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Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging before we get started. Just as a reminder, you can listen to both of my podcasts ad free by becoming an insider. Just go to Ben Bickman.com or click on the link at the top of the show. Notes welcome back to the Metabolic Classroom. I'm Ben Bickman, biomedical scientist and professor of Cell biology. The topic for today's mini lecture is one that connects your gut health directly to metabolic problems. Lipopolysaccharide, or lps. This molecule, produced by bacteria in your intestines, can trigger inflammation throughout your entire body when it escapes into your bloodstream. Understanding how LPS gets out of your gut and what you can do to stop it is crucial for preventing insulin resistance, fatty liver disease, and the chronic inflammation that precedes it. Let's start with the basics. LPS is a large molecule found in the outer membrane of gram negative bacteria. These bacteria naturally live in your intestines by the trillions. Under normal circumstances, LPS stays safely contained within your gut. But when your intestinal barrier becomes compromised, a condition often called leaky gut, LPS can cross into your bloodstream. Once LPS enters circulation, it triggers a powerful immune response. Your immune cells recognize LPS as a foreign invader and release inflammatory molecules called cytokines. This creates what we call in the biz metabolic endotoxemia, a state of chronic low grade inflammation that disrupts insulin signaling and promotes the other problems that I mentioned. Now, when I use the term low grade, that's a very deliberate term because it might not be that your body's reaching a point of inflammation that would be clinically red flagged, but it's still higher than it ought to be. So the intestine and its lining is very important here, and no surprise, it is a remarkably sophisticated structure. The intestinal lining is designed to allow some things to come in, but not everything. So it's designed to absorb nutrients while keeping harmful substances out. And think about the sheer number of harmful substances there could be yucky, bad, toxic things. And whatever you may be drinking or eating, the barrier itself consists of a single layer of epithelial cells. And these epithelial cells are connected by specialized structures called tight junctions. But to truly understand how LPS escapes from your gut into your bloodstream, you need to understand the two fundamental different pathways by which molecules can cross this gut barrier. It's helpful to think of your intestinal lining as a brick wall where the epithelial cells are the bricks, and the tight junctions between these cells are the mortar between these bricks. Molecules can cross this barrier, this brick wall, in two different ways. It can either move through the cells or between the cells. The transcellular pathway is the route through the cells themselves. This is how your body absorbs things like nutrients. When you eat protein, for example, it's broken down into amino acids. These amino acids will bind to specific transporters on the surface of the cell, and then these transporters will actively move the amino acids. It will pull them in through the cell and then release them on the backside, getting into the bloodstream. This is a very selective process. The intestinal cells will decide what gets through and what doesn't. Imagine it's like bouncers standing at the entrance of a club. They're deciding who can come in and who can't. The same principle applies to things like sugars or fats or vitamins and minerals. Each has specific transport proteins that recognize and move these molecules across the cell membrane. Again, no surprise. The transcellular transport is tightly regulated. You want your body and these cells to be able to control what can cross and how much can cross at any given time. It's the designed pathway for absorbing the things that we need. The paracellular pathway is the route between the cells, and it's through these tight junctions that will seal the spaces where the cells meet. That's the. That's the mortar in that, with the metaphor of it being like a brick wall under normal, healthy conditions, the tight junct, highly selective barrier, they do allow some things to pass, like water and very small ions, although it's in very small amounts, but they will block any large molecules, certainly bacteria and bacterial products like lps. But here's where the problem begins. When your tight junctions are damaged or their proteins are disrupted that are keeping them locked together, the paracellular pathway becomes pathologically permeable. The spaces between the cells will widen. Now, large molecules that should never enter your bloodstream, including lps, including even some undigested food proteins and bacterial fragments, can leak through. This is the essence of leaky gut. To understand how the barrier breaks down, I think it's helpful to know what holds it together. Again, we're