The Inflammation Doctor: This Simple Organ Regulates 83% of Our Metabolism

Dr. Kassam, as a gastroenterologist, you've probably seen a lot of really interesting things. But one of the areas that's been emerging that's interesting to me is the link between our gut health and actual body composition, like gut health and fat loss, and improving the effects of a diet. Can we kind of give an overview of how that potentially works, and then maybe we can dive into mechanisms and some other stuff there? Absolutely. So let's take a step back and start the landscape of where this field went from a microbiome and metabolism perspective. And I think probably the first study that unlocked everyone's brain was a really elegant study out of the University of Washington. Pete Turnbaugh and Jeff Gordon did. And they took mice that had never seen bacteria before. And they found a set of twins, human twins. One was obese, and one was really lean, pretty skinny. And they took the bacteria from the humans and put them into the mice. They took the skinny stool and put it into the mouse, and the mouse got skinny. And they took the obese stool and put it into the mouse, and the mouse got obese. And everyone was like, what's going on here? That's wild. How can that possibly be? And this has set us up on a bit of a journey on understanding how the microbiome interfaces with metabolism. The hypothesis at the time has evolved to where it is now. So one hypothesis at the time was, is perhaps the food that's going through the gut that usually just gets passed through you, if you have a set of obese microbiome, that it is able to take that caloric intake from things that would otherwise pass through your system and give it to the host, confer more caloric reservoir for the host, and therefore more mass. Versus a lean individual where that byproduct just goes right through you, and it doesn't really matter. That was the hypothesis at first. That hypothesis is changing over time, but that was initially kind of evaluated. And so there's been a set of human experiments actually in clinical trials for something very crude. So we'll take a detour in a second on something called fecal transplants. I'll take a step back. I met the microbiome in a very different way. I had a patient that had a terrible case of a terrible gut infection, and we ended up doing a fecal transplant on her, and she was gardening two days later. And this set us on a journey of doing a lot of fecal transplants as a way to understand cause and effect, but in humans. And so a very smart group in Europe, Max Newdorp, did a study actually in metabolic syndrome with fecal transplants. And he took basically a skimmy stool from a healthy donor and put it into individuals that had metabolic syndrome. And they saw an improvement in the metabolic factors, which is really interesting in their insulin sensitivity basically. Very complicated study, but it was very, very compelling. So it kind of mimics a little bit around metabolism. A couple of studies, one in which I did, and one in which actually I did was done at Mass General Hospital, have started to look at fecal transplants and obesity. And I think the data is not quite there yet, but it's starting to get a little bit closer because it's probably not the thesis around food kind of going through you, but rather around the biology related to GLP-1. Yeah. For a long time, it's been kind of a discussion of what Firmicutes and Bacteroids, Bacteroids, however you say that one, it always troubles me, but where one was more, I think Firmicutes is associated with obesity, and that was for a long time. And it's still to this day referenced a lot, but are those really the primary bacterias anymore, or have things shifted away from that discussion? Things have really shifted. I think there's a really nice review this past year in the Journal of Nutrients that really asked that question, is this still the hallmark for obesity, this ratio that everyone keeps citing? And they did a very thorough review of an analysis of the literature, globally actually looked at many different countries and many different studies and the resounding answer is no, it's not conclusive. And there's too many confounding variables that this really isn't the driver. And that's an association, right? And I think what really drives kind of science for is not just chicken or the egg, but what's the actual biology, what's the actual pathway that we're hitting that leads to potential changes, and then test that in a rigorous way. So where are we at right now? So there's this master molecule called butyrate, a super important molecule that is made by bacteria, certain bacteria, they're churching fatty acids. And this butyrate molecule has a really important metabolic impact. It actually interfaces with the cells in your gut, something called L-cells that produce GLP-1, intestinal GLP-1, a little bit different than what all the rage is with GLP-1 injections for systemic effect. And this GLP-1 interfacing allows a connection to the vagus nerve. And studies are starting to emerge that that actually is another pathway for decreasing satiety, decreasing appetite, which has become one of the more leading hypotheses that's going on in the microbiometabolic world. The second one is that obesity and metabolic conditions are multifactorial. And although there are many factors that go into it, an additional one is actually low-grade chronic inflammation. And so an inflammatory cascade is being targeted by many groups as an additional new mechanism of action for individuals with obesity. So that's another pathway in which you're being evaluated. What about from the standpoint of insulin resistance as well? I know that butyrate, provionate, all these short chain fatty acids play a very critical role in how glucose is utilized and signaling there. What are we starting to uncover within the recent years there? That's exactly right. And I think that's the study that I was referenced with Max Nudorp is that there's a huge impact through butyrate to that pathway for insulin sensitivity. We're seeing those results through that exact same pathway for how we're dealing with our sugars, essentially. And so I think that's something that's particularly exciting is not just the mass, but also the metabolic capability. What about even muscle protein synthesis and the potential for muscle building? Are we starting to see anything there? Yeah, we are. I think it's a couple of different things. Maybe talk about the biology, then the preclinical, then the clinical. So the hypothesis is that certain microbes have the ability to improve