69: Leaky Gut Explained - Dr. Ben Bikman on Gut Health and Inflammation

Hello and welcome to the Metabolic Classroom. I am Professor Ben Bickman, a biomedical scientist and a professor of cell biology. Today's topic is just a perennial favorite, if you will, where this is a topic that people seem to think about and worry about very often, very frequently, namely, leaky gut. Enough with the long winded introduction to today's lecture topic. Let's just get into it. As the name implies, of course, with leaky gut syndrome, we focus primarily on the gut. Now, just by way of appreciating the topic, there are only so many entry points for stuff to get from outside the body into the body. Of course, we have our airway when we breathe things in. Some of the things we breathe in can get from the airway and down through the lungs and then actually move into the bloodstream. My lab has actually published a few reports on that. For example, there are fine particulates of a particular size that are small enough to get in through the alveoli, the lining, the small kind of functional unit of the lungs. And when they get in, they can cause problems. The skin, of course, is also a barrier that can allow things to move into the body. This is one of the reasons why, although this is a topic for another time, time, I am so appreciative of the things we put on our skin and kind of always ask myself if what I'm putting on my skin right now is this something I would put in my mouth? Because whether we want to admit it or not, it sounds a little bizarre to say it that way, but a lot of those things that we put on our skin can move in. So those are two of the three. And then of course, the most relevant and the one we think of the most readily is the gut itself. So the intestines represent the primary method of or, or entry point for things getting from outside the body into the blood. Now, one final point about the intestines, before we actually get into the topic really, is that it's, it's one thing for something to come into the mouth. Some of those things that come into the mouth will just stay in the intestines and then come out of the intestines at the back end that hasn't really gone into our body. Now you're saying, well, what are you. Of course it's in our bodies. Yeah, kind of. You could think of the human body in a sort of general and maybe even dumb way as a tube that if something goes in the top of the tube and just comes out the bottom of the tube, was it really in the body. Did it actually get worked into the body? No, I would suggest it didn't. So when we talk about leaky gut and. And things moving into the body, I mean that it actually in this case is moving from the tube of the intestine into our blood. So it has to get through those layers or the gateways, because the gut does act as a gateway in the body. So to understand leaky gut, we appreciate its remarkable structure where as. As the. As the digestive organ in the body, it is so important at deliberately and in a controlled way moving nutrients, macronutrients, you know, the main kind of calorie sources and building blocks of the bodies. Proteins being building blocks, calorie sources being fats and carbohydrates, but also micronutrients, like all the minerals and vitamins that we need in order to be healthy. All of that is moving in to the blood from the intestine. But of course, there are lots of things that shouldn't come in. There are a lot of things we may breathe that we don't want to come into our blood. There are a lot of things in particular people put on their skin that they don't want coming into their blood. So too, there are things that get consumed or are already living in the intestines in particular, which we'll talk about that should not. That might be fine in the intestines, but do not belong in the blood. So in order to keep all of this, to keep things in their proper locations, the gut lining, you know, or the lining of the tube that is our intestines, it consists primarily of a single layer of a specialized type of cell called epithelial cells. Now, we have epithelial cells in various other parts of the body, including the three entry points I mentioned earlier. Skin is epithelium. The airway has epithelium. So too does the gut. Now, other places do as well, like reproductive tracts, the cardiovascular system. So we have other epithelial cells. But basically, if you can think of something that needs to have a lining to it, that's going to be epithelial cells. Now, the epithelial cells are interesting because of their structure. Not only their structure them with each individual cell, that's not actually what I'm referring to, but how they act as neighbors where epithelial cells form what is famously called tight junctions. So as I'm awkwardly acting this out here with this little boom mic here, you can see here I have two epithelial cells, and these two epithelial cells on their own are Doing what they need to do. But in order to do what they need to do, which we'll talk about, they are tightly bound together. There are myriad proteins that in that ensure that these junctions are very tight. And