talking about the mortar between the bricks. Tight junctions are very complex structures made of several protein components. And I'm going to mention the main ones that have been shown to be relevant in research. So the first one is something called Zonula occludens 1 or just Z01. I'll refer to it as that this is what's called a scaffold protein that will anchor the tight junctions to the cell's internal skeleton. Think of it as the framework that keeps everything in place. When Z01 is reduced or mislocalized, meaning it's not found in the right spot, the entire tight junction structure will suddenly become unstable. So what's binding the cells together starts to kind of fray apart. Another one is occludin. Occludin is a transmembrane protein that spans across the cell membrane and interacts with occludin on an adjacent cell. So this is almost like the hooks and loops of, like, Velcro helping lock things together. And research has shown that when occluding is phosphorylated or altered at specific sites. This can certainly happen with things like oxidative stress and inflammation. It will detach from the Z01 molecule I just mentioned, and then the seal between the cells, the mortar, starts to fragment. And then one other part that's important in this process is claudins. Clawdins are a family of proteins that determine the selectivity of the tight junction. So different clawdin types have different properties. Some clottins will form barriers that tighten the junction. Others form selective pores that will allow specific ions to get through the mortar. That tight junction, the specific combination of claudins expressed in, in the intestinal cells will determine how permeable the gut barrier is. And of course, when these proteins are all functioning properly, your gut barrier is functioning properly, it's strong, and it is, most importantly, selective nutrients cross via the regulated transcellular pathway. Remember, that's going through the cell while the paracellular, meaning between the cells, that pathway will remain very, very tightly controlled. But through dietary factors, intestinal inflammation, other things we'll get to in a moment, that paracellular pathway will open up inappropriately. Now that you understand the structural proteins that hold the tight junctions together, you need to know about the signaling molecule that tells them to come apart, and that is zonulin. Zonulin is the only known physiological modulator of tight junctions that we've described, that has been described and identified so far. Think of it as a master switch that controls how permeable your intestinal barrier becomes. When zonulin is released by your intestinal cells, it will trigger a cascade of events that causes the tight junction proteins to disassemble, and the spaces between them will start to widen. So the mortar is crumbling and the bricks are being pushed further apart. The mechanism is elegant, but of course it's problematic when it is dysregulated. Zonulin can bind to receptors on the surface of these intestinal cells and the binding will activate a series of proteins. You know this activation cascade and ultimately causing Z01 to detach from an anchoring position. Simultaneously, you have other molecules, like actin filaments within the cell that will reorganize and polymerize. But the combination of this is that the cells will contract and pull apart, allowing the junctions to be much wider. Under normal circumstances, you can have this being part of a defensive mechanism. When your small intestine is exposed to certain bacteria, zonulin release will cause a temporary increase in permeability, essentially flushing out the microorganisms as part of your innate immune system response. This is zonulin working as intended, a quick opening and closing of the barrier to deal with a threat within the intestines. The problem arises when zonulin release becomes chronic or excessive. Research has identified two primary triggers for zonulin secretion, bacterial exposure and gluten. But importantly, dysbiosis is imbalanced Gut microbiome, specifically with an overgrowth of gram negative bacteria. Remember, gram negative bacteria are those that have lps. This can cause a persistent zonulin elevation. These bacteria continuously stimulate zonulin release, creating a chronically permeable gut barrier. And there's relevant human evidence on this. Studies examining patients with type 2 diabetes or inflammatory bowel disease, or rheumatoid arthritis, and even cardiovascular disease consistently show elevated serum zonulin levels alongside elevated LPS levels. The correlation is striking. When zonulin is up, intestinal permeability is compromised and endotoxemia follows. Or this, and then the chronic inflammation. What makes zonulin particularly important for metabolic health is that it connects gut barrier dysfunction to systemic diseases. Elevated zonulin levels can predict the transition from asymptomatic autoimmunity to active inflammatory disease. And in the context of metabolic