Master The Microbiome: A Deep Dive into Nutrition and Gut Health

The microbiome has to be one of the hottest, sexiest, and most mind-boggling niches in health, wellness, and medicine to date. What's to come is a compilation of high-yield videos that you can watch in series like you're binge-watching The Big Bang Theory, only this is nerdier, or listen to this like a podcast. We will discuss the relationships between the microbiome and fermented foods, fiber, coffee, food addiction, mental health, calories, and more. Get ready, this one's dense. Food addiction is real, and it might be caused, at least in part, by a virus. And no, this is not some conspiracy theory about the Big Food Illuminati engineering a bioweapon to get you to buy their tasty treats. Although, as I say that, I hope I'm not giving them any ideas. Oops. But seriously, this video is going to speak about brand new data, actually published yesterday as I record this, in the journal Nature Metabolism that suggests a virus can contribute to food addiction. We are going to break down what the data say and what they don't, and why this might actually be a hopeful finding. Before I get to the rest of this video, I just want to flag that this is a special video. Because at the end I'm going to include an exclusive clip from the research team themselves made specifically for my audience, for you. This is part of my initiative to help amplify the researchers' voice and bring you as close to the science as possible, so stick around until the end. Now let's get back to it. But first, let me clarify that food addiction is indeed real and can be defined based on criteria for a substance use disorder from the DSM-5, Diagnostic Manual for Mental Health Disorders. This includes taking a substance in larger amounts than was intended, inability to control substance use, taking a substance for longer than was intended, and continued use despite adverse consequences. Specifically, the Yale Food Addiction Scale and Yale Food Addiction Scale 2.0 has gained widespread acceptance as a clinical tool for assessing this condition, food addiction. Now, here's another fact. The brain talks to the gut and the gut talks to the brain. More to the point, the microbiome, the community of organisms, bacteria and otherwise, living in our intestines, well, they can influence our brains and therefore influence our minds and mental health. That's not controversial. It's a biological fact, although one that lacks a bit of specificity. So now here's another question: what shapes the microbiome to shape the brain and shape the mind? Well, there are many things, but one that is understudied is viruses. Specifically, bacteriophages, viruses that attack bacteria, have the capacity to shape the microbiome and by extension shape human metabolism and the brain and human mind. So running with this logic, the researchers behind this study first looked to see if there was an association between any viruses and higher Yale food addiction scales. Scores in humans, and indeed they found one family of viruses stood out, the microviridae. The presence of microviridae family viruses was positively associated with food addiction scores, in not just one population, but also in a validation human cohort. In other words, to confirm their findings, the researchers checked multiple independent human populations and found the same association. More microviridae viruses associated with worse food addiction scores. And to add to the story, they looked beyond that, looking at BMI and even waist circumference, a better marker of abdominal fat than BMI, and found also an association between the microviridae and abdominal fat or waist circumference. Then to dig a little deeper, they looked at what specific species of microviridae family viruses was most abundant and found it was a virus called Goku-Shou Virus WZ2015A. Say that 5 times fast. And no, I don't think there's any association to Dragon Ball Z. Then if that weren't enough, they did functional magnetic resonance imaging, brain scans of the human brain in another cohort to look at how this Goku-Shou Virus WZ2015A— no, I'm not really gonna say it 5 times fast— associated with changes in brain activity and found higher levels of the Goku Sho virus associated with changes in the dopamine networks in the human brain. In fact, they found changes that align with research on the brain dopamine effects of drugs like morphine and cocaine. So now we have a specific species of virus associating with higher clinical food addiction scores and brain activity states, dopamine states, on fMRI imaging in humans. But they went a level further to demonstrate a causal relationship. The researchers then transplanted human samples with and without the Gokushou virus to mice and found that the human-to-mouse Gokushou virus transfer the transplant indeed caused food addiction-like behavior in the mice. In this case, in response to chocolate-flavored pellets. So they were causing chocolate addiction in mice with a human Gokusho virus from human poop. That's what they did. Now that's pretty cool. We have a specific species of virus that can be transmitted between organisms and in so doing transmit features of food addiction. How crazy is that? But again, we have to ask how. Now, I'm gonna spare you a lot of technical details and scientific jargon, basically a jargon tsunami, and just say they found that the Gokushou virus messes with the metabolism of precursors to dopamine and serotonin, which are the amino acids tyrosine and tryptophan respectively. But more to the point, an intermediate of tryptophan metabolism named anthranilic acid that is lower in humans with more of this food addiction goku shou virus actually showed a protective effect against food addiction when supplemented to food-addicted mice. How exactly it does that is not yet clear, nor whether this relatively simple molecule could protect human patients against the food addiction virus. This research is so new, literally this was published yesterday as I'm doing this. But given what we now know about higher microviridae, Gokusho virus levels in humans associating with more and worse food addiction and obesity and higher waist circumference and dopamine brain changes in humans, well, the spotlight of metabolic knowledge is shining really brightly on this hot topic, and the black box of mental health is looking just a bit more illuminated. Isn't that exciting? I'm so excited and so curious that I might even go get a tattoo of "Stay Curious" on my bicep. Actually, that's what I'm doing this afternoon. Anyway, I'm super pumped. Let me know what you thought about this video, and as always, stay curious. I'm excited for the next one. I am just so enthusiastic to be here teaching and learning with you. There is just so much to learn. And moments like this when I get to read this kind of paper, just, you know, write about it, talk about it to a camera, and then feed your enthusiasm back to me and then back to you and then back to me. It's just the best. So thank you and have a great day. Now, as promised, here's a clip from one of the authors specifically made for you. I asked him, why are these data important? And what's the next step in this research? Here's what he had to say.

Hi, Nick. So thanks for getting in touch about our research. I'm curious what we plan to do next and why we're excited about these findings that we found. So first off, the gut is not just about digestion. So every time it's more clear that there is a connection between the gut and the brain, and the gut can influence the way we think, we believe, or we behave. However, most of the studies so far, I would probably say more than 90% of the studies, just focus on bacteria. But we know that the gut microbiota is much more than that. You know that in the gut microbiota we have viruses, we have fungi, or even we have protozoa. And actually, viruses are the most abundant entities on the planet. And despite this, they have been largely overlooked when it comes to human health. In addition, most of these studies focusing on the gut-brain axis are just associative. So we don't really know whether the gut microbiota is responsible or is the result of a particular disease. And plus, most of the studies just focus on what kind of microbes we have in the gut, so their composition, but completely neglect or overlook what are they doing, what are actually they doing, that is their function. And this is a really big deal because maybe you and I, we have different, completely different microbes, but maybe they perform the same function. So maybe this difference, that doesn't matter. So we tried to address all these