in fact, that is what they're called, these tight junctions. They're supposed to be tight. The reason those junctions are supposed to be tight is that we want to ensure normal intestinal transport. So let's get into that and then we'll talk about when things go wrong. So normal intestinal transport with normal conditions, normal health of the gut. Nutrients, like I mentioned earlier, macronutrients, like amino acids, glucose, fats, those will get absorbed through the epithelial cells. So if we go back to my two fists that were acting as epithelial cells bound together, when macronutrients and micronutrients, again, minerals and vitamins and things, when they want, when they are coming from the gut into the blood, they do so through what's called transcellular transport. In other words, the epithelial cell will see this molecule, the macro or micronutrient, recognize it as being an appropriate fit, and then will allow it to come in. And it, when it does come in, it comes in through different transporters or channels. Those are terms that you think are the same, but they actually are used pretty distinctly. So there are transporters and channels that will allow these things to come. In some instances, there is this vesicle movement. But regardless, the epithelial cell will say, okay, I recognize you, you can come in. It's almost acting like a bouncer where you're kid, these things are trying to get into a club. Not that I would know. I've never gone into a club in my life, having lived a very unique life, if you will. But nevertheless, the molecule is allowed to enter because the epithelial cell has doorways or entry points designed for it. But in order to do this, of course, in order to control what comes in, the epithelial cells work together to ensure that there's not a back door, there's not some sneaky way, a back alley for these molecules, for molecules that are not supposed to get in, to actually get in, to slip through. And that brings us to the next point, which is how does it look when things are slipping through this, when. When transport of molecules is compromised? So when the gut gets a little leaky or permeable or more porous, if you will, where things are now coming in that shouldn't be coming in, it's because the tight junctions between the epithelial cells have Become weakened or damaged. This then leads to a type of transport called para trans cellular transport, not trans cellular. It's not going through the cell anymore, now it's going between the cells. So the molecules that we'll, we'll get into, some of them now are passing between the cells. So it's like we had two bouncers at the, at the door to the club standing shoulder to shoulder and the only people that were getting in is because the bouncer would physically escort the person in who that's normal healthy transcellular transport of micro and macronutrients with paracellular transport. Now it's as if the, the, the, the guards here, the, the bouncers have stepped apart from each other and now some little miscreants are able to slip between them paracellular. So this of course allows not only potentially harmful but also just much larger molecules to be slipping through, including so molecules and microbes, as I usually say, that now can slip through these gaps. And there are health consequences to this as we'll get into. There are all kinds of things that can slip through. I, in the time that we have, I want to make you familiar with what I argue is the most relevant one. And it is coincidentally a molecule that I've studied and published on fairly extensively, particularly during my fellowship many, many moons ago. So that molecule, the, the perhaps most famous and relevant molecule that slips through with leaky gut is a molecule called lipopolysaccharide. Generally that we just abbreviate this as lps. It is a large molecule that's actually a component of the membrane of a particular family of bacteria that are inherent in the human microbiome called gram negative bacteria. Now that does not, it should not imply that they're just uniform villains. They have a part, they are part of the microbiome and indeed part of a healthy microbiome. However, they belong in the gut and their, their surface cell membrane molecules like lipopolysaccharide, which is one way of identify how they identify each other, they belong in the gut as well, not in the blood. So with the LPS now it starts to act as an, it's often referred to as an endotoxin because of its ability to trigger very strong immune responses. When these bacterial cells break down and release the LPS and then it's now getting normally. Ideally this LPS would just be eliminated with feces, just the process of moving waste through the intestines. However, when it gets into the blood, because it's enabled to slip through or between the epithelial cells now it's creating a problem. So the source, as I noted for LPS is from the gut. And you can measure LPS in the plasma. I've done this. It's not hard to do. Labs can do this when you get your blood drawn, although it would be an uncommon request. But it is common enough that almost everyone will