycle where then, you know, you sort of have a slow sort of Insidious more permeability effect because more help. Yes. And other inflammatory molecules and other things are getting into the brain and then it's, you know, changing the phenotype of our microglial cells, for example, and this sort of this vicious cycle of neuroinflammation. So why should we care about, you know, blood-brain barrier?
Down. Well, the blood-brain barrier is key for brain Aging. In fact nearly 50% of all dementia, including Alzheimer's disease, began with the breakdown of the smallest vessels in the brain. In fact, biomarkers of blood brain barrier breakdown proceed classical. Biomarkers of Alzheimer's disease, like Tau Tangles and amyloid beta 42 aggregates.
LPS in circulation. Also affects the way. We feel so healthy individuals that are injected with LPS.
Experience symptoms of depression, depressive mood feelings of social disconnection. They also have elevations in inflammatory cytokines, like tnf-alpha and il-6 compared to people that are injected with a saline control. There have been a variety of studies that have now sort of established causation with respect to the role of inflammation in in depression. And basically, in the way we feel in our mood,
And there's been a variety of mechanisms that have been sort of delineated. One of those has to do with the metabolism of tryptophan. So tryptophan is an essential amino acid, we get from our diet. It is transported into the brain. Once it's in the brain. It gets converted into serotonin, which is an important neurotransmitter that regulates mood, it regulates cognition. It regulates impulse control long-term planning. It's important for a variety of cognitive functions. Well, if there
There is a acute inflammation or even sort of low-grade chronic inflammation. This can shift the metabolism of tryptophan such that tryptophan is not transported into the brain. Rather. It's converted into a metabolite called kind of learning and kind learning has been shown to accumulate in the brains of people with depression. Also nerd General disorders kind yearning gets converted into a neurotoxin called Quinta lenok acid, which also has been associated with a variety of
Psychiatric disorders, bipolar disorder schizophrenia as well as neurodegenerative disorders have exercised on here because exercise as most people here are familiar with it's very, it's been shown to be important for brain health for cognition. For the way we feel and part of that is because it increases the transport of tryptophan into the Brain before any conversion into kind learning. So, it actually increases the transfer of tryptophan in the brain and also the conversion of tryptophan into serotonin.
So, sort of a summary of this part of my talk is that intestinal permeability can lead to the leakage of bacterial products, like lipopolysaccharide, LPS into circulation and we talked about cardiovascular health and atherosclerosis, but it also affects the brain and it can generate inflammation. Inflammatory responses that can change tryptophan metabolism change the way serotonin production is made.
But also it affects the blood-brain barrier and that can also affect the way. Our brain is aging. So LPS in circulation is not a good thing and maintaining a healthy gut barrier is important for both cardiovascular health and for brain health, but there's other there's other mechanisms by which LPS can sort of wreak havoc on our health. And this has to do with The Binding of something that's a receptor on almost every single cell in our
ADI, it's called toll-like receptors. We have these everywhere. We have them on our immune cell. So toll-like receptor 4 tlr4, LPS binds to these receptors. And when he does on, when it does this an immune cells, of course, there's lots of, you know, lots of inflammatory responses that are generated, but it also leads to what's called inflam Aging. The Aging of our immune system, where our immune system because becomes less robust at protecting us against pathogens. As we age, it also becomes better at
Making inflammatory cytokines and doing it in a sort of like, you know, shotgun approach, you know, where the it's kind of like there's a lot of collateral damage, The toll-like receptors when their inner when they interact with LPS on muscle tissue. It's been shown to impaired glucose uptake into muscle tissue, which of course, would affect metabolism, cause metabolic dysfunction on liver cells. It's been shown to play a role in non-alcoholic fatty liver disease. And in the brain, we talked about
About a few problems with the breakdown of blood-brain barrier. It's been shown to also lead to depression as well as neurodegenerative disease.
So let's talk about what happens when these toll-like receptors on immune cells are activated and inflammation, inflammatory biomarkers or elevated. So for example, people that are this is a different study than I. When I mentioned previously, this is an even lower dose of LPS. When people are given a low dose of LPS such that there's really no clinical symptoms. No, clinical end points that were noticeable.