anabolic capability. So helping break down proteins into more effective manner. I think that's one piece of it. And the corollary is certain microbes help prevent catabolism in a bad way in an inflammatory way. So that's what the hypothesis was. And so there was a really interesting preclinical study, a mouse study, where they took high-functioning strong elderly individuals and low-functioning weak elderly individuals, humans, defined by grip strength. And they put them into a bunch of germ-free mice, the same kind of mice that I was telling you about earlier. And something remarkable happened. The group that got the high-functioning strong microbes became stronger, and the other ones didn't, essentially based on mouse grip strength. And so that was a fascinating study to show. And then there's been a really nice study on the human side on the, it was a meta-analysis, just a matter of meta-analysis, aggregating a lot of data out of the UK, Norwich University, and show that actually probiotics seem to be, some probiotics just seem to be associated and linked towards increasing grip strength in the elderly population. So that's kind of starring to see some of that data kind of translate, although kind of still emerging. Interesting. What would your hypothesis be from a mechanistic standpoint? What is that you think is doing? Why would you get stronger from your microbiome? I think it's back to like, are we able to optimize protein breakdown better? So kind of what I was talking before is like anabolic. Are we optimizing the protein that's getting into our cells effectively and into our building blocks? And if certain microbes are able to do that more. And then similarly, are we decreasing the catabolism, the breakdown by avoiding microbes that are inflammatory in nature? What about from a fatty acid oxidation perspective? Any evidence there from fat burning? Ah, there's, there is some data that's starting to emerge around fat burning and there's like white adipose versus brown adipose. And, and thinking about that, I think that data is still pretty early, I would say on the directionality of it. There isn't the same, there's a cross-sectional data, meaning we see differences. We don't know you yet know the causal pathway yet, but it's interesting. No, it's totally interesting. And, and just because you have an increase in fat oxidation doesn't necessarily mean you're right. It does literally mean you're burning fat, but it doesn't mean you're burning fat in the sense that people might think, right? You can improve just by improving lipid profiles and by improving glucose oxidation, you a lot of times improve fatty acid oxidation and just the ability to substrate switch, so to speak, at a mitochondrial level. One of the areas I find particularly interesting, we talked about a little offline is the microbiome of an athlete versus a non-athlete, like super fascinating. I think, believe it's pronounced, is it Villanella? Villanella. Villanella. Yeah. Can you, if you are familiar with that study, just get an overview of that because it's just so fascinating. Yeah, there's a study done by Alice Kostich and Jonathan Scheiman at Harvard Medical School, and they looked essentially at, at athletes. And they were able to identify that certain athletes were able to break down lactic acid better than others. And the key bugs that helped them do that was these Villanella species, which they thought were really powerful. And so they actually turned that into an innovation and started to test that out in terms of kind of where they're going. It's an interesting space for performance because I think it makes a ton of sense. It's like, yes, of course, we're like, marathon runners have a different way of metabolizing lactic acid. And so I think their work there is really incredible. Did they do any transplant with that? Did they test it? Is that where that study went down? Did they take marathon runners and take that bacteria and put it in a mouse model? I can't remember what that is. I don't think they did the testing directly in that way in terms of like mouse model swapping the way that I've said, but I think it was a kind of a clear pathway from a biology perspective as a nature medicine paper a while ago. Yeah. And that might just be the tip of the iceberg with that too, right? It's like, I think it comes down to this efficiency and ability to break down by-products and break down waste products too. You know, it's like when you look at, I don't view lactic acid as a waste product. I mean, it's very functional from the, you know, all kinds of different cycles that you're going to use it for, for energy metabolism. But I think that people forget that, that there's this element of, okay, what are you extracting from your food, but also what are you able to metabolize, recycle, eliminate, things like that. Are there bacterias that are more, how do I put this? More prone to help waste elimination compared to absorption, for example. Like are there strains of bacteria that help us move particles out? And the reason I say that there's a little divergence from what we're talking about right now, but from the perspective of like microplastics and things like that that are moving through, are there bacteria that can help us expedite removal of those? This is a really interesting area of science. There's specifically around microplastics and are able to kind of break down. There's some really interesting data from a Turkish gastroenterologist who looked at a certain set of microbes still very early that are actually able to break down microplastics and actually kind of sequester them and then eliminate them. And so I think that's an area of ongoing science. Even with heavy metals, there's some interesting data that's talking about microbes being able to maybe potentially impact heavy metals. So the science is really still maturing there, but it's an area that I'm keeping my fingers on the pulse very, very closely because it's super important. I can imagine a world where we have an ability to actually have, augment, you know, our lived environment with an environmental solution. That's very exciting. It's what is it, bile acid sequestration or something, I think is what it is, right? Now we do, we know many of our microbes that do that in some ways, we do that. So secondary bile acids essentially are produced by many microbes. And that's actually what's helping for people that have that C diff condition I was mentioning before. I have terrible diarrhea. It's really working through a pathway related to bile acids. Yeah. Cause I can essentially, I think that's what I've seen. At