have some degree of LPS in their blood. We of course, just want much less. And we also want molecules that can defend against the lps, which I'll get to in a bit when we start talking about some of the solution to this. So now, one important point, and I'm going to revisit this when I start talking about some of the explicit disease consequences of lps, is that when LPS enters the bloodstream, it can bind to these surface receptors that are on cells. Virtually every cell has these called toll, like receptor 4, TLR4. Generally, these, these are thought to only exist on immune cells. And while they are certainly heavily present on immune cells, they do exist on other cells as well, like muscle cells, liver cells, fat cells, et cetera. And then in, once it's when, when LPS has bound to TLR4, it will then initiate a series of events within the cell that we could generally just referred to as an inflammatory cascade. Now, when you think about inflammation, in this case, we have to be a little careful because often when people think of inflammation, and I realize we're still talking about leaky gut syndrome, but this is a consequence of leaky gut. When we think about inflammation, we often want to think about a big red, angry, swollen wound. And that's really a matter of a little bit of edema or water accumulating there and just much more blood flow where the blood vessels have really dilated. That's all part of the classic or prototypical inflammatory response. But there is this. What starts to happen with leaky gut syndrome and to a lesser degree with other scenarios, just like obesity, the person has a chronic inflammation, but it's, it's subclinical, it's low grade, it's a low grade systemic inflammation. So if the person went in and got a blood test and measured LPS and C reactive protein and TNF alpha and interleukin 1 beta, these, these pro inflammatory proteins called cytokines, they would be high if, so if they measured this inflammatory panel of markers, they would be elevated. Now, not elevated to the point that the person has an overt illness, not that they have a cold or a flu, let alone an autoimmune disease. However, it's not where you'd expect it to be in an otherwise healthy person. So that's why it's often referred to as subclin. It's not that they have, or in the most extreme instance this, they would call it sepsis. Sepsis is when there is just this massive inflammatory reaction going on in the body. Another way of describing this or that has been described in the research on this topic is metabolic endotoxemia. So earlier I'd mentioned that LPS is referred to as an endotoxin toxin because it's capable of initiating an inflammatory response, an endo, because it's within the body. And so metabolic endotoxemia starts to touch on this idea. Anytime you hear the suffix emia, by the way, that means in the blood. So that just means that the LPS is coming into the body through this leaky or permeable gut and now it's increasing inflammation throughout the body. So that is as we now move on to some of the consequences of leaky gut and in also consequences of lps, which is the most famous consequence and manifestation of leaky gut. We can go, we can go through these. And the first one being just the systemic inflammation that I mentioned earlier, when the, when the endotoxins, LPS being the most abundant and relevant, enters the bloodstream, they trigger this low grade inflammatory response which then increases the risk of myriad cardiometabolic diseases. As I also LPS is connected on its own to numerous complications like fatty liver disease, heart disease, the inflamma. Many people believe that atherosclerosis or the formation of plaques in the blood vessel is largely a consequence of these kinds of inflammatory aggravators that far from being some problem of cholesterol, it's rather a problem of you're just sort of scratching at the endothelium of the blood vessels with these pro inflammatory triggers, LPS being the relevant one here. Now we let me maybe just reiterate one final point before we start talking about some of the triggers for this. When LPS goes up, it activates TLR4. And this does in fact conclude a thought that I was kind of long windedly getting around to earlier, which is when we think of inflammation, we think of the big red swollen angry wound. And yet you can have cells that are not at all involved in inflammatory responses, like muscle cells that also have this in that instance. It's not that when LPS comes and binds to TLR4 on a muscle cell, it's not accurate really to say that the muscle CE becomes inflamed however, that same pathway of events, you know, when LPS comes and knocks on the door, TLR4 being that door, what it's telling the muscle cell to do will have some redundancy of with. With what you would see in an actual prototypical immune cell like a macrophage. So it's the same pathway and process, although the macrophage would take it further and then have a different overall response. But what would be in common is that both cells would become insulin. That's work that I've done pretty extensively. So think about the LPS promoting