The individuals had a up to two hundred fold increase in their inflammatory biomarkers. So, they had a twenty five fold increase in tnf-alpha, a very powerful pro-inflammatory cytokine, and a hundredfold increase in aisle 6, which is also a pro-inflammatory cytokine. They also had an increase in markers of insulin resistance home, why are increased by 32% and markers of insulin, sensitivity sensitivity decreased by 21 percent. So this is, this is kind of
Is that even a low dose of LPS? Remember, LPS originates from the gut can massively increase biomarkers of inflammation and, you know, the the levels of LPS were talking about are chronically elevated in people that are overweight and obese. So we're going to talk about that in a minute. But inflammation itself has been shown to play a role in aging. It's been shown to accelerate epigenetic aging clocks. So these are epigenetic signatures that have been identified by
Dr. Steve Horvath, dr. Morgan Levine and others to basically be able to biomark biological age. There was a study that was done by dr. Levine and colleagues where people who had head and neck cancer that were undergoing radiation and chemotherapy treatment combined their epogen. That they had this treatment done, and immediately after their treatment there, epigenetic clocks accelerated by five years. So that's like, they had aged five years.
Six months to a year. Later there, at most people's epigenetic, agent clocks, were turned back to Baseline, return back to normal. Except for people who still had elevated inflammatory, cytokines, those individuals with an elevated inflammatory, cytokines at the six-month Mark or one-year Mark after their treatment still had massively aged. Epigenetic agent clocks. So, chronic inflammation. Can accelerate epigenetic aging. It's also been associated with
Accelerating aging itself. In fact, suppression of inflammation, has been shown to be important for aging and the quality of life as well as cognition. So, this was a cohort large cohort study out of Japan where a variety of biomarkers were measured in individuals that were elderly individuals. That were centenarians that they were 100 years old individuals that were semi supercentenarians. These are individuals that are 105 years old or in.
You are 110 years old and a variety of biomarkers were measured everything from long-term fasting blood glucose levels. So hba1c to liver function to lipids to kidney function, to telomere length, and amino senescence, to biomarkers of inflammation, and the only bought, and the only thing that was predictive of an individual basically living to the next stage, was suppression of inflammation, solo markers of inflammation, and that was also the only thing that was predictive of cognition.
Nishan like being cognitively cognitively capable in older life as well.
So I think probably what most people are interested in now are okay. Well, it seems as though it's really bad to have LPS in our circulation and it originates from our gut, when our gut barrier is, in some way, shape, or form compromised, intestinal permeability occurs. So let's talk about some lifestyle factors that are known to affect got permeability or intestinal permeability since we've been talking about the brain and we've been
Think about the role of LPS, from the originating from the gut on the brain. It's a two-way road. So the brain also affects the gut and I think that anyone in this room, who's gone to graduate school or med school or any kind of higher education, and as experience, the massive stress probably has felt some kind of gut symptoms. I know I did. I mean, there was definitely a, there's an association between being chronically stressed and having a GI problems.
Mmm, and it took me a while to figure that out when I was in graduate school. I didn't know what was wrong. I thought maybe I had, you know, IDs or something and turned out. It was actually stress. So there's been some nice studies done. In fact, people giving a presentation has get, get release, LPS into their circulation. So in fact, you're probably measure my LPS right now, I'm sure it'd be off the charts compared to yesterday when I was having fun with my family at Disneyland, but a lot of the mechanisms have been worked out.
On this. And in fact, one of the stress hormones that is released when we are stressed is corticotropin-releasing hormone. And this binds to a type of immune cells that are present at the level of the gut called a mast cell. There are receptors for corticotropin-releasing hormone on mast cells and when so when that stress hormone binds to the Mast Cell, the Mast Cell releases proteases which then degrade a bunch of proteins that make up the tight junctions. That hold our
tunnel gut, you know, member membranes are antara sites together. And so this causes again, this is a intestinal permeability. This is what happens and that allows food antigens to leak in history. Circulation allows LPS to leak into circulation. It allows other things as well, bacteria. So this is, this is how psychological stress in the form of a talker giving or financial stress or, you know, social relationships. Lots of, there's lots of different taking care of his sick.