issues. And we actually found that these microbiota bacteriophages are responsible for food addiction by altering the metabolism of the main neurotransmitter, that are serotonin and dopamine, as you have really really well explained. And here is the other really interesting finding. And it's that the viruses have high individual specificity. So it means that they are unique to each person, but they are really stable over time. They can last for several years. And actually, microviridae are the most stable in the human gut. This is really important considering this specificity and stability because it opens the window for new treatments to personalize the treatment against, and in this case, to tackle food addiction. All that said, there's still a lot that we don't know. So for example, we have seen that this Microbiota Bacteriophages influence the metabolism of serotonin and dopamine, but we don't know exactly how. For example, are these viruses directly responsible or are they influencing the gut bacteria that in turn then modify the levels or the metabolism of these neurotransmitters? These are big, big questions that we are trying to address. And finally, I would just like to make a clarification because we are talking about bacteriophages. So this means that these are viruses that infect bacteria but not human cells. This is important to avoid any kind of misunderstanding because I've seen in several posts that they talk about viruses that are attacking us or are infecting us, but this is not the case. They are just infecting bacteria. So don't worry if you see this kind of thing. And lastly, thanks again for reaching out and your interest in our research because it's really awesome to see that there is people that is interested in this connection between the brain and the gut and particularly in the role Bye.

Coffee isn't just a morning pick-me-up anymore. It might be a microbiome wake-up call too. And this might be one way coffee exerts its many health benefits. Or at least that's the claim circulating around a brand new paper published in Nature Microbiology. I know, we all want this to be true. But is it? Well, I actually have great news for you., but you're going to need to delay gratification just a little bit, just like waiting for that delectable cup of brew at your favorite coffee shop. This video will reveal what the researchers discovered, but it's also going to be a broader masterclass on coffee. I'm going to tell you how much coffee to drink to get the health benefits. I'm going to compare caffeinated versus decaf. I'm going to answer common Q&As about polyphenols, mycotoxins, and much more. I hope you've had a cup or two already this morning, because you'll need to focus for this one. Okay, let's get into it. First, coffee intake has already been associated with lower overall mortality, reduced cardiovascular disease-related death, and lower risk of type 2 diabetes, among many other positive health effects. But nutritional epidemiology, the study of diet and health in large populations, has its limitations because it only looks for correlations. To solidify coffee's health halo, what we want is a complementary biological mechanism, a physiological story that helps this all make sense. So let's introduce the protagonist of this particular story, a gut bacterium named Lassonibacter a.saccharolyticus. I know, I know, that sounds kind of like a Harry Potter spell, and me looking sort of like Daniel Radcliffe doesn't help. But while this L. sonobacter might not be magical, I do think the microbiome's governance of our health is just as amazing and mysterious, and hopefully I can convince you of that. Anyway, what the researchers did to discover this L. sonobacter asaccharolyticus coffee connection, coffee link, was take information they gathered from highly detailed food questionnaires, including data on over 150 specific foods associated with microbiome samples, and then looked for connections between specific foods and microbiome signatures. And among the over 150 foods analyzed, coffee stood out for having the clearest microbiome signature. Now, for further analyses, the researchers broke up participants into 3 groups: the never drinkers, who consumed less than 3 cups per month, the moderate drinkers who consumed more than this but fewer than 3 cups per day, and the high drinkers who consumed more than 3 cups per day. What group are you in? Anyway, the strongest correlation between coffee consumption and the microbiome was this Lassonibacter asaccharolyticus bug. And because I know you're wondering, and I was wondering when reading this paper as well, the association was independent of caffeine. So, high level, yes, in this case, decaf also counts. The researchers also showed that Lassonibacter a.saccharolyticus is rare in newborns and young children, and rare in samples from ancient populations. These groups Ancient populations and children have low coffee intake, or at least they should. I hope you're not feeding your neonate coffee. And across nations, coffee consumption is also linked with Lasonibacter levels, reinforcing that the connection exists at both the individual and broad population levels. And finally, to hammer home the point, hammer home the connection, they finally showed that Lasonibacter a.saccharolyticus grows better outside the body as well, in vitro, when fed coffee. So all these lines of evidence point to a model whereby coffee intake stimulates Lassonibacter asaccharolyticus growth in the human microbiome. Now, the next obvious question is, does Lassonibacter asaccharolyticus actually do anything? This question is actually quite difficult to answer. But one way to begin unraveling the mystery is to look for metabolites associated with coffee intake and associated with Lassonibacter abundance that are known to exert positive health effects. One such compound the researchers discovered was quinic acid. Quinic acid is a natural compound found both directly in coffee and also appears to be influenced by Lassonibacter asaccharolyticus levels. It's thought to contribute to coffee's perceived acidity and slightly sour, sharp quality, and although its metabolism is quite complex—quinic acid metabolism is very complex, it undergoes many biotransformations by the gut—literature shows that quinic acid and its derivatives, its metabolites, have antioxidant and anti-inflammatory properties, which could provide a mechanistic basis for some of coffee's associated health benefits, including on the brain and on the cardiovascular system. Now, on these health benefits, because I know you want to know what they are, another landmark umbrella review of 201 observational studies and some randomized controlled trials as well found that coffee intake was associated with 17% reduced risk of all-cause mortality 19% reduced risk cardiovascular disease-related death, 15% reduced risk of cardiovascular disease, 18% lower risk of developing cancer, 30% reduced risk of developing type 2 diabetes, and 36% reduced risk of Parkinson's disease. Pretty impressive. This umbrella review alone, it can't claim causation, but the consistency of the results and really the impressive effect sizes across the board are encouraging. Oh, and the biggest effects, the most positive health benefits, were seen at 3 to 4 cups of coffee per day. Now, since we will probably never have a 20 to 30-year randomized controlled trial on coffee, and before you say "I volunteer," bear in mind randomized does mean you could be placed in the coffee-restricted group, for 2 to 3 decades. Still volunteering? I thought not. Anyway, sorry, tangent aside, what we need to do to piece this puzzle together, because we probably will never have that 20 to 30 year randomized control trial, is we need to couple the large population data with biological rationale mechanisms as they were doing in this new research. So the connection between coffee, L. asaccharolyticus, quinic acid, and other microbiome-derived metabolites, it could be part of elucidating, clarifying this picture. For example, one can imagine a scenario where quinic acid and its derivatives scavenge, gobble up harmful free radicals, reduce levels of inflammatory molecules like TNF-alpha or interleukin-1 beta, prevent LDL particle oxidation, and improve blood vessel function and circulation. Now, I'm not claiming this is all proven in humans beyond a shadow of a doubt. What I am saying is that the literature, the epidemiological population, and the mechanistic collectively and rather consistently point to the health benefits of coffee, with the greatest benefits seen at around 3 to 4 cups per day. Now, the research, it's still steaming