least the paper that I read just last week on it was like, bile acids can bind to, well, fat soluble toxins, but that also including like MNPs, right? Like some of these micro and nanoparticles of plastic, which may not like remove them from your body, but if you could expedite their transit through the gut, because I think we've seen other literature that suggests that like the microplastics do absorb just like food basically. So it's like, it's just fascinating. I think that's a good point on elimination. So here's something kind of interesting. So there are certain bacteria in the gut that have the genetic code to be able to metabolize estrogen. So here's the thesis. So estrogen normally in women produce bovaries, actually gets conjugated and then deconjugated in your liver. And then it gets excreted out into your poop essentially. But certain microbes in the right context are able to convert that inactive estrogen to an active estrogen to then confer to the host. And so, there's a thesis around potentially, and certain microbes can actually potentially increase estrogen for perimenopausal women. So that's kind of an interesting area as well for certain microbes. So it seems as though, I mean, people are always looking for a takeaway. I mean, if you had to give people from a metabolic standpoint, what would the takeaway be as far as gut health? And I'm sure it's probably similar for a person that's just looking at general gut health, but from a body composition, fat oxidation, glucose metabolism, what strains would you recommend people kind of focus on? And maybe what are a couple of foods that people could focus on? Yeah. So I think overall, I think that the key thing to take away for this occasion is butyrate. Butyrate is the most important driver of metabolic health and general gut health in many different ways. That's number one. Number two, how do you increase your butyrate, right? I think there's two kind of paths there to think about. One, you can increase the prebiotics that help drive butyrate. So for example, inulin, which is found in Jerusalem artichokes and leeks, for example, from terms of whole foods, pectin found in apples, rye and whole wheats. These are all things that have been driven to increase butyrate. In fact, even some dark chocolates have been shown to increase specifically butyrate. The second piece is augmenting your diet, supplementing your diet with probiotics that increase butyrate. So DSO1 actually just presented data that suggests that DSO1 is actually increasing butyrate, which I think is a really important piece of the story as well. So I think those are the two elements to think about. What you can optimize in your diet, but also recognize that you need to have the bugs there to begin with. Bugs that increase butyrate, for example, that's an example. I think it's helpful for people because I think it's, although diversity is important, when you talk about diversity of people, it lacks the specificity that people sometimes want when it comes to adherence. They go, okay, you're telling me just to eat diverse, so you want me to eat the blue Doritos and the red ones? That's like diversity, but being able to give the specificity of like, okay, how do we eat more butyrate-producing, I'm not saying butyrate-producing foods, but foods that encourage the production of butyrate, right? And I think that that is extremely important and extremely helpful because people would even do a Google search on that. Like, okay, how do I increase these foods? Because they want this, what is this end result? What is the end of this cascade? And then when people understand those short-chain fatty acids and how those act as signaling devices within the body, it's a little bit more digestible, no pun intended for it, right? It's like, okay, I eat this food, sure, it's good for my gut. I don't really care about what's going on in my gut because I can't see it, feel it, or touch it, right? It's just there, right? But when I actually think about, okay, well, what are they producing that acts as a signal to help my body actually function better in a way that I can actualize? Absolutely. And not only on the metabolic side of the house, that GLP-1 pathway, but that barrier function that we've talked about, it's super important, actually decreasing inflammation and inflammatory cascade, something called HDAC. And so for all the reasons, butyrate to me, that's the one place, and it's best to have a factory of bugs that actually produce it kind of naturally. And that diversity is good. The reason why I mentioned that before is because there's cross-feeding. Those sub-elements are required potentially for those butyrate-producing organisms to do their job. And so I think that specificity is important, but in a broader context. So real quickly, is cross-feeding like, okay, bacteria break down food, produce something, and then it gets cross-fed on that? Exactly. So say, for example, you have like, I don't know, two bugs. One's a butyrate-producing organism. One is a bystander, I'll call it. The food actually goes to the bystander to convert that food into a metabolite that the butyrate-producing organism needs to grow directly. That produces butyrate. So the microbiome is complex in that way. So there's interrelationships, but you need to know you have to have the right ecosystem around that butyrate-producing organism. In isolation, it won't get the necessary cross-feeding byproducts required for it to grow. That's fascinating. Okay. I've never really heard it described like that. I'm struggling to find an analogy for that. I'm trying to think like, okay, if you have a person that's doing something, but I'll have to think on that one. I've always thought of cross-feeding as, yeah, essentially you've got, okay, if you eat an onion and you get that prebiotic effect and that bacteria is sort of producing something, then the bystander then has the ability to utilize it. But it kind of sounds like it's almost the opposite. It's like the bystander utilizes this at the main focus, the main bacteria can then do its job. Exactly. And it's probably, it's feeding both, but directly, both components are necessary, right? I think it's an important piece that sometimes gets missed when we talk about the microbiome. Yeah, no, for sure. It's definitely a more advanced topic when you're talking about the microbiome for the lay person. Well, Doc, where can everyone find you and where can everyone find DSO1? Absolutely. So you can find me at DrZainSays, D-R-Z-A-I-N-S-A-Y-S on X, and then on LinkedIn as well. And then find us at z.com. Right on. Thank you, brother.