And remember, there's lots of ways that a person can be stressed, graduate school, but it's kind of I think it's important to realize that managing. Our stress is really important for our, you know, our gut basically and for helping to prevent intestinal permeability.
Probably not surprising what's called an obesogenic diet, something that can lead to obesity. This is a combination of high fat, high sugar, low fiber. So you can feed people high fat, high sugar, low, fiber diet, and after about four weeks, you know, they're LPS levels are increased by 71 percent. I would argue that you could just do this and then one hour later measure that because there's something called postprandial endotoxemia, which is the the
Release. As I mentioned, LPS is a type of endotoxin. So it's often you'll see in the literature, the the words interchange, lipopolysaccharide, LPS or endotoxin. So so food itself, you know, I mean, when we eat meals, there's postprandial inflammation. Part of that postprandial, inflammation can be, you know, connected to LPS. That is released, not all of it, but part of it. So an obesogenic diet something that can make people, you know, get fat can also
Increase LPS levels.
Obesity itself has been associated with higher circulating levels of biomarkers of intestinal permeability, such as Sonia, one and we'll talk a little bit more about zhan yuan in a minute. And so there's been this sort of, is it the chicken or the egg? Or what does it is that the Obesity that causes LPS to be released? And you know, from intestines and caught is, is basically causing intestinal permeability or is it is it the diet that's causing the Obesity that's doing it. And it turns out it's probably both. There seems to be evidence of both.
You things occurring. And so, then when you have again, it's one of those Vicious Cycles because you have the diet that's causing the Obesity to, you know, that's basically wreaking havoc on your gut health and an LPS basically and then the Obesity itself is also doing it. And in fact, weight loss can decrease markers of intestinal permeability. So people that were obese that that decrease their BMI by about seven were also able to decrease markers of intestinal.
Permeability and there's a million reasons why we should, you know, lose weight. If you're if we are overweight or obese, obesity in extreme cases, very extreme cases. Can can have a massive effect on lifespan. So extreme obesity. This is a meta-analysis of about 20. Prospective studies found that extreme obesity. A BMI between 40 and 42. 45 is associated with a seven-year decrease in life expectancy morbid obesity. This
BMI between 55 and 60 is associated with a 14-year decrease in life expectancy. So there's, you know, there's every reason to want to lose weight and particularly, you know, lose fat and visceral fat. And there's a lot of ways that that can happen. I know a lot of great speakers at this event will discuss that but probably one of the easiest ways that doctorow just mentioned a moment ago, is caloric, restriction, and it's there's a lot of ways that you can get to.
Alaric restriction, You Can Count Your calories and diet you can skip meals. You can you know exercise and Skip meals, there's lots of ways to do it, but I think the at the end of the day, the reality is that, when you when you limit your food intake, you can, you can lose weight. It's effective.
Binge drinking is something that also has been identified to cause massive LPS release from the intestines. Probably a lot of people that already have underlying gut issues or more familiar with this because they probably noticed when they drink alcohol, they might start to have got issues. And, and so binge drinking. This is, this is for women about three to four drinks. And for men like four to five. So it's a lot. I mean, this is more relevant for a college audience. And, you know, to be honest.