hot, but it's already showing some strong results. So, coffee? It's good. Now, switching gears a little bit, here are my responses to some common question and answer. Question 1: What's healthier for you, a light roast or a dark roast? Answer: I think a light roast is healthier. Unroasted coffee, also called green coffee, is rich in chlorogenic acid, which we talked about a little more in this video, Go see that for more. Anyway, chlorogenic acid, it can improve glucose metabolism and actually maybe even reduce sugar intake. Lightly roasted coffee contains more of this compound and may have a health edge. But above the light versus dark roast debate, I think having your coffee without added sugar and without artificial sweeteners is the most important thing to optimizing the net health benefits of your coffee. That's my opinion. Okay, question 2: Should you be worried about mold toxins, also called mycotoxins, in coffee? This is an area of controversy for sure. Personally, I don't think it's a huge concern, but it is a potential concern that I wouldn't sneeze at. Toxins like aflatoxin B1 and ochratoxin A can be found in some coffees and cause health problems, or potentially cause health problems in some people. Now, if you're worried about this, you can shop specifically for coffees that advertise they have been mycotoxin tested and are mycotoxin free. I'll reinforce that I'm not personally super worried about mycotoxins in my coffee, but you're of course entitled to select your beans based on your priorities. I'm also not read up on all the mycotoxin coffee literature. When I went to look last, there were almost 400 hits on PubMed for the combined terms mycotoxin in coffee, so it's obviously an area of interest. And maybe my opinion will change as I read more. That's how scientific opinions should evolve. Anyway, question 3: What coffee bean is the highest in polyphenols? There are two common types of coffee bean, Robusta and Arabica. Studies show that Robusta, also called Coffea canephora, has higher levels of polyphenols,, and these levels of polyphenols decrease more when roasting. So, an unroasted or lightly roasted Robusta will probably be your highest polyphenol content coffee. Now, tell me in the comments, what other questions or shareable knowledge do you have? And finally, because I do like to have fun, here's some coffee fast facts to wind us down that you can drop at your next dinner party. Okay, fast fact 1: the discovery of coffee. Legend has it that coffee was discovered in Ethiopia by a goat herder who noticed his goats became more energetic after eating the berries or the cherries of a particular plant. Turned out that was the coffee plant. Okay, fast fact 2: the most expensive coffee in the world is called Kopi Luwak. The main factor of its high price is the unusual method of production. It's produced from coffee beans which have been partially digested by the Indonesian palm civet cat and then excreted. Yes, it's expensive poop coffee. The civet cat eats the coffee cherry within which is the bean, and the coffee cherry is fermented in the cat's intestines. Prices do vary, but wild-collected beans can be priced up to $1,300 per kilogram. And a single cup of kopi luwak can run you more than $50. Now, fast fact 3: globally, people consume around 2 billion cups of coffee per day. Yes, 2 billion per day. And Finland takes the gold medal for the most coffee consumption per capita at about 22 to 26 pounds per person per year. And finally, fast fact 4: the current world record for the oldest cat was named Cream Puff. She lived to a ripe old age of 38 years and, get this, drank coffee every morning and had bacon and eggs as well. So this feline n 1, or I guess maybe n 9, is consistent with the data saying coffee is associated with lower mortality. Fermented foods like kimchi, kefir, and sauerkraut have a serious health halo. And the fermented foods market is booming, estimated to grow over $500 million over the next 4 years. But are fermented foods really gut health superstars? And if so, how? Today we're diving into a fascinating new paper published out of Stanford in the journal Cell Metabolism, and we're gonna separate fact from fermentation fiction. Now, in this video, I'll provide you my 7 favorite bites of knowledge from the article, and I'm going to gift you a recipe that a friend and I created just for this video. And after watching the video, if you think it was not too bad and you don't want me to be sour, please click subscribe. It really helps. Anyway, with that, moving on. Fact 1: There are 3 types a fermentation. Did you know that? Now, technically speaking, fermented foods are those transformed by microbial growth and enzymatic conversions. The most common bacteria is lactic acid-producing bacteria. They're the most common fermenters, but other microbes can do the job too, like acetic acid bacteria, filamentous molds, and yeast. Here's how it works at a high level. The addition of salt and access to preferred nutrient sources for the growth of these fermenting microbes promote their growth, leading to early community dominance in the microbiome of the food. Now, onto the 3 types of fermentation. There's spontaneous, starter culture, and one called backsloppen. Now, in spontaneous fermentation, microbes from the environment they are what initiate fermentation. This means there will likely be more variability in the final microbial community. By contrast, the use of a starter culture allows for a more reliable final product of the fermented food. Starter cultures are often used in dairy products, and they allow for more precision in developing the final product. This is neither good nor bad per se,— it's just different. Finally, back-slopping is when a portion of the previous fermented food is incorporated into the next batch, propagating the microbial community. This is common for sourdough bread and kombucha. Now, moving on and getting more interesting, food safety. The case of cassava. One of the benefits of fermented foods is they can enhance food safety. The microbes that are responsible for the fermentation can produce other antimicrobial peptides that kill off pathogens or otherwise help detoxify food. And a great example is cassava, a starchy tuberous root native to South America and a staple food for over half a billion people, but that in its raw form contains high levels of a neurotoxic cyanogenic glycoside. Consumption of unprocessed cassava therefore can lead to the development of an irreversible neurological disorder called Kanzo that causes irreversible paralysis of the legs. However, fermentation of cassava massively reduces levels of this neurotoxin, turning a poisonous food into a tool for human nutrition. Isn't that interesting? Okay, moving on. Fact 3: Increased nutrient availability. Fermentation can increase the nutrient availability of food, and recent studies reveal that fermented foods tend to have more vitamins and minerals, like increased levels of vitamin C, B12, vitamin K, riboflavin, and folate, as compared to their unfermented counterparts. So you get more nutrient bang for your buck by having fermented foods. Okay, now we're going to get more technical. Activation of key receptors, focusing on one called HCA2. Metabolites made by microbes can also lead to the activation of receptors like hydroxycarboxylic acid receptor 2, or HCA2. Activation of HCA2 has anti-inflammatory effects and may even increase bone density. Pretty cool, right? Compounds made by the gut like hippuric acid activate HCA2. I reviewed a bit on hippuric acid in a prior video on visceral fat. You can see that video for more, but briefly, foods like green tea and wild berries might also help to increase hippuric acid levels through processing in the microbiome, although they themselves aren't fermented foods per se. Moving on, we talked about HCA2, how about HCA3? In addition to HCA2, great apes, including humans, but not other animals, also have the HCA3 receptor. And the only known activator of HCA3 is a compound called D-phenylactic acid, made by lactic acid-producing bacteria, and it can be elevated in the blood after eating sauerkraut or kimchi. Now, there aren't a lot of great animal models for HCAC since it doesn't exist in many animals other than great apes. So it's hard to know exactly what it does, but there is some thought that it plays a role in immunometabolism and energy storage since HCA3 is expressed on many immune cells and fat cells, adipocytes. But at present, its exact function remains somewhat of a mystery. I suppose the science needs to ferment a bit more. But before we jump to Fact 6 about the anti-obesity hormone GLP-1, I