inflammation, and then the inflammation, or that inflammatory pathway, to be a little more precise, causes insulin resistance. And then, of course, with insulin resistance, you now have gone through the gateway of all of the plagues of prosperity, but compounded by the overt inflammation itself, also contributing to problems. So take, for example, atherosclerosis. You may have insulin resistance now promoting some degree of vascular pathology where the blood vessels aren't dilating very well. They're very narrow, so blood pressure is very high. That can damage the blood vessel wall. But then you combine that with the LPS that's circulating, causing inflammation, now you're making a problem even worse. All right, now let's shift gears and talk about some of the dietary and environmental triggers that can exacerbate leaky gut. Because after all, diet and lifestyle play an enormously relevant role in maintaining or disrupting the integrity of the gut barrier. Okay, the first one. So now we're talking about the noxious stimuli that can turn leaky gut on or enhance the permeability or leakiness of the gut to things that should not be coming in from the gut. First one, I start with for a reason, because the evidence really is so convincing and it is so abundant, namely the humble sugar fructose. So fructose is a powerful stimulant at compromising the gut membrane. Now, of course, this is very, very common anytime you're eating sugar or high fructose corn syrup, or I would even add, drinking a lot of fruit juice, because there's even evidence on this that's a lot fructose that the gut has to deal with. And fructose has been shown to alter the tight junctions in the intestinal epithelium. Indeed, it has been shown to do through do so through a few distinct mechanisms. First and foremost, and there'll be a link to this in the show notes. Go et Al in 2021 found that fructose consumption can decrease the expression of some essential critical Tight junction proteins. There are three in particular. Fructose has been shown to compromise the expression of Z01, that is the letters Z01, that's an acronym Z01. Occludin and Claudin, they have some similarities in some of the terms, although they're all spelled a little differently just to make things extra confusing. But again, what Guo et Al in 2021 found was that fructose reduced all of those junction proteins, Z1, occludin and claudin. That of course weakens the intestinal barrier, increasing permeability and allowing harmful substances like LPS to move from the gut into the blood. Second, fructose can change the composition of the microbiota, leading to some imbalances of the microbiome that can promote intestinal inflammation. This can indeed include increasing the population of the gram negative bacteria, where what was once a nice quiet component of the very busy microbiome becomes a very rowdy, obnoxious group because there's just so much more of it. That was work. Again, we'll have this linked in the show notes from Zhang et Al in 2021. Also, one final mechanism that fructose has been shown to increase intestinal permeability, AKA promote leaky gut syndrome, is that it can promote oxidative stress, which contributes to the further the compromising the function of those junction proteins Z1, occludin, claudin 1. And then with that degradation comes this more porous epithelium or what should be a tight, tight barrier now has all these gaps in it. So fructose is a very important contributor to compromising the permeability of the intestines. Also, as we have just started this laundry list of noxious stimuli, polyunsaturated fats can do this. In fact, in a little bit I'm going to talk about a specific study, so I'm just going to grease the skids a little bit with this refined seed oils and we'll revisit the topic in a moment. So while there are some of course polyunsaturated fats that are considered essential, namely the DHA and EPA, the Omega 3, if there's an imbalance in the consumption of Omega 6s and Omega 3s, and there is, that has been shown to contribute to gut permeability. And just to be very, very precise, the excessive consumption of the omega 6 fats is compromising the integrity of the gut barrier. And again, I'm going to highlight a study in just a few minutes that talks about this in more detail. But to be very clear, that is linoleic acid. That is the fats from refined seed oils. I don't blame refined seed oils for every ill. I think that we all. We should have some caution, some temperance in vilifying this. But in this case, the evidence is pretty compelling. All right. Gluten, of course. Now, not everyone responds to gluten poorly, but gluten, a protein that is in wheat and other grains, can be a significant trigger for leaky gut. Of course, this is relevant in people with a gluten sensitivity or outright celiac disease. Not everyone has this. But gluten can cause the release of a protein called zonulin. And zonulin regulates tight junctions. And so more gluten compromise, increasing zonulin. That can lead to increased intestinal permeability or leaky gut syndrome. Alcohol also can damage the gut lining. I know