But it's important to keep in mind, right? I mean, you know, binge drinking binge drinking does increase LPS and think most of us are probably more interested. What about moderate alcohol consumption? What effect does that have? And there's been associations with moderate alcohol, consumption and small intestinal bacterial overgrowth. So the bacteria in our gut and mostly are localized to the distal end of our large intestine, or colon as it's called bacteria are not really supposed to be in the small intestine. I mean, this is where fats are
It's where simple sugars are absorbed proteins. So the complex carbohydrates are mostly broken down in the:. But when bacteria, make their way into the intestines, it can cause problems, it can cause Zone yolan release and we'll talk about why that's important for intestinal permeability in a minute. But so there is some connection between moderate alcohol consumption and in small intestinal bacterial overgrowth. I will say this, I mean, there's not a ton of literature on this and it's quite, you know,
Likely, like like we all know observational studies. There's a million factors. I mean, maybe it's a combination of people that already have some underlying gut issue, or maybe it's a combination of people that are eating obesogenic diet and drinking alcohol or their stress and they're drinking alcohol, you know, maybe it's a two-hit hypothesis, like it. We don't really know, but it's something to keep in mind. Alcohol can be hard on the guys, specially in combinations with other things that are hard on the gut like stress, for example,
So let's talk a little bit more in detail about the zone yilin, that I've mentioned a couple of times. Again, looking at the intestinal gut barrier. We have our entire sites that are connected together through tight junctions. So gliadin is one of two proteins that is present in gluten. So gluten is found in a variety of different types of whole grain sources gliadin, bind to a receptor on the, on the surface of our intestinal.
Little cells called the CX C R3 receptor. And when that glad and binds to that receptor, it causes the release of a protein from our antara sites, our gut cells called Zone yulin and Zone, yilin then binds to a series of other receptors present on the are epithelial cell surface. When that happens, this then causes tight junctions to is disassembled and when that went to disassembly of are tight, junctions happens again, that's intestinal permeability. We can have things.
Going from our gut into our circulation, like LPS. A lot of this work was pioneered by dr. Eliseo, Fasano at the University of Massachusetts hospital. It is thought that, you know, so people with celiac disease, it's thought that gliadin is the major problem for them because of this, this mechanism, the release of Zone yulin, and therefore disassembly of the tight junctions, which actually stay disassembled for quite a long time and allow LPS to then go into circulation and do all the things that we
Talked about with people that don't have Celiac. It's thought that it might be a more transient opening and closing. So just to kind of play devil's advocate here, you will, you think? Okay. Well, if gluten has gliadin, and gliadin is going to release Zone yulin, and that's going to disassemble my tight junctions, even for a 30 seconds. Like, I don't want that, right. So I mean, that's kind of what I'm thinking, but again, to play Devil's Advocate, when you, when you look at some of the observational data,
And people that are eating whole grains. We see that people that are eating whole grains seem to have a lower all-cause mortality. For example, compared to people are not eating it. Now, again, as doctorow, point out nutritional observational studies are just, I mean, it's like a disaster for establishing causation. And I think, I mean, I could just point out like 10 things. But, you know, with studies like this, for one whole grains, include a variety of gluten and on gluten containing proteins, the non-gluten ones wouldn't have gliadin. So the
For things like quinoa. Buckwheat oats Millet, you know, barley the other would be okay. Well then maybe people are eating whole grains are just eating less to respite for refined grains. And in fact, that is the case people that are eating whole grains. Are eating less refined grains. And so there's a million. There's a million things that you can look at here. But at the end of the day, it's still, it's still kind of makes you go. Well, maybe, you know, maybe I shouldn't freak out too much. If I have a little bit of gluten and the same goes, when you look at for biomarkers of inflammation, people that eat whole grains have.
Lower biomarkers of Pai, one and also of C-reactive protein compared to people that are not eating it. But again, people that are eating these whole grains. In fact, if you look at the methods of this section, it's all whole grains. It's not just gluten-containing ones. So we know that whole grains are a good source of of fermentable fiber for bacteria, in the colon and fermentable fiber is then by many bacteria, convert it into butyrate. So butyrate is a short chain fatty acid. It is the major
Our energy source for colon is sites. These are your these are the, the entire sites that gut epithelial cells that I was talking about. They're producing about 70 percent of all the energy for, for those cells. And so, so it there's also been a variety of studies that have shown. For example, if you, if you give butyrate to an animal, it can prevent LPS leakage and it can prevent the formation of atherosclerosis in animal models that are predisposed to
Ooh this, for example, so, so butyrate produced by bacteria in our gut is actually, is actually a good thing. There are a lot of different dietary sources of butyrate these in better that don't include gluten. So pectins, for example, or type of fermentable fiber. This is found in Barry's it's found in root. Vegetables, is found in Citrus, beta-glucans are really good source of fermentable fiber, they're found in mushrooms oats and barley inulin is another source of fermentable fiber. It's found in garlic onions and artichokes and resistance.