want to gift you a recipe my friend Martina Slorjova at KetoDietApp created just for me, and now for you. She knows I love macadamia nuts. I'm a macadamia nut monster. And when we were discussing this paper, she proposed a fermented macadamia nut hummus. And it's our gift to you. The recipe is linked in the video notes. And if you need the raw ingredients, you can get a lovely discount from my friends over at House of Macadamia I've been using their product for over 5 years, 15% off with discount code NICK15. With this discount, you can buy the kilo bag, my favorite, and the cost per ounce is only 84 cents. So super economical. Anyway, getting on. 6. GLP-1 augmentation through probiotics. GLP-1 is the anti-obesity hormone produced by gut cells that leads to increased satiety. Research shows that certain probiotics like L. reuteri and Akkermansia mucifilia can increase GLP-1 levels. Now, while exact products and protocols to increase these microbes in the gut are still being developed, there are human studies showing that compounds like short-chain fatty acid supplements bound to inulin, a fiber, can increase GLP-1 production and alter weight, and lower liver fat levels. Again, the science needs more time to ferment, so I don't want to make any extravagant claims, but if you like sauerkraut on your burger, it's likely healthier than a bun. Unless you make really good sourdough bread buns, then I suppose that would also have a health benefit. 7. Lactic Acid. First it's sour, then it's sweet science. Now, let's chat about lactic acid, which is obviously made by lactic acid-producing bacteria, that we already talked about. Lactic acid itself can activate the receptor GPR81 on immune cells and reduce inflammatory responses, including in the colon, in the intestines. This may be one mechanism by which fermented foods have been shown in human randomized trials to reduce inflammation. And this GPR81 receptor, it's also expressed on fat cells and may lead to increased lipolysis, or the release of stored fat, as free fatty acids, ready to be burned by mitochondria for fuel. And activation of GPR81 may lead to a decrease in the hunger hormone ghrelin. Pretty cool, right? It's pretty amazing what lactic acid can do. So wrapping up, what have we learned? Fermented foods aren't just delicious, they're little powerhouses of microbial magic, enhancing nutrient availability, detoxifying to SAVA, activating receptors, and even influencing whole-body metabolism. From boosting food safety to potentially tweaking GLP-1 levels, these foods are doing a lot more than just adding a tangy kick to your meals. But as with any good fermentation process, the science is still bubbling away. There's plenty more to uncover about how these foods interact with our microbiome and overall health. Now, if you're excited as I am to see where this field is heading, stay tuned, because the future of fermented foods is notto thing short of fascinating. We've been told for years that fiber is a must-have for gut health, and that without it, your microbiome will crumble faster than a stale bran muffin. But what if I told you, you don't actually need dietary fiber at all? Sorry salad, apologies artichoke, bad news broccoli. Fiber might not be as essential as you've been led to believe. Now, before you throw your kale smoothie at the screen in frustration, let's break down the science together, because the truth about fiber is way more complex and interesting than simply good or bad. And importantly, if we don't address the the nuances of this matter together, we will never advance the discussion. So in this video, I promise you I'm going to review facts about fiber that you should know, things other people might not tell you or might not be aware of, citing data on fiber and inflammation, microbiome diversity, short-chain fatty acids, and I'll also explain where fiber elimination can actually be therapeutic. Now, this video, it's meant to advance a conversation, not end one. With that, let's dive in. Inflammation. Some people argue that fiber-rich foods are anti-inflammatory, but that's not entirely true. For example, a landmark randomized controlled trial published in the journal Cell found that some people were inflammatory responders to dietary fiber. Meaning when they ate fiber they had more inflammation. Reading straight from the paper: Taken together, these data suggest divergent immune system responses to the high fiber intervention, with high inflammation participants exhibiting broad increases in steady-state immune activation, which means inflammation. To be clear, this was not the majority of participants, and it's also worth noting that those with with lower microbiome diversity tended to be the inflammatory responders to fiber, raising the hypothesis that there might be protocols by which one could train up your microbiome such that it responds with a healthier anti-inflammatory response to fiber and fiber-rich foods. It's possible. But the fact remains that some people do have a pro-inflammatory response to dietary fiber, and that this could have negative health consequences and contribute to or exacerbate chronic diseases. Another interesting discovery and point on this paper is that fermented foods were far more universally anti-inflammatory. So, as a practical tip, if your goal is to reduce inflammation and eat an anti-inflammatory diet, I'd capitalize on kimchi over broccoli. Make sense? Okay, moving on. Microbiome diversity. One point that's often raised is that fiber depletion or elimination will decrease microbiome diversity, which is a presumed marker of good health. We're gonna unpack that in a moment. And this is fair speculation at a population level. In fact, it's even speculation in which I myself have engaged. However, there are deeper nuances that I heretofore haven't gotten into. First, microbes in the gut can feed off more than just fiber, and eating a low-fiber diet does not necessarily lead to decreased microbiome diversity. For example, in one impressively comprehensive case study, a man who had been on a carnivore diet for 4 years had his microbiome compared to that of omnivores and plant-based people. And reading from this study, the comparison showed surprising results. The carnivore's gut microbiome did not stand out with regards to alpha or beta diversity, indicating that that it did not lack richness or diversity when compared to its omnivore counterparts. And the study also reads, our study indicates that adherence to a carnivorous diet does not cause detrimental changes in the gut microbiome. Instead, it suggests the effects on the gut microbiome are due to combined influences of dietary regime and lifestyle rather than just meat consumption alone. Further research is needed to identify which components of the carnivore diet could act as prebiotics in the absence of plant-derived prebiotics and maintain gut health over time. Granted, this is a case study, but even an n 1 is sufficient to make the point that even with complete fiber elimination for 4 years, the microbiome doesn't just get starved off. It's not that simple. And if you want to toss another really interesting wrench at this microbiome diversity issue— If you can dodge a wrench, you can dodge a ball. What? Ow! Consider that more diversity isn't necessarily better. In fact, in a recent 2025 study published in Cell, Researchers tried to restore the human gut microbiomes of those in industrial settings with a diet mimicking non-industrialized dietary patterns. And ironically, the diet they chose was primarily plant-based, featuring beans, sweet potato, rice, cucumbers, cabbage, artichokes, peas, and onions. But this plant-based diet decreased microbiome diversity. I'll repeat that. The plant-based carbohydrate-rich diet decreased microbiome diversity. Nevertheless, some cardiometabolic benefits were noted, including weight loss and improved inflammatory markers. So, the big picture takeaways here are two: one, a low-fiber diet, even a no-fiber diet, doesn't necessarily decrease diversity. And two, more microbiome diversity isn't necessarily better. Okay, moving on. Short-chain fatty acids. Another criticism of low fiber diets is that they will reduce levels of beneficial compounds made by the gut called short-chain fatty acids, or SCFAs for short, which are the products, or thought to be the products, of bacterial fermentation of dietary fibers. However, when we look at the human data and consider the physiology, the story evolves. For example, in a 2024 randomized controlled trial comparing people eating a low-fiber ketogenic diet for 12 weeks to people eating higher-fiber diets, short-chain fatty acid