What are your thoughts about gut health as it relates to metabolism, energy utilization and balance? Yeah. So the first thing I'll say is I'm not a gut health expert, but I feel relatively comfortable talking about it based on conversations I've had with people who are experts. One being Suzanne Devkoda, are you familiar with her?

Well, she's sort of a phenom in this area from what I understand. So she was actually doing her masters when I was doing my PhD in layman's lab. So she was one of my lab mates. Terrific. And, you know, the other thing to say is even gut health experts and Suzanne will tell you this, they're like, you know, talk to me in 20 years.

We just know so little. I think that's an overall thing that people don't understand is the scientific consensus moves very, very slow and probably for good reason. Because if we just flipped our scientific consensus based on one study, I mean, it would be a mess, right? So it's going to take time before you really understand the implications of the gut and what it means.

So when it comes to weight loss, there probably is a role in there. I mean, we've seen that there's something going on now, whether that's, is it something where a gut microbiome makeup that's more obese resistant, perhaps it extracts less calories out of the food you eat, right? Uh, or perhaps it's elevating BMR.

Although I, I think that that's probably somewhat unlikely. Do you think it could impact the way satiety signals are? So that's, I mean, back to the brain again. So that's, we know that there's a link in the gut brain access. And so my suspicion is that it probably is, uh, working via appetite regulation.

So that, I mean, if we look at, um, if we look at the most effective, um, obesity treatments out there, which is like semaglutide. Uh, I mean, you consistently see a, you know, 15%, you know, on average loss of body weight, which is massive and people keep it off.

Um, that is a GLP one mimetic, which is a gut hormone. And it basically just is a very, very powerful appetite suppressant. Uh, not, well, I guess I'm interrupting, but hopefully with a purpose, um, there's this really interesting study and it's in mice admittedly, but, uh, published in a neuroscience journal recently.

And the, basically the takeaway is that like so many things in neuroscience, it, the GLP one works in two parallel pathways in the brain. It seems to impact neurons in the hypothalamus that control satiety. So exactly what you're saying. And in the gut, it seems to create a, um, the, an activation of the mechanosensors in the gut.

So the perception is that the gut is full even or fuller, I should say not full, because I think people who take, um, semaglutide don't feel bloated unless I don't know what they might, but that one feels as if their gut is actually fuller because these mechanosensors that send stretch or sending signals to the brain.

Oh, like I actually have some food. I'm not empty down there. Right. Um, anyway, I, I, I'm tickled by this result mostly because every time I hear about a drug or a, or a molecule having effect, we think it has an effect at one location, but it's kind of interesting that, especially for something like, um, appetite regulation, that it would be impacting body and brain in parallel.

Anyway, forgive me. I'm, you can tell I'm, I'm, uh, it's really excited about this. And, and here you are telling a neuroscientist me that a lot perhaps circles back to these brain mechanisms of satiety. Yeah. I mean, I think that, and especially looking at the research on leptin, you know, like we used to think, okay, metabolism is mostly like liver based.

And then, you know, there's, um, there's, uh, you know, metabolism in the adipocyte and skeletal muscle, but none of this stuff exists in isolation. There's so much crosstalk between these pathways. And that's, you know, when we get into mechanisms, the one of the things I love mechanisms, but one of the things I tell people is keep in mind that when you're dealing with an outcome, right?

So like when I say outcome based, we're talking about physical outcomes, like a weight loss, fat loss, changes in blood markers, whatever though, that is the summation of thousands of different mechanisms. So sure. Sometimes you can affect a mechanistic pathway and you get kind of straight down the line outcome, but not always, you know, whenever you make a treatment or, you know, kind of anything into the system, it's like throwing a pebble in a lake, right?

It creates ripples and we don't always know what those are going to be. Right. Um, and that's why, I mean, we've seen, you know, certain drugs, well, it works on this pathway. And then they list off all the side effects and you go, well, how would it create that many side effects?

It's because nothing for the most part, they don't just work in one place. There's multitude of places it works. Um, and, and to your point about, um, semiglutide and the effects on, uh, mechanosensors, it's probably why a lot of people report actually kind of like low grade nausea, um, when they're using semiglutide, uh, because of that, because if you're, you know, that feeling is usually not like a real comfortable feeling, but I mean, it will get you to not eat.

So I think there's absolutely likely a connection, uh, but we haven't fully elucidated how that works. And when you think about how complicated the gut is, I think I heard something like there's more, you know, there's more cells in our microbiome by far than there are in our body.

So we're actually more in terms of a cell per cell level. We're actually more bacteria than we are eukaryote, right? There's a Justin Sonnenberg, who's one of the world experts on microbiome. He's in the lab upstairs for mine at Stanford, and, um, he has this idea. It's just an idea that because we are indeed more bacteria than we are cells, the question is who's the host and who's the passenger, you know, like maybe we're, we are just, maybe they're exploiting us to take them around and interact because they interact and grow on one another.

And so this idea that this freaks people out, Lex Friedman will love this, that maybe human beings are just actually the vehicles for the microbiome and not the other way around. Anyway, kind of a, um, a scary thought. Um, do you do anything specifically to support your gut microbiome?

Are you a probiotic guy or a fermented foods guy or a fiber guy? So again, I'm going to kind of go straight down the line from what I've heard from Suzanne and other experts. So if you want to improve gut health, one of the biggest levers, the three biggest levers you can pull is not eating too many calories, exercising, there's a, there is a connection between exercise and the gut and fiber.

So we, it is of the things we know, dietary fiber seems to positively impact the gut because it is a, what's called a prebiotic. So your gut microbiota can take, especially soluble fiber, although there's actually some evidence, at least in mice, that they, it might be able to use some insoluble fiber as well.