Search is another source. And it's found in green, bananas and cooked and then cooled potatoes. So, these are other dietary sources of fermentable fiber that are known to increase butyrate or and also increase butyrate producing bacteria in the gut. But there's other lifestyle factors that can affect butyrate as well. So a mega Three fatty acid consumption is able to increase the concentration of butyrate producing bacteria in the gut aerobic. Exercise training can increase the production of butyrate.
Eight producing bacteria in the gut, independent of diet and try. I'm restricting eating is also able to increase the production of different types of butyrate producing bacteria in the gut because bacteria in our, in our intestines are also on our circadian rhythm, much like every cell in our body are on a circadian rhythm will hear a lot about that from dr. Sachin panda in a couple of days but time restricted eating basically having the absence of food seeing our gut
Is important for for basically decreasing, you know, non butyrate types of producing bacteria and increasing butyrate producing types of bacteria in the gut.
What about dietary fat? So if you were to, if you were to take, this is the studies been done. If you take 300, you know, calories in the form of a glucose beverage or orange juice or cream heavy cream. And you look at first inflammatory biomarkers after consumption of those 300 calories from either of those beverages order. There's no calories in water. Inflammatory biomarkers will be elevated in the glucose containing beverage, and they'll be
Didn't heavy cream, but not the orange juice. Only, they have a cream increases LPS. The the glucose does not which is very interesting. There. There are meta-analysis that have been done looking at fat and LPS and it seems as though fat can be hard on the gut particularly saturated fat without fiber. Now, does that mean fat is bad? No, I think that we've established that quite nicely over the last couple of decades.
I think that it if you look at the quality of evidence here, you'll see a couple of things. One that most of the fat sources used are processed oil their coconut oil or palm oil and when you look at the high-fat studies, they're mostly given also with a biscuit or something that's refined carbohydrate. And and there's enough evidence out there to show that saturated fat in combination with refined carbohydrates seem to really be key for increasing LPS.
From the gut. But I just kind of wanted to point this out because I think, as we are kind of Shifting. There's a metabolic Paradigm here where we're learning, maybe fat and saturated, fat isn't as bad as we thought that. We shouldn't just throw everything out there. There. There are still things to consider and there's a lot of interacting and nuanced factors here. And I think that looking at the effect of dietary fat on LPS leakage from the gut is one that we should probably explore more and explore it better.
So saturated fat and then and then polyunsaturated fat in the form of Omega-3 has been shown to lower, LPS, leakage from the gut in the form of omega-6 like vegetable oil. In humans. If the vegetable oil is, is heated. It increases LPS like its from the gut, but if it's not heated, it doesn't seem to have any effect in humans. In animal studies, omega-6 will increase LPS leakage from the gut but animal Chow when the
Mermaid, it's possible that the omega-6 is heated. I mean, there's just no telling I think the bottom line is also when you look at some of these studies, when you have saturated fat with a fiber Matrix, the LPS response is blunted. So it kind of made me like I like cream in my coffee and I was kind of looking through all this literature. And and the one thing that I really seem to see consistent was like, when you just have fat, like just fat, like putting butter in your coffee, your cream in your coffee, like it does seem to be harsh on the
Cut and a variety of mechanisms, haven't worked out on that bile acids, which are, you know, increased for the absorption and digestion of dietary fats are, you know, is one thing that's been shown to basically affect gut permeability and the the fiber actually slows the absorption of the fat much like it does with glucose as well. So, I do think that I may reconsider putting so much cream in my coffee because that might be affecting my LPS, but the other thing is emulsified,
Fat seem to be really bad for LPS liquid leakage. So, does this mean that a ketogenic diet is bad for our gut or is leaking LPS and their circulation? No, there's no evidence of that. And in fact, there's such profound changes in metabolism when you're in ketosis, that it's quite, I think a good hypothesis that that, you know, any if there even was LPS leakage, that maybe there would be a blunting of the inflammatory responses or in fact, like I mentioned in a question to dr.