levels, including the key SCFA butyrate, were not reduced on the ketogenic diet after 12 weeks. Furthermore, it's worth noting that the ketone body beta-hydroxybutyrate, has structure and functional overlap with butyrate. No surprise, right? You can tell from the names. In other words, even were butyrate levels reduced on a ketogenic diet— again, this was not the case in this study, but even if it were the case— beta-hydroxybutyrate can carry out many of the functions that butyrate can, including fueling cells that line the gut and stimulating various important cell surface receptors. So simply put, a low fiber, low carb diet does not appear to reduce short-chain fatty acid levels. Okay, finally therapeutic fiber elimination. It's important to bear in mind that every person's circumstance is different, and some people may be dealing with gastrointestinal conditions that could actually benefit from fiber reduction or even complete fiber elimination. In some cases of irritable bowel syndrome with constipation, fiber elimination can actually improve constipation, as reported in this widely circulated report where those who stopped fiber intake completely had increased bowel movement frequency and 100% elimination in symptoms of bloating and straining. Sounds pretty good if you have IBS with constipation. And for those with inflammatory bowel disease, IBD, fiber elimination can also be beneficial. In fact, treatment-resistant cases of Crohn's disease are pretty responsive to fiber-free diets and can be prescribed and promote remission in 60 to 85% of cases. The mechanism is thought to have to do with changes in the microbiome, particularly in an intestinal pathobiont called Mucis beryllium. As has been reported in this paper in Cell, Host, and Microbe, which you can read if you want more. And of course, there is our case report in which 10 people on a carnivore diet went into complete remission from inflammatory bowel disease. Now, I'm not saying our case series is gold standard evidence. I think it's pretty good. It's not an RCT. But there's no denying that these patients, these human patients benefited and lives were saved. These are real people with real stories. So what's the bottom line here? Fiber isn't inherently good or bad. It's about context and individual responses—your n=1 story, your n=1 microbiome. While fiber can be beneficial for some people, others may actually thrive on a low-fiber or even zero-fiber diet. Gut health is not one size fits all. Can a ketogenic diet reduce your risk of colon cancer? Well, new research looks extremely hopeful. In this video, we're going to walk through the data together, explain what it means, and tell you which foods are richest in the key fat that researchers reveal is key to the anti-colon cancer effects of a ketogenic diet. But first, First, let me give you a quick sense of the human burden of colorectal cancer. That's the broader term, colorectal cancer, but to save you syllables in this video, I'm just going to say colon cancer. Fair? Okay. Colon cancer is the third most common form of cancer worldwide, with approximately 2 million new cases diagnosed each year. And that rate is increasing. It's not exactly clear why colon cancer is becoming more common, especially among younger people, those under 55 years of age, but it's thought to be linked to lifestyle factors, including obesity, smoking, and diet. So let's jump into this research, which was conducted in microbiome-humanized mice. What the heck is that, a microbiome-humanized mouse? Well, what this means is that to make this experiment more relevant to people, more relevant to human beings, researchers created humanized microbiome mice. Specifically, what they did is they took stool samples from 5 healthy human beings, mixed those stool samples together to make a microbiome cocktail of the human microbiome, and then gave that to mice that had no microbiomes of their own. They then treated these humanized microbiome mice with compounds that cause intestinal inflammation and predispose the mice to develop colon cancer. After that, the mice were fed either a chow control diet with carbohydrates or a low-carb, high-fat ketogenic diet, which increased circulating levels of ketone bodies in the mice. And impressively, here are the results. You ready? The keto mice exhibited fewer tumors, smaller tumors, and overall had a much, much lower tumor burden. Then, to prove a causal connection between the microbiome shift via the ketogenic diet and protection against colon cancer, the researchers did what's called a fecal microbiome transplant. They transferred microbiomes from the keto-fed mice into other mice who hadn't eaten a ketogenic diet. And remarkably, the microbiome transplant from the keto-fed mice to recipient mice transferred the anti-cancer protection to the recipient mice. So simply put, in a nutshell, the ketogenic diet changed their microbiome in a way that protected against colorectal cancer tumor growth. So the next obvious question is, how? The ketogenic diet selected for bacterial communities that produced more of a fatty acid called stearic acid, which is an 18-carbon saturated fat. The stearic acid had two main effects to fight the cancer. One, the stearic acid caused tumor cells themselves to die through a programmed cell death pathway called apoptosis. And two, stearic acid suppressed inflammation in the intestines by decreasing levels and activity of an inflammatory immune cell called a Th17 cell. It's this one-two punch targeting both the cancer cells and the inflammatory tumor microenvironment that made the stearic acid produced in response to the ketogenic diet by the microbiome such a potent anti-cancer compound. And it's also worth noting, as a quick tangent, ketone bodies themselves may help prevent colon cancer and reduce cancer progression. The mechanisms by which ketones exert their direct anti-colon cancer potential are complex, but likely include that ketone bodies reduce inflammation, they help with intestinal stem cell renewal, and they signal through various cell surface receptors, like HCAR2. For more details on colon cancer metabolism, check out this review article. It's actually by a friend of mine, Dr. Joseph Sedlak, MD, PhD. He's a classmate of mine at Harvard Medical School. Now, you might be wondering, well, the microbiome made stearic acid, right? But what if the mice were just fed more stearic acid directly? Does dietary stearic acid have the same effect? In other words, does it matter whether the stearic acid was made by the microbiome or simply eaten in food? Well, the researchers were smart and anticipated your question. So mice not eating a ketogenic diet were supplemented with stearic acid, and the researchers saw a similar anti-cancer effect. So the takeaway, the conclusion, is it appears that either dietary stearic acid or microbiome-derived stearic acid can offer the same or similar protective benefits against colon cancer. That said, Practically speaking, it's easier to eat more stearic acid when you're following a low-carb, high-fat diet. And importantly, overall dietary context likely matters when it comes to overall cancer risk in a real-world human setting. But more on that in a moment, after we discuss what foods are rich in stearic acid. The word Sterate actually comes from the Greek word for tallow. Tallow is rendered beef fat, and is about 15-20% stearic acid as the proportion of its overall fat. But there are even richer sources of stearic acid, including cocoa butter, which is about 34% stearic acid, and shea butter from the nut of the African shea tree, which contains over 30% stearic acid, and in some cases up to 50%. Now, if you've been paying attention, and I hope you have, you might have observed that one implication of these data is that beef fat could have an anti-cancer property due to its stearic acid content. That's a provocative possibility since red meat intake is traditionally thought to be linked to increased colon cancer risk. So what's the truth? How do we reconcile these observations? Here's how I think about it. First, stearic acid is just one compound among many in the complex food that is red meat. For example, iron overload in the wrong dietary, in the wrong genetic context may promote colon cancer. It's possible. So it's important to remember that one study never really reveals the whole truth. It's part of a larger picture. Even if it's really interesting. Second, since we can't perform interventional trials, like randomized controlled trials, that intentionally cause colon cancer in humans, for obvious reasons, we typically refer and rely upon epidemiological studies, which are