what you're thinking now. You're thinking, gosh, Ben, you are just singularly vilifying every indulgence. I don't mean to. I don't mean to. There are still a lot of other things you can enjoy. But if you're worried about your gut, alcohol is another one you need to be careful with. Chronic alcohol use is particularly associated with compromised gut barrier function. Then the last one that I just feel compelled to add is not one we eat, but rather how we feel. Namely, that is stress, psychological stress. And I would add the hormones that mediate that, such as cortisol, can weaken the tight junctions over time, once again increasing the permeability of the gut, thereby promoting the onset and progression of leaky gut syndrome. Okay, now, at this point, you may be feeling a little discouraged. I just listed all these things you enjoy indulging in. Perhaps there is some good news, but it would of course require the discomfort of changing some habits. Perhaps. So the good news is that there are strategies that can help restore gut integrity and enhance and correct the. The leakiness and the permeability. So let's talk about some of those variables that can help promote a healthy gut barrier. First, one is one of my favorite topics because I get to talk about fat, which I feel like I need to defend very frequently because I feel like it is very often miss or much maligned fat is vilified unnecessarily. There are two fats in particular I want to talk about alth. One can fit within the general umbrella of the other. So firstly, small chain fats or. Or short chain fatty acids. Short chain fatty acids, especially butyrate, are produced generally by fermentation but you can consume some, some dairy products just can have butyrate right in it, but we can make it as well. And I'll talk about that more in a moment. Butyrate has been shown to be a very good fuel for the epithelial cells and can enhance but can strengthen the intestinal barrier by promoting the production of the tight junction proteins, like those proteins I mentioned earlier, Z1 occludin and cloudin one. So two, two fold benefit there from the short chain fats, promoting the expression of those proteins that help create the tight junctions and acting as a fuel for the epithelial cells, keeping them well fed and nourished. Now the next. And these short chain fats actually fit into this, which is saturated fats. So I want to explore with you very briefly an intriguing study that sheds some light on the role of saturated fats in gut health. Now, most people, when they think about gut health and saturated or just saturated fat in general, they think that there's only bad things to say about saturated fat. Well, this article published in the journal Nutrients, challenges that view. So the overview, the study generally was framed to understand how the different types of dietary fats, like for example, saturated fats from dairy fat, polyunsaturated fats from corn oil, so that's omega 6, and monounsaturated fats, olive oil, affect the gut. And they found that the polyunsaturated fats, like those from corn oil, actually caused intestinal inflammation and broke down the barrier of the intestines, saturated fat. In contrast, for milk, they looked at dairy fat actually promoted a compensatory inflammatory response. In other words, it actually had a good or a healing response, promoting general intestinal recovery and healing, dare I say the word. Although that nowadays makes me sound a bit hippie. Nothing about me is hippie, I assure you. And also it improved the gut barrier function, so it tightened up those, those, the barrier, the epithelial cells. So pretty direct evidence there. Again, just to really put a fine point on it, the corn oil comprom, it promoted intestinal inflammation and weakened the tight junctions. Saturated fats did the exact opposite. These fats from dairy. Now, dairy has a lot of different fats and I'm an advocate of all of them. I think dairy fat is one of the most overlooked beneficial things we can eat. So the saturated fats from dairy fat were found to recover or heal the gut and tighten the tight junctions, so making them work even a little better. Now, another thing, this isn't so much something you eat, but something rather we create, and that is LDL cholesterol. In fact, I placed this deliberately in the conversation where I did, because some of the fear of saturated fats in the diet is that some people have an increase in LDL cholesterol when they eat saturated fats. This has overwhelmingly been viewed as a negative. Let me suggest that in this case, it's a benefit people don't. In another. I've talked about this in previous metabolic classrooms, but in another world, in another timeline, if you will, in. In another part of the multiverse, LDL cholesterol was, would have been discovered and discussed as a hero of the immune system, rather than an apparent villain of the cardiovascular system. In our timeline, in our world, LDL cholesterol is viewed uniformly as a villain that needs to be squashed at all costs and diminished to the lowest possible levels. To hell with the substantial global