So I'm very interested in the production of beta-hydroxybutyrate during ketosis and how this may travel perhaps even to the intestines and effect colon is sites and energy metabolism metabolism in our gut cells that are helping maintain the gut barrier and I would love for anyone to do some experiments on this because I think it's a really interesting and wide-open field that no one's looked into. And I honestly if there's any graduate students looking for a, you know, their dissertation
I think it would be really interesting to look at that. So you can biomark intestinal permeability a variety of biomarkers in the literature. I mentioned Zone, you'll in a big one. The lactose Mannitol ratio directly measures to non metabolize sugar molecules that are able to permeate your intestinal mucosa. This is something that a primary care physician can order for anyone. I'm actually going to try to get this done. Now, that I've really been diving into this, this literature. I'm going to try to do it after a couple.
All of different types of meals that I eat. And it seems as though one hour after a meal, is when you really get the peak of an LPS response from food, so I'm personally going to try this out. This is all just me experimenting here. So I'm not, you know, saying that this can really tell me much but this is used in the literature. Back to estimate all ratio is used as a biomarker for intestinal permeability.
I wanted to get into a mega three because it was quite clear that omega-3 in human studies and an animal studies seems to blunt the LPS, the postprandial and talks endotoxemia, as it's called, or the LPS response after a meal. And there's been a variety of mechanisms that have been worked out to understand how this is and it seems as though there's there's a few things happening. I mentioned already, omega-3, increases butyrate producing bacteria, butyrate producing bacteria.
Help prevent intestinal permeability like that's been shown. The other thing. The other way is that omega-3 increases the production of something called intestinal alkaline phosphatase ER IAP as it shown on the screen. So if we're looking again at our gut barrier quote-unquote, we have our in Terror sites connected by a tight junctions, the intestinal alkaline phosphatase. It does a variety of things, one it, can it basically, degrades, and destroys, LPS itself. It also changes the
LPS producing bacteria in the gut. So it seems to to decrease the LPS producing bacteria and then increase the, the butyrate producing bacteria. So this is another way that omega-3 may affect inflammation, like, through a totally different mechanism than all the other mechanisms that we already know about. And omega-3. I just want to spend spend a moment talking about, because it's so important and low omega-3 intake. From Seafood has been identified as one of the top six preventable causes of death.
This was this was a big study that was published a few years back out of Harvard and omega-3. There's a variety there's three different sources of it. So there's a plant source of it. You can find in walnuts or flax seeds or chia seeds. This is alpha linolenic acid or a la. And then there's the omega-3 that is found in Seafood. So there's the micro algae. But also the fish and all the, you know, the sea animals and sea creatures that are eating the microalgae accumulates in their in their adipose tissue. So there's a
Cosa Penton, you know, Cassidy, PA, and there's docosahexaenoic acid DHA and so it was the omega-3 from Seafood that was identified as being responsible. So basically not getting enough omega-3 from Seafood, was that was identified as leading to eighty four thousand deaths a year. So, 84 thousand deaths a year were attributed to low Mega three and take from Seafood. That was comparable to trans fats, which was responsible for 82 thousand deaths.
Year, literally like the same and if you walk into any grocery store and you look on the shelves, like everything's marketed. No trans fat. This is zero trans fat. Everyone knows that trans fats are bad. Everyone knows that trans fats are bad for our health. And so people, it's in the public mind. Do not eat trans fats and yet Omegle. Omega-3 intake from Seafood was identified to cause the same amount of deaths as trans fat, but nobody's thinking about omega-3. You don't walk into a grocery store and see all the foods. We don't have omega-3 or we do.