complicated by healthy user bias, imprecise measurements, often by food frequency questionnaires, and various unmeasured confounders. So they're not always that dependable and they can be misleading. And third, the overall dietary and metabolic contexts, they really matter. This study is actually a proof of principle showing how an eating pattern, specifically a carbohydrate-restricted ketogenic diet, can change the microbiome and host metabolism and potentially alter how specific foods or compounds affect the body. So to repackage what I just said with an example, it's entirely possible that a fatty ribeye steak could promote cancer when eaten with a side of fries by someone with obesity, while that same fatty ribeye steak could suppress cancer when eaten in the context of a clean ketogenic diet and/or by a healthy individual. To be clear, I'm not claiming that's definitively the case. I'm just saying dietary and metabolic context matter. The case on stearic acid ketogenic diets, meat, and cancer, it's far from closed and there are many levels of nuance. But if you want my opinion, overall, eating an anti-inflammatory diet, an unprocessed diet, is more likely to reduce your risk of colon cancer than any effect that could be had by ribeye, lamb chops, or a chocolate bar for that matter. How does psychological stress impact gut health? And how can we use new science, new knowledge to improve our gut health and our mental health? These are the questions I'm going to try to answer today. So if you or someone you know has ever suffered from bloating, constipation, or GI upset, which I think covers most people, you will want to watch this video all the way through. Now, in this video, I promise you: 1. Specifics. I'm not gonna wave my hands and use generalist terms, but speak about specific causal cascades linking brain to gut and gut to brain based on new and exciting science. 2. I'm gonna offer you actionable takeaways and practices that I myself am going to try to implement because In truth, this is one video I'm making as much for myself as I am for you. Okay, let's get into the data. The paper in question was just published in Cell, one of the top journals in the world, and is entitled "Stress-Sensitive Neural Circuits Change the Gut Microbiome Via Duodenal Glands," the duodenum being part of the small intestine. At a high level, The researchers discover a pathway whereby activity in a brain region associated with stress and emotions, the amygdala, controls the vagus nerve, the 10th cranial nerve, that connects the brain to the gut and the gut to the brain. And in so doing, the brain can toggle the activity of glands in the intestines called Brunner's glands that make mucin that that feeds the microbiome, which can in turn influence GI symptoms and gut health. So again, at a high level, the brain talks via the vagus nerve to Brunner's glands in the intestines that make mucin that feed the microbiome, and this can impact gut health and in a reciprocal fashion impact brain and mental health. Now let's look at some of the data together. Now, I do say some of the data because there are 163 figure panels in the main text alone. That's not even including the supplement. I know, right? 163. And if I went through all of these, I think we'd be here for about 18 hours and I'd probably stress you out, which, as you will learn, can have a negative material effect on your gut health. So, Let's first introduce the leading gut bug in our story, Lactobacillus. Now, there are actually many different species in the genus Lactobacillus, but for the sake of simplicity, consider Lactobacillus good guy gut bugs. They're common probiotics and also the primary genus found in many considered to be healthy fermented foods like yogurts, sauerkraut, kimchi, and so on. Shown here, the researchers found that by stimulating mucin-secreting Brunner's glands in mice, the Brunner's glands provided nourishment to lactobacillus to promote their growth. However, surgical removal of these Brunner's glands negated this effect and depleted lactobacillus levels. So this shows that mucin-secreting Brunner's glands are important for promoting Lactobacillus growth. But the question, what controls Brunner's glands? Well, they found the vagus nerve directly connects the brain to the gut and specifically connects the brain to Brunner's glands. So if you cut the vagus nerve, the brain can't activate Brunner's glands and Lactobacillus are depleted. So the brain is what's controlling Brunner's glands. Along with peripheral hormones. But now, the vagus nerve, what is it? It's involved in parasympathetic, rest and digest nervous system activity. This is in contrast to the sympathetic, fight or flight branch of the autonomic nervous system. So, high level, we start to form this picture whereby calming vagal parasympathetic rest and digest nervous system activity activates Brunner's glands. And if you want specifics, it's through releasing acetylcholine, a neurotransmitter, onto M3 muscarinic receptors, if you want the details. But this increases mucin production from Brunner's glands to feed and proliferate Lactobacillus. And this is consequential because the microbiota in your intestines can directly, and through reciprocal activities on the nervous system, alter gut function and gut symptoms. In fact, if you knock out Brunner's glands, or you cut the vagus nerve connection to Brunner's glands, this can lead to severe gastric bloating, as you can clearly see here, it's quite profound. And it can also lead to leaky gut, increased gut permeability, and heightened immunoreactivity. Now, let's complete the picture by adding the master controller to the system, the brain. They found, the researchers found that one critical brain region, the central amygdala, which is the core of an almond-shaped brain center involved in emotions and stress response, was the master regulator. Indeed, the researchers found that activation of the central amygdala enhanced signaling through the vagus nerve and thus increased Brunner's gland activity to lead to increased lactobacillus and improved gut function. So in this way, the central amygdala in the brain associated with your emotion directly controls the microbiome, which is freaking fascinating. And they show that stress inhibits the central amygdala and that stress lowers Lactobacillus levels. Thus, zooming out once again, stress inhibits a brain region leading to decreased signaling to mucin-secreting glands, Brunner's glands, starving the good guy gut bacteria. And while you can't exactly do these causal mechanistic experiments in humans, these data are very likely relevant to humans, as it's been well documented, shown previously, that stress is associated with reduced Lactobacillus in multiple primate and human studies.. But going well beyond this correlation in humans, the researchers actually did something quite brilliant in my opinion. They studied surgery patients who had a region of their guts removed, the region containing Brunner's glands. Specifically, they took patients who underwent surgery for non-metastatic gastrointestinal stromal tumors. And what they did was they compared those who had the region of the intestines that contains Brunner's glands to other patients who had similar tumors but who had surgery with a slightly different part of the intestines removed so that Brunner's glands were actually preserved. So you get this really interesting comparison. It's ingenious. And indeed they found immunological changes consistent with the mechanistic data shown in this paper. Now, this is somewhat an aside, but I think it's a brilliant example of how you can couple rigorous causal animal mechanistic models with observational data in humans and natural experiments in humans to demonstrate that the former, the mouse studies, are most probably relevant to the latter, human studies. So in summary, these data are consistent with a model whereby the central amygdala in the brain signals through the vagus nerve to increase secretions from Brunner's glands, which feed lactobacillus, leading to better gut barrier function, better autonomic tone, less GI upset, less bloating, and overall better GI function. Conversely, stress decreases signaling from the central amygdala to Brunner's glands, thus depleting lactobacillus, starving them off, leading to bloating, leaky gut, among other unfortunate effects. Now, really quickly, before getting into the actionable takeaways that I promised you, astute viewers might have noticed that stress equates to less central amygdala activity, even though the amygdala is often thought about as the fear, fight, and flight region of the brain. So this