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4. Considerations for dietary fat and endotoxins as it relates to ketosis | Dominic D'Agostino

[Rhonda]: Have you been lookinghow long have you been doing this modified ketogenic diet? [Dom]: It, sort of, evolved from 2008 to '09, I started experimenting with it because that's when I got interested in using [Rhonda]: And you've continued on ever since then? [Dom]: Yeah, I've never really gotten out of ketosis

[Rhonda]: It's quite a long time That's quite a long time [Dom]: Yeah If I did, I may have reverted back to, like, a low-carb Paleo which is maybe up to 40% to 50% fat or protein on some days So I've been a little more liberal on the protein at times, but yeah, I've been following it for a long time

And I do blood work really consistent [Rhonda]: Well, the reason I ask is because, it's the one, like I mentioned, I'm very interested in nutritional ketosis, which is why I'm excited to talk to you because you know so much more about it And I'm trying to, like, get to the bot-,there's this conflict in my head with eating a lot of fat and its effects on the gut because I know a lot of my gut researchers, a lot of my friends are, kind of, looking at gut health and one of the main things that you do induce endotoxin, which is released from bacterial cell membranes I remember it's one of main things needed to induce gut permeability is if you have a high-fat diet You feed mice, you feedthis is all done in animals, of course, which is There's lots of problems with that, but [Dom]: What's the typical fat source for that? Is it lard or is it? [Rhonda]: A variety of different fat sources

There's lard, there's corn oil I mean, so there's there's a variety of different fat sources, but fat itself in order to be digested, you have make these bile acids like deoxycholic acid, which which causes endotoxin release It also acts as a surfactant I mean, it's like a detergent So, I'm not convinced that it's not not healthy, but I'm not

I'm, sort of, trying to get to thethere's a disconnect in the literature because there's so much information out there showing the benefits of a ketogenic diet, nutritional ketosis [Dom]: Let me ask this question real quick So when endotoxin is released from these bile acids, so there would be a predictable, a characteristic cytokine profile that would reflect that, right? [Rhonda]: Yes, so there's a cytokine profile and you also measure endotoxin in the blood, which is a very tricky thing to do because there's a lot of false positives and I know someone who's trying to develop an assay to make it actual-, because he's very OCD about it It's not out there for clinical use yet because of that reason, and even doing it in animal studies, there's a lot of researchers that don't really do it right, measuring endotoxin [Dom]: Is there any benefit to endotoxin? So when I go exercise right, and you measure my blood and we look at reactive oxygen species or inflammatory mediators, you could look at the blood and say, "Don't do that, this is not a good thing to do

" Whereas if you have periodic spikes maybe and endotoxin, is it stimulating a hormetic effect where it's enhancing my resilience or resistance to toxins, do we know that? [Rhonda]: So endotoxin, I would say based on everything that I have known and researched and from my interactions with people that have been doing this research It's not like reactive oxygen species where there's it's a potent signaling molