Transcript
Progressive Insurance/Capital One Advertiser (0:00)
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Skyrizi Psoriasis Patient (1:01)
my perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA, a prescription only 150 milligram injection for adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.
Skyrizi Medication Warning Narrator (1:28)
Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
Skyrizi Psoriasis Patient (1:40)
Thanks to Skyrizi. There's nothing on my skin and that means everything.
Skyrizi Closing Narrator (1:45)
Nothing is everything.
Skyrizi Psoriasis Patient (1:48)
Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyriz-SIZZY to learn more.
Ben Bickman (2:07)
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. Welcome back to the Metabolic Classroom. I'm Ben Bickman, Metabolic Scientist and Professor of Cell Biology. Thanks for letting me be your temporary professor while we cover a topic that rarely gets discussed in the realm of metabolic health and that is the mouth. Specifically, we're going to talk about how the health of your gums, the tissue that holds your teeth in place, can have a profound and far reaching impact on your metabolism. That includes your insulin resistance and even the level of your heart functioning. Well, most people, when they think about gum disease, think about just a dental problem, that maybe they have bad breath or maybe they have a toothache. But the evidence tells a very different story. The mouth, it turns out, isn't just the entry point for the food we eat. It can also serve as a gateway for chronic systemic inflammation. And once inflammation escapes from the mouth and enters the rest of the body through the bloodstream, that's why we use the word systemic, the consequences then also ripple outward in ways that can include not only insulin resistance, but, as you'll see, also cardiovascular disease. So today I want to take you through what the mouth looks like when it's healthy, versus diseased. Who's at risk? What's actually happening mechanistically when gum disease goes systemic, and what the data tell us about the downstream metabolic consequences. I'll also leave you with some practical takeaways because this is one of those topics where awareness alone might actually change some of what you do. All right, to get started, it might not be too surprising to you to hear some of this, but the mouth is home to a lot of microorganisms. Now, the scope of it might surprise you. There are over 700 known identified species of bacteria that live within your mouth. Most of these bacteria are harmless. Many of them are helpful, and they, between these ones, form a balanced ecosystem that lives within I guess what we could call a thin film that's coating our mouth and teeth. But when that ecosystem remains, when it remains balanced, the gum tissue is healthy and everything is working well and those bacteria are staying where they belong. The gums, in this instance, will form a tight cuff around each tooth, and that creates a nice physical barrier that will prevent the bacteria in the mouth from moving into the body. But when things go wrong, you get a condition called gingivitis. I bet you've heard that before. That's just inflammation of the gums. If this is left unaddressed, then gingivitis can progress to periodontitis. And periodontitis is when the inflammation has gotten so bad that you have some destruction of the tissue and bone that support the teeth. The gum pockets can deepen. In this case, the bone can get weaker. And what was once a sealed barrier becomes a chronically inflamed and even somewhat ulcerated wound. So it's Leaking a bit now. And here's the critical insight. That inflamed ulcerated tissue around the teeth is in direct contact with your blood, your circulatory system. And now when bacteria, and also the toxic molecules that they make breach that tissue, they will enter your bloodstream. This isn't a particularly rare event. It's just that in severe periodontitis, anything we do can trigger what researchers call bacteria. So the bacteria moving into the blood too readily. And periodontitis is not uncommon, based on which source you're looking at, we. There's an estimate that about a quarter to half of the global population has some form of periodontitis, some degree of severity. So this is not something that's rare. It's surprisingly common. Now, when we talk about bacteria, the one most implicated in periodontitis and the systemic consequences that I'll outline, it really ends up often revolving around one single bacterium, and that is P. Gingivalis. This is a, what's called a gram negative anaerobic bacterium, meaning it will thrive in a low oxygen environment, even if it's, you know, somewhere deep in the, in, in a, in the gum pocket, you know, tucked between the gums and your teeth, where there might not be a lot of blood flow or, or air. But it has a remarkable arsenal, if you will, of virulence factors. So one of the things that I've focused on the most in my career as a scientist, and I'll highlight some of that research in a moment, and I will highlight more of that here, is the fact that P. Gingivalis produces a molecule called lipopolysaccharide, or lps. That's a component outer membrane. If you have been a longtime student of the metabolic classroom, you've heard me talk about LPS multiple times now. LPS is one of the most potent inflammatory signals known to biology. It's the molecule that's responsible for the extreme inflammatory response seen in a condition called bacterial sepsis. It also produces enzymes called ginger pains, which are proteases that can actually directly digest the proteins in cells that are receiving it. These gingipains can allow the Gingivalis bacterium to tear through the periodontal tissue and as we'll discuss, can subsequently wreak havoc in distant tissues as a result. But here's a detail that makes P. Gingivalis particularly insidious. Its lps, while structurally different from classic bacterial lps, it can interact with these receptors on the cell called toll like. Receptors like a toll booth, T, O, L, L, toll like Receptors. These fall into kind of a broad family of cell receptors. But when it may, when the, when the LPS binds these toll like receptors, it can initially BL an acute immune response. So the ability just to just fight an infection. But it also in turn triggers a chronic, systemic, albeit subtle level of inflammation throughout the rest of the body. It's not an explosive fire of an acute infection, but rather this sort of smoldering, slow burning fire of chronic inflammation. And as we know in metabolic research, chronic low grade inflammation is one of the primary drivers of insulin resistance. You've heard me describe that abundantly in the past. It's one of the cardinal causes. In fact, my own lab has looked closely at what P. Gingivalis LPS does inside gingival cells at the level of the mitochondria. What we found, I think, was quite interesting. These were dental students that helped us do the work in combination with the undergraduates in my lab. When we treated human gingival cells with the LPS from the P. Gingivalis, the mitochondrial respiration went up. In other words, the mitochondria were, were breathing more, they were working harder, they were consuming a lot more oxygen. Now, you might think, well, that's a good thing. Well, here's kind of the paradox, because while the mitochondria were indeed consuming more oxygen, they were producing far less ATP. So the cell was burning fuel, but it wasn't making anything useful from it ATP. Instead, that increased mitochondrial activity was generating reactive oxygen species. So it was using the oxygen oxygen to drive oxidative stress. And we also saw increased mitochondrial fission, meaning the mitochondria were fragmenting due to this noxious stimulus. So even at the cellular level, right there in the gum tissue, the P. Gingivalis LPS is corrupting the ability of the cell to create adequate energy. And in turn, in fact, in contrast, it's amplifying the production of oxidative stress molecules. And that oxidative burden won't stay local. It just becomes, it becomes another contributing factor in addition to the systemic inflammation that's coming from the mouth. All right, now let me walk you through the mechanisms by which gum disease can impair insulin signaling throughout the body. This is the heart of today's lecture, and I think that the mechanism is fascinating and well supported. The first pathway is what I'll call the cytokine spillover mechanism. When P. Gingivalis and other periodontal pathogens infect the gum tissue and immune cells will flood that little micro area and begin releasing pro Inflammatory cytokines. Now, you can, when you hear the word cytokine, you can just replace that with protein if you'd like. So these are little molecules that are turning on inflammation. Some of the most notable ones here are the cytokines called TNF alpha and a bunch of interleukins like interleukin 6 or inter. Interleukin 1 beta. These cytokines are produced locally, but in significant periodontal disease, they spill into systemic circulation. TNF alpha in particular, is one of the most well established disruptors of insulin signaling. It disrupts the insulin, what's called the insulin receptor substrate 1, or IRS1, which is immediately. That's like the first event when insulin binds to the insulin receptor. The next thing will be IRS 1 getting activated. Well, TNF 1 Alpha blocks that, so it effectively is stopping that insulin signaling cascade right at the beginning. And thus the cell starts to become insulin resistant. Now, just as an interesting aside, that phenomenon is among the first I ever saw when as a young master's student, I became interested in studying metabolism and insulin resistance specifically. So I am very attuned to this particular field of research because it was the birth of my interest in metabolism. Now, if we go beyond the cell and look at a whole organism, we see in animal models some additional and very compelling research. When scientists administered small amounts of P. Gingivalis LPS to mice, over time, the animals developed demonstrable glucose intolerance and significant insulin resistance. Interestingly, their fat tissue expressed significant elevations in inflammatory markers as well. And they found reduced IRS one function. Remember, that's the insulin receptor substrate in both liver and adipose tissue, the two main tissues. They focused on the second mechanism. So the first is the cytokine spillover, which is the one that I certainly ascribe a lot of interest in and support for, but the next one is a little more direct, where P. Gingivalis produces those gingipains, and I'd mentioned those a moment ago, the ginger pains can actually degrade the insulin receptor itself. Now, remember when I mentioned ginger pains a moment ago, I described them as proteolytic enzymes. So these are protein cutting enzymes or protein eroding enzymes. And they can reach insulin target organs, like some of the big famous ones, skeletal muscle, liver, and adipose tissue. Once the bacteria have entered that systemic circulation, when these ginger pains encounter the insulin receptor on the surface of those cells, they can physically degrade the receptor protein, eliminating the cell's ability to bind and respond to insulin. So this isn't just cytokine mediated interference but with the signaling, but in this case with the ginger pains, it's direct destruction of the receptor itself. The third mechanism involves the liver. Specifically the liver is the I. We could call the liver the master regulator of glucose metabolism. It can store it as glycogen for later release and it can even make new glucose from scratch via gluconeogenesis with either fasting or carbohydrate restriction on a low carb diet. Oral administration of P. Gingivalis in mouse models, so in mice, disrupts the liver's ability to regulate glucose metabolism by affecting multiple genes. Gene and remember, the relevance of a gene is that the gene becomes a protein and then the protein will do something. Genes that promote gluconeogenesis are upregulated in these instances, meaning the liver keeps making and releasing glucose even if it shouldn't. And genes that promote insulin sensitivity and glucose storage are down regulated in response to P. Gingivalis bumping up. So this pattern is essentially a recipe for fasting hyperglycemia and driving towards type 2 diabetes. The fourth mechanism involves the gut microbiota. The oral microbiome and the gut microbiome are connected of course through this a gut oral axis. That's not surprising. When you swallow some bacteria, some of them can get down into your guts. If you swallow P. Gingivalis in particular, it has the ability, if there's a lot of it, to colonize the gut and disrupt the intestinal microbiota composition in ways that can further exacerbate inflammation and the subsequent metabolic dysfunction. Some researchers have even shown that P. Gingivalis can translocate across the intestinal wall, driving additional endotoxemia from the gut. So the the P. Gingivalis, if it's able to get down into say the small intestine, is able to move through that intestinal wall and get directly into the body. Taken altogether, these distinct mechanisms paint a pretty picture. And it's consistent. Chronic periodontal disease creates a state of persistent low grade inflammation from the bacteria. So the bacteria getting in and the endotoxemia so the LPS levels getting too high. This is just a slow leak of the bacteria and their their byproducts getting into the bloodstream. And the consequence of this is this turning on of systemic inflammation. And that in turn will disrupt insulin signaling and impair systemic glucose metabolism.