syndrome, zonulin elevation may be one of the earliest detectable signs that your gut barrier is failing and that you have some metabolic endotoxemia beginning. The therapeutic implication is there, and I think it's clear any strategy that will reduce zonulin signaling will help maintain barrier integrity. Prevent LPS from getting in. Now, why even talk about lps? LPS is a large molecule. It is far too big to cross through the healthy gut tight junctions via the paracellular route. And it doesn't have transporters to cross transcellularly. Under normal conditions, LPS will stay safely contained in the gut. But when tight junction proteins like Z01 or occludin and claudins or are disrupted, that paracellular space will widen. Now, LPS can leak between the cells entering that space and getting into your bloodstream. Once it is in circulation, LPS triggers the inflammatory cascade that we discussed earlier. This is one of the reasons why maintaining a tight junction is so important. So what makes the barrier breakdown? There are a handful of variables here, and I want to focus on the ones that I believe are most relevant when it comes to dietary factors, because there are several. And let's examine the two that I believe are the most significant. Fructose and omega 6 fats. Fructose consumption has of course, increased dramatically with the widespread use of sugars and high fructose corn syrups. Research demonstrates that high fructose intake directly compromises intestinal barrier function and increases LPS movement into the blood through multiple mechanisms. Preclinical studies show that oral administration of fructose exacerbates problems in the liver. And that is a relevant marker because the liver is directly downstream of the intestines. So if things are leaking through the liver, leaking through the gut wall, if things are leaking through the gut, the liver is the first one who has to see that it's kind of the front line of what's coming in from the gut. The mechanism here involves reduced expression of z01, that is the critical tight junction protein that I mentioned earlier. This then allows the translocation of LPS through the portal vein and directly into the liver. This gut derived LPS then promotes inflammation and even fibrotic or scarring changes within the hepatic tissue or the liver. This interaction between fructose stress and the gut barrier is particularly concerning. Research demonstrates that high fructose combined with restraint stress. So in an animal model, upsetting the animal and making it stressed can increase this disrupted barrier even faster than normal. So this ends up being a wicked combination of stress plus fructose, which, if we're being honest with ourselves, is, is a pretty common occurrence within human daily living as well. Now let's move on to the fats. The ratio is what's important here. The ratio of omega 6 to omega 3 fatty acids in your diet profoundly affects your gut barrier. Modern western diets contain excessive omega 6 fatty acids, primarily things like vegetable oils or so called vegetable oils, but they're seed oils, corn oil, soybean oil, sunflower oil. This creates an inflammatory environment in your intestines. Diets enriched with omega 6 polyunsaturated fatty acids dramatically alter gut microbiota composition. In a mouse model where they were fed high omega 6 diets, researchers observed significant enrichment of a family of bacteria that includes many gram negative or LPS producing species. This we could call is a type of microbial dysbiosis and no surprise in these animal models it was associated with a heavy degree of colitis, so inflammation of the gut and increased susceptibility to normal bacterial infections. Remarkably, fish oil supplementation or omega 3 attenuated these negative effects. The addition of omega 3 fatty acids reversed the omega 6 induced dysbiosis, reducing LPS containing populations and improving overall microbial balance. However, the research revealed an interesting complexity. While fish oil improved the microbiota and reduced colitis, it simultaneously impaired LPS activity, which in some contexts changes it changed the overall ability of LPS to move in and act or harm the body. One other line of research in animals finds that when they could genetically modify mice to make its own so the animals could make their own Omega 3s so it was no longer essential in the diet, they were making it all the time. What they found is that that was sufficient by changing to change the omega 6 to omega 3 ratio and it was enough to totally oppose the effects of endotoxemia. And what's important is that they were able to get that ratio of omega 6 to omega 3 to about a 1 to 1 as opposed to in normal human diet typically about 15 or 20 to 1 where we're eating about 15 to 20 times more omega 6 than omega 3. It's not overall feasible in a human diet to get it to one to one, but it is certainly feasible to get it closer to like a 3 to 1 of omega 6 to omega 3. And there's human evidence to suggest that could be sufficient.