We have it from see, we are Seafood was fish. We have omega-3. It's really important. And I think it's, I really like this, because it the way I like to think about food, is what we should be eating. What do we need to? What is the point of eating, right? We're supposed to be getting nutrients micronutrients easier essential vitamins, minerals, fatty acids, amino acids, were supposed to be getting these from our food, but we're not, and instead of focusing focusing so much on what we shouldn't eat. We should focus on what we should be eating. And honestly, when you do that, like you,
I need the other stuff. It's like, well, that doesn't contain what I need. So I'm not going to eat it. And I think it's just a simplified way of looking at diet and it really helps, you can always focus on what not to eat and still be deficient in important vitamins and minerals and micronutrients. So, I really think it's an important way to back to the omega-3. It's just, it's really, I think they're to me. There's overwhelming evidence. Now, that omega-3 is really important for health. So, the omega-3 index is was identified.
By dr. Bill Harris and his colleagues Clemens Von shaky back in 2004. This is the omega-3 fatty acid level in a red blood cell membrane, and it's a long-term marker of your omega-3 status compared compared to something like, what 95% of people measure, which is omega-3 in plasma phospholipids. So, red blood cells, take about 120 days to turn over, so they have quite long of a half life. And so, if you
Really
want to know someone's omega-3 status. You have to measure the right thing. Otherwise, you could be borrow marking what they had for dinner a couple of weeks ago and it's like, oh, I had fish a couple of weeks ago and then all of a sudden they're they're marked as someone that's got high omega-3. So I think this is also a potential for a lot of confounding literature, but on top of that again, you just we have to measure the right thing to like, get good information, right? So, a high omega-3 index has been associated with a 90% reduction in sudden.
Cardiac death in the United States. The omega-3 index is about 4 percent or lower when I say, a high omega-3 index. I mean, eight percent or more so high. Omega-3 index has also been associated with a five-year increase in life expectancy. So people, with an omega-3 index of 8% or more have a five-year increase in life expectancy compared to people with a omega-3 index of 4 percent or Lord.
Interestingly in Japan people have a 5-year increased life expectancy compared to United States, and they also have an Omega 3 and X greater than a percent.
And I want to sort of end my talk with something that sort of blows my mind and I think you guys will find interesting as well. And that is that Lo omega-3 index ale omega-3 index of 4 percent or less was comparable to actually to spew smoking. So everyone knows that smoking is bad for health. If you look at the red line, the red curve here, Lowell omega-3 index and a smoker had the lowest life expectancy the green, the top, the highest life expectancy was a high omega-3 index, eight percent or more and a nonsmoker, but if you look at
Orange here. That was a smoker with a high omega-3. Have the same life expectancy as a nonsmoker, with Lo Mega three.
So again, omega-3 seems to be extremely important for health. So I'm going to end my talk with that. We talked a lot about intestinal permeability, the role of intestinal permeability, and cardiovascular health in in our brain health. We talked about the way we feel, we talked about lifestyle factors that can regulate it and Devil's Advocate stuff to think about as well. And with that, I'll say thank you so much for listening and I hope you guys learned something interesting and enjoyable to
make.
Thank you so much, Rhonda. We're going to open up the floor for questions and we have some questions coming in from the virtual platform. So and many of them you you answered during as are coming in you answered them. And but one I think you may have answered, but I didn't catch it. Is there a lab test?
For circulating lipopolysaccharide or LPS. Is there a commercially available lab tests available that people can utilize to measure this?
Is my mic. Do I need to stand by this room could. Okay. So the there is a lab test for circulating endotoxin and it's notoriously terrible because it's like false. Positives are so easy. So I mentioned the lactulose to man Mannitol ratio that is a much. I think more accurate biomarker of intestinal permeability, which would I mean directly measuring LPS would be great. But until we have a better sensitivity, a say, I think that it's
It's prone to false positivity.
So I have a question, just the button. Sorry for intestinal permeability. We've connected with a group that are using Peg 400 as one of the tests and I would like to get your opinion on that.
You know, I don't know much about that one. So I'll say beyond the scope of my
knowledge. You have a question. If there's a role with nonsteroidals in affecting and test.
Sternal permeability.
Great question. I don't know the answer. I think that's a really interesting. In fact, there may be a literature on. I just am not aware of.