evidence, albeit correlational. But it's all correlational. That suggests people with the lowest LDL levels actually die more, including dying from sepsis and infections. So these serious inflammatory challenges. The person with the lowest LDL appears to have a very, very weak immune system, and that is generally part of what's going to kill them. In contrast, people with the highest LDL levels not only tend to live longer, but they also have much less fear of infections, let alone something as severe as a septic shock or sepsis. And that is because of what LDL does. This is why I suggest that rather than being viewed as a villain of the cardiovascular system, which I don't think is fair at all, it should be viewed as a hero of the immune system. LDL has on it these mall, these, these areas called LPS binding domains, where it literally can sense, it can scavenge LPS from the blood. So let's say that you've had a certain amount of LPS come in from your intestines, which is where it comes from. LDL will bind it, take it to the liver and dump it into the liver for the liver to then dump it into the intestines, back into the colon, where it can be dumped, ultimately get out of the body. Actually, the liver would put it into the small intestine, then it'll go to the colon and then out of the body through the bile duct on the front end. So LDL cholesterol, far from being this problematic molecule when it comes to lps, at least, is very, very beneficial. Again, this could explain why the correlational evidence suggests people with higher LDL have much lower risks of infections and inflammation, because LDL is literally Binding, scavenging, it's searching for and binding to the lps, saying, lps, you naughty little child, I'm not going to let you wreak havoc in the body. I'm going to ground you. I'm going to put you in timeout. Dumping, taking it to the liver and dumping it out from the body into the intestines. Now, final points about helping the gut barrier work better very quickly. Fiber. So probiotic, rather prebiotic fibers. So soluble fibers, the reason they appear to be so beneficial is because of what they get turned into. Whereas soluble fibers don't nourish the human body, they don't give us energy. The microbiome does get energy. And when the microbiome digests or metabolizes the fib, the soluble fiber, it actually turns it into short chain fats. So one of the reasons I think prebiotic fibers can be healthy is their subsequent production into short chain fatty acids. Now one final note on that before moving on is that I think fiber is most important when a person's eating carbohydrates. If a person is generally eating very little carbohydrate or not eating any carbohydrate, then I think the need for dietary fiber starts to go down. As carbohydrate consumption goes up, the need for dietary fiber, soluble fiber in particular, I believe also goes up. Then lastly, probiotics and fermented foods, just populating the intestines with healthy bacteria and then the products of fermentation, which again are short chain fatty acids, are going to be healthy. Now, one last point from a study that I just saw recently, the rare sugar allulose. There was a very neat paper published by Bake B A E K. I think it's a Korean group in 2023. The title is a bit long, so I'll just give you the first part of it, but we'll have this in the show. Notes. Allulose enhances epithelial barrier function by tight junction regulation. All right, that's enough. Although the title does go on, what they found essentially in their experimental models is that allulose increases the expression of the tight junction proteins. All of the ones I've already mentioned. Allulose increased Zo1 expression, occludin expression and cloudin1 expression. And remember, those are the critical proteins, like the Velcro pieces that bring the epithelial cells together and keep them nice and tight, thereby helping reduce the likelihood of anything slipping through, reducing that paracellular transport. Independent of that, allulose was actually also shown to significantly reduce the inflammatory response from lps. So remember, LPS is the main villain that we focus on when we talk about leaky gut syndrome. These things that are slipping through. LPS is the most famous of them. Allulose. The allulose treatment reduced the inflammation. In fact it was about by half. You can see when you look at the study which will be in the show notes. All right. We covered a lot and it is a relevant topic. So I really hope that today's lecture was helpful to you understanding your own physiology and your own health. Perhaps there are some habits you need to do let engage in less frequently or maybe there are some foods or practices to engage in more readily. Regardless, I hope the information has been helpful. But of course it is only as helpful as it is implemented. So I really do hope that anytime you feel like you've learned something, as much as that gratifies me as your honorary professor, I really hope that it in turn leads to a change in behaviors where relevant. Until next time, thanks for tuning in. More knowledge, Better health.