might seem counterintuitive if you're following, but basically, brain regions are heterogeneous, with different neuron populations that carry out many different jobs. So I wouldn't take this as a paradox, just a complexity. And if that went over your head, ignore this last bit, but I did just want to mention that for the uber neuro nerds out there. Now, what can you do to leverage this new knowledge to intervene on this pathway to improve your gut health? Well, perhaps the most actionable and inexpensive modality, is through stress reduction exercises. This includes deep breathing, physiological sighs, yoga, meditation, or just doing whatever relaxes you. Now, on the physiological sigh front, this is a technique brought to my awareness and popularized by Professor Andrew Huberman. It involves a specific pattern of breathing that activates the parasympathetic nervous system, and it consists of a double inhale followed by a long exhale, like, "Sniff, sniff, hoo, sniff, sniff, hoo, sniff, sniff, hoo." And I'll link to more information on that below. And on the user-specific relaxation technique, I want you to seriously contemplate what relaxes you. Often this falls into the category of guilty pleasures. And if you're anything like me, type AAA, you may even avoid these activities by virtue of the fact that they aren't classically productive. However, in sharing the data presented in this video with you, I want you to contemplate that what might not seem productive may actually be productive insofar as it's good for your gut health and, by knock-on effects, your metabolic health. So yes, that means, for For me, taking myself as an example, I can rationalize curling up on the couch in a ball and binge-watching Game of Thrones or Marvel movies as a metabolically healthy intervention. What do you think of that? Kind of a nice free pass to enjoy yourself, right? But seriously, enjoyment, relaxation, social connection, these are all really important to gut health and metabolic health and mental health, of course. In addition, consuming fermented foods containing Lactobacillus may be beneficial consistent with this literature, including things like sauerkraut, kimchi, pickles, yogurts, and so on. I personally really enjoy kefir. Recently, I accidentally gave myself depression. To make a long story short, I just had to undergo aggressive antibiotic therapy for 10 days. It was super unpleasant, and while the diarrhea sucked, and it did, Worse still were the mood changes. As I purged my microbiome, I noticed a distinct depression, a hollowness, a loneliness, an emptiness that was particularly bad when I woke up in the morning. Now, I do not mean to diminish the experiences of those living with crippling chronic major depressive disorder, but for me, this was a really distinctive experience. One I'll definitely remember. And everyone around me noticed it. I just wasn't myself. And when I stopped the antibiotics, within 2 days I was back to my normal mood status, which is I think relatively chipper at baseline. So what gives? What happened? Well, coincidentally, shortly after I recovered from my self-described antibiotic-induced depression syndrome, a paper was published in one of my favorite journals, Cell Metabolism. That made me very happy and cast a new light on my experience. This new paper shows how rhythms in the microbiome can causally impact brain activity and stress responsiveness, with clear implications on mood status and mental health. To be more specific, fluctuations in the microbiome change the expression of genes of your DNA in your brain, in brain centers that govern circadian rhythm and the hypothalamic-pituitary-adrenal axis, which controls cortisol and stress hormone rhythms. And screwing with the microbiome, as through aggressive antibiotics, literally screws with patterns of gene expression in the brain and downstream fluctuations in whole body stress responsiveness, and behavior. Now, while these causal mechanistic data that we're going to talk about do need to be collected in animal models, there are strong and clear clinical ties, as these physiological pathways are conserved across mammals, from mice to humans. And more to the point, many human mental health conditions are characterized by microbiome dysbiosis, imbalance, and dysregulated circadian rhythms. But with that, I want to dig into the data with you. One of the first things the researchers did in this paper is highlight the natural rhythmicity of the microbiome and the stress response axis, the hypothalamic-pituitary-adrenal axis, where your hypothalamus tells your anterior pituitary to release a hormone that tells your adrenal glands to make cortisol, the stress hormone. Now, it's really important to note that the brain centers involved in circadian rhythm, including the suprachiasmatic nucleus, which is the master regulator of your circadian rhythm, are interconnected with those involved in emotions and stress responsiveness. For example, the SCN talks to the hypothalamus, which controls the body's stress hormone fluctuations as we just described, and both talk to the emotional brain, including the amygdala, the fight-or-flight center of the brain, and the hippocampus. This is all super interesting, and here's something else really interesting. When you treat animals, or potentially humans, or Nicks, with antibiotics, you not only screw up the microbiome's rhythm, but you also screw up rhythms in hormones like cortisol, as you can see here, and change gene expression patterns in the brain. Yes, antibiotics to your gut can change gene expression patterns in your brain. For instance, here, this is Figure 1K from the paper. And if you look at this heat map of rhythmically expressed genes in the suprachiasmatic nucleus, you can see in the control, each row represents a natural ebb and flow whereby darker colors are more gene expression. But when you hit the mice with antibiotics, the gene expression in the brain's circadian rhythm regulatory center, the suprachiasmatic nucleus, gets all screwed up. By analogy, it's as if you had a beautiful sand sculpture—this is the nice rhythmicity of the brain, nice normal rhythmicity of the brain gene expression patterns—and antibiotics are like a wave that just smashed the sand sculpture. It's pretty stunning. And this pattern was mirrored in other brain centers like the amygdala, the fight-or-flight center, or the hippocampus. And messing with the microbiome with antibiotics also led to important changes in neurotransmitters in the brain, like the prominent excitatory neurotransmitter glutamate, which you can see here. This is Figure 3H-K in the paper. Now, I can't overstate how impactful the influence of the microbiome is on overall brain function, since the changes we're describing in gene expression and neurotransmitters have knock-on effects. For example, the blood-brain barrier is the gatekeeper of the brain, but changes in gene expression patterns that occur with microbiome manipulation, including changes in genes coding for blood-brain barrier tight junction proteins. They change with microbiome manipulation, literally making the brain leakier at specific times, as shown in this figure. And all this has a direct impact on behavior, since the brain is the basis for the mind, and the mind controls behavior. And now to hammer home the point that all these changes are causally influenced by the microbiome, what the researchers did was transfer microbiomes from antibiotic-treated mice taken at different times of day to mice without their own microbiomes. This is called a fecal matter transplant or a microbiome transplant, and they were able to recapitulate the stress cortisol responsiveness in a clear circadian-dependent manner. Showing the causality of the microbiome in the influence of antibiotic treatment. Okay, now I know that's a lot of detail and jargon, and you may have noticed I've been intentionally vague on the specific microbiome changes and particular circadian-dependent changes in brain gene expression and stress responsiveness. And that's intentional because I'm trying to build to what I think is most important and practical for you to take from this video today. And truth be told, nobody can yet provide you with precision protocols to optimize your brain gene expression patterns and stress axis given these data. These are early and exciting data, but they are early data. However, we can extract truths and practical advice. So here are 3. The first truth is that your mind and your mood are influenced by your microbiome. It's not that your brain is a complete puppet on your microbiome's strings, but it's also not an unfair analogy either. So