Uh, I think Suzanne was doing a study looking at hemicellulose and actually seeing that some like specific forms of microbiota flourish with hemicellulose, suggesting that they may actually be getting some kind of fuel out of it, which is really interesting. Uh, again, in mice, so, you know, just huge caveat.

So your gut microbiome can produce these short chain fatty acids from, by fermenting, uh, this, this, this soluble fiber. And there's quite a bit of evidence that these volatile fatty acids, which can be then actually, uh, reabsorbed into the liver, that they have some positive effects. Um, like for example, butyrate, when they've done butyrate supplementation, they've actually seen positive effects on insulin sensitivity.

So what we seem to understand is that more diversity seems to be better. Fiber seems to be positive. Prebiotics seem to work much better than probiotics. Supplemented prebiotics. Yes. So the problem with most of the probiotics is they're typically not concentrated enough to actually colonize. And even if you do colonize, what happens is like, let's say you colonize, um, some microbiota that you didn't really have much of, if you're not fueling it with the appropriate fiber, it's not going to stay anyway because it's essentially going to starve.

So the research seems to really clearly suggest that eating enough fiber, which is again, a prebiotic, that that is a better way to get a healthier gut per se than probiotic. What fiber sources do you use? And I think I'm only, I realize there's a huge array of choices out there, but people will want to have some ideas as to how they could perhaps mimic what you're doing.

Yeah. And I would just say diversity, right? So, you know, uh, some there's, there's various evidence from various different fiber sources, um, fruits and vegetables, obviously, um, you know, grains, some whole grains, uh, some cereals, uh, and then various other sources. So this is one of the things where we don't really have a good idea if, you know, this one source of fiber is better than another source of fiber.

We just know that fiber overall is pretty good. And one thing I'll tell people is like, if you want a longevity hack, I mean, fiber is kind of the longevity hack. If you look at some of these cohort studies, there was actually a recent, really large meta analysis of over a million subjects.

Um, and basically what it showed was that for every 10 gram increase in fiber, there was a 10% reduction in the risk of mortality. And that extended specifically also to cardiovascular disease and cancer. So one of the things I'll tell people when they get like really into, you know, whether it's intermittent fasting or, you know, all these other things, they, that's great.

That's great. Are you eating like over 50, 60 grams of fiber a day? And I just, cause it's conceptualized 50 to 60 grams. So if I already, uh, like, uh, a bowl, like a, let's just say a quarter plate of broccoli. Um, and the broccoli isn't stacked to the ceiling.

The broccoli is just reasonably stacked on there. Approximately how many grams of fiber is that? If it's like, uh, like two cups of broccoli, which is a lot. Yeah. So if you're like 200 grams of broccoli per se would probably be like five, six grams of fiber. And I need to get how much per day?

Well, I would say I would typically what the recommended dose is, is 15 grams per thousand calories intake, because if you're eating, you know, low calories, it's, it's difficult to get enough fiber in. Uh, but based on, and again, these are cohort studies. So, but you can't do 20 year long randomized human control trials.

Unfortunately, that doesn't really appear to be a top end, at least for the benefits of fiber. The, it probably boils down to like how much you can tolerate without feeling uncomfortable. Right. Right. Because if you're eating like a ton of fiber, I mean, at some point it's not going to be very comfortable.

Exercise becomes uncomfortable or hazardous. Yeah. And I actually, uh, kind of touching on that because I think it is important. Um, you know, a lot of people have kind of in the carnivore community said, well, you don't need fiber. You poop just fine without it. And I'll always say, well, pooping is the last reason to have fiber.

Like, yes, it does help. It does seem to make, uh, elimination easier. Uh, you can, you know, do it more frequently adds bulk to stool, but that's not why you should eat fiber. Why you should eat fiber is because of the effects of mortality. And, you know, some of the pushback will be, well, this is healthy user bias.

And what I'll say is. Meaning healthy people do this and therefore it's working. Healthy people eat more fiber and therefore. And I mean, yeah, there's, there's something to that. But if it was just healthy user bias, typically you would see some disagreement between the studies. And a great example of that is like red meat.

So not every study shows red meat has an association with cancer and mortality. There's, there's differences depending on the population used. Depending on like what they define as high red meat, low red meat, whether it's processed, unprocessed. But I have not found a study on fiber and cardiovascular disease and cancer and mortality where it did not show improvements from higher fiber.

So to me, that suggests that that effect is real. And so again, you know, as much fiber as you can get in comfortably, I would try to do it because it seems to have some really powerful effects and is good for the gut microbiome. The other thing that may be a consideration for the microbiome is there's some evidence that saturated fat may not be great for the microbiome, that it reduces the prevalence of some, some of the more positive strains of bacteria.

And that appears to be, um, not so much from the saturated fat itself, but from the bile in products that combine with saturated fat seems to have a negative effect on some of these more, um, healthier forms of gut microbiota. But again, this is really difficult because we don't even know necessarily yet which species of gut microbiota are positive or negative.

And that's, I mean, this gets into some of these studies where they may call it dysbiosis. Sounds scary, but dysbiosis just means that the gut changed. Right. It doesn't necessarily, I mean, it doesn't tell you anything qualitative about whether the change was bad or good. Uh, and so these are just things I think we need to keep in mind when we talk about this stuff, that this stuff is still very much in its infancy, but in terms of the big lever levers, I mean, it's pretty much fits with what we know about a healthy lifestyle exercise, don't eat too much, consume a good amount of fiber from diverse sources.

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