Next week at a couple of comments. And a question, the first to really question myself as some colleagues, published a paper recently where we talked about in part alternative metabolic pathways in enterocytes and you see based on the preclinical data that we have. So far. The MCT one is expressed on the basolateral membrane of entire site, so they can take up ketones from circulation. And actually, the common pathway with butyrate is a see to acetyl co a before it goes.
Is the mitochondria, so they actually have converging metabolic pathways. So we think that ketones can be used to fuel entire sites. The the second thing when you're talking about LPS. I think what you're really talking about is e.coli LPS because that's what's used experimentally and it's really good at developing inflammation. I do it in my lab. I was doing it on Monday. However, there's you know, LPS on any type of Gram-negative.
And there's an increasing body of literature that says that actually LPS from various bacteria directly communicating with the immune system that immunomodulatory. This is our gut talking to us. And so, just talking about LPS go, you know, increasing in the blood and that being bad. I don't think is really right and pretty much everything that we do increases circulating up yet. So you go for a 30 minute Jog and you'll increase, intestinal permeability will increase FPS. And so where the rubber really meets the road is in metabolic.
Disease because it's only when you are insulin resistant that having elevated, LPS is an issue because being insulin resistant, the first place increases circulating LPS, but then you also have a scenario where things like transient increases in LPS, like postprandial endotoxemia. You don't have the beneficial anti-inflammatory effects of an insulin Spike to counteract that and then you also going to have things like a discordant lip balm like protein profile, where you can have more small dense LDL where LPS is going to bind to and not be cleared. So
So, I wonder if we should be focusing Less on LPS, because we're always going to have someone. It's always going to go up intermittently. And if we just actually do the things that we know work to improve insulin resistance, then that's really going to solve the issue.
I think that you brought up some really interesting points. I think, for me the way, like looking at the effect of The toll-like receptors and understanding toll-like receptor activation from LPS. And I think, you know, there with anything, there's a hormetic stress kind of effect, right? Like, you can go exercise and have a little bit of
Personal permeability and it's a type of exercise. We have a whole host of beneficial adaptive responses that are going to counter that. You're so your net effect is going to be lower inflammation. Right? Even if toll-like receptors are being activated on immune cells and liver cells and muscle tissue and brain, right, you know, in the microglia, for example, so I think there's a context is important. And so it's not like the same as if you have someone who has, you know, a chronic low level of constant, LPS leakage, but I do think that
The toll-like receptor and looking at the effect of toll-like receptor activation and The Chronic Insidious type of activation of. It is kind of more what I'm thinking, you know, I think that's kind of connecting them in the sense of the more sort of chronic low-grade Activation. So so yeah, I think that, I think that you brought up really, really interesting points. And thank you for telling me about the beta-hydroxybutyrate,
we have time for two more questions.
Maybe mine will be quick.
Is there a reason why someone
With intestinal permeability who we treat with a lot of the things that you said and feels better. They're
so quick often to come back into it versus some people
seem to be like, they
just don't experience intestinal permeability, no matter what they eat or do. Yeah, I mean, I think that even getting to the young gentleman's point, you know, you have a variety of factors that are affecting it and that's kind of why I mentioned with the saturated fat. I mean, you look in the literature and it's like, yep, saturated fat intestinal permeability.
80. But when you start to dive a little deeper, it's like, oh, but the saturated fat was a certain type of this processed oil and maybe it's the pulmonic acid, plus the, you know, refined carbohydrate or maybe it's the alcohol plus the stress, or maybe it's like multiple things in combination with genetics getting to the, you know, personalized response. I mean, some people respond terribly to ketogenic diets and some people respond great. So, I mean, there's always individual variation. There's a lot of communal, there's a lot of contributing factors to health and
It is it's hard to just say like there's one villain and there's one like you know, what do you call a good guy or hero? Right.
Thank you so much for listening. We have new overview articles available on the website on topics, like intestinal permeability the blood-brain barrier as well as toll-like receptors learn some of the interesting brain and behavioral effects of toll-like receptor activation or the important relationship omega-3 DHA has in suppressing blood-brain barrier. Permeability, some of the discussions.
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