if something is messing with your gut, be that antibiotics, dietary changes, or insufficient sun exposure—a lot of you know I'm on a light kick right now—be mindful of your mood because the awareness of the connection might be your first step to correcting the problem. I think awareness alone can be super, super powerful. Second, get and stay in a rhythm as best you can. Give your microbiome and your body overall species and evolutionarily appropriate signaling to stay in tune. These are actually called Zeitgebers, these cues. It's kind of a fun word for you, and they include and highlight natural sunlight. Get it where you can. And regular meals, ideally during light hours and avoiding late-night eating. In effect, being regular and routine with your Zeitgebers provides circadian cues and allows you to act as a conductor of sorts for the clocks all over your body, helping to appropriately synchronize them and synchronize the orchestra of clocks within you. And third, while precision healthcare on these matters is not here yet, It is around the corner, and if I were a betting man, I'd bet that within the next 5 to 10 years, we'll have tools like microbiome analyzing toilets that will collect and analyze your data and send that pile of information to an app on your phone to inform your dietary and lifestyle practices. It's gonna be pretty cool shit. You knew I couldn't get through this video without at least one pun. And finally, if you're like me and need to take an aggressive course of antibiotics, Brace yourself. I'm certainly not saying antibiotics are bad, but oh boy, they can hit like a train. Ketogenic diets are known to have a metabolic advantage, meaning all else being equal, if you eat the same number of calories on a ketogenic diet, you'll weigh less than on a non-ketogenic diet with carbs. And the mechanism behind this has been largely a mystery, but new research in Nature Metabolism has revealed how a non- ketones, a class of molecules made on ketogenic diets, might help calories pass right through you. And the curious thing is you can actually already buy these molecules, or molecules that intersect with the pathway I'm going to explain in this video. So stick around and I'll explain these data, give you better insights into the physiology, and then you can doo-doo with that what you want. Let's go. I'll open with lines straight from the paper that I think tee up, frame the whole paper quite nicely. The low-carbohydrate ketogenic diet has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by ketogenic diet consumption, although the particular gut microbes or metabolites involved are unclear. So what the researchers did to start is they started in mice— we'll get to the human data in a little bit— but they started in mice and fed them a ketogenic diet or a standard chow control diet for 7 weeks and looked to see what metabolites are increased by a ketogenic diet. And they found that levels of 6 taurine-conjugated bile acids were increased by a ketogenic diet. Taurine is an amino acid, and you can attach it to bile acids to make taurine-conjugated bile acids. As a quick tangent, no, you can't just supplement taurine to boost levels of these. This is limited more by microbiota metabolism. So don't go wallabyopsy yourself by buying a bunch of taurine for the purposes of the data shown in this paper. That won't work for weight loss. But anyway, they showed a subset of these taurine-conjugated bile acids in the mice were indeed causal for weight loss. Because when they supplemented mice on a standard chow diet with two of these taurine conjugated bile acids, TDCA or TU-DCA, that it caused weight loss and improved glucose tolerance in the mice, even though they were on a standard chow diet. Also, for shits and giggles, literally shits and giggles, they did fecal transplants from ketogenic diet-fed mice to mice fed a standard chow control diet and found that mice receiving the ketogenic diet fecal transplant, the ketogenic diet cultivated microbiota lost 18% of their body weight. That's like Ozempic for mice. They next went on to identify what key microbiota that is either increased or decreased on a ketogenic diet is mediating the effect, the weight loss effect, and they identified a particular bug in the mice, L. murinus ASF361, that was depleted by a ketogenic diet. Now, the name of the bug isn't particularly important. The important thing is that the bug harbored a genetic sequence coding for an enzyme, BSH, that breaks bonds in conjugated bile acids. So basically, a ketogenic diet, by virtue of depleting levels of this BSH-coding microbiota, decreased levels of the enzyme that would otherwise break up the towering conjugated bile acids, allowing the TDCA and the TU-DCCA towering conjugated bile acids to rise, causing weight loss. But how, how do these towering conjugated bile acids cause weight loss? Well, pooping calories. Yes, pooping calories. Indeed, when the researchers took feces from mice treated with towering conjugated bile acids and threw it into a bomb calorimeter and blew it up, there was indeed more calories in the feces from mice treated with towering conjugated bile acids than controls. Don't make an explosive diarrhea joke right now. Don't do it, don't do it. Okay, good. And they found that mice treated with a ketogenic diet or transplanted with microbiota from ketogenic diet-fed mice also pooped more calories, and that this effect was erased by treatment with antibiotics. So all these data are consistent with the idea that a ketogenic diet depletes levels of BSH encoding microbiota so that towering conjugated bile acids can rise, leading to pooping of more calories. But now, what was the precise mechanism for this anti-absorptive effect? Well, towering conjugated bile acids, the TDCA and the TU-DCA, downregulate an enzyme called carbonic anhydrase 1, or CAR1. And they also found that CAR1 inhibitors, carbonic anhydrase 1 inhibitors, the drugs methazolamide and topiramate, also reduced intestinal fat— intestinal calorie absorption and caused weight loss. But now I'm sure you're wondering, well, what about data in humans? Well, they collected data in humans, including a cohort of 416 adults, and found an inverse association between bile acids, particular conjugated bile acids, and BMI, such that lower levels of particular conjugated bile acids were associated with higher BMI, which has been shown previously. But what was really cool and novel in this paper is that in an interventional trial in which human adults underwent a ketogenic diet for 12 weeks and lost on average 5.27 kilograms, they found that the ketogenic diet also increased levels of the conjugated, the taurine conjugated bile acids, TDCA and TU-DCA. And they found that the ketogenic diet depleted levels of BSH-encoding microbiota. So completely consistent with the mouse data, they're showing a ketogenic diet depletes increased levels of bugs coding for this BSH gene that will be predicted to break down conjugated bile acids, particularly the towering conjugated bile acids. Levels of those towering conjugated bile acids increase in association with weight loss, perfectly consistent with the mouse data. It really comes together as a complete picture. How cool is that? What's more, there are other observations in humans outside this study that are consistent with these findings. For example, bariatric surgery is known to increase levels of TDCA, and the CAR inhibitor drugs I mentioned earlier have been known in clinical observations to to exert anti-obesity effects, although previously the mechanism was unknown. Pretty cool. So what, what are the big takeaways? Well, PAR inhibitor drugs are already prescribed, and taurine conjugated bile acids, in particular tUDCA, are available for purchase. You can even go buy them on Amazon. To be clear, I'm not recommending that you do so because the research on tDCA or tUDCA supplementation for weight loss and the safety profile over the long term has not been studied. But the researchers themselves advocate that these might be potential weight loss therapeutics candidates. So I just wanted to throw that out there. You can do with it what you will. I'm not recommending you go buy anything. And I'd also caveat just mechanistically that this certainly isn't the whole picture with respect to the metabolic advantage of ketogenic diets, which have also been shown to increase energy expenditure separate from intestinal energy absorption. So really, I just wanted to come here to share these data with you, as always, test my restraint from making bathroom jokes. I think I did a pretty good job and hopefully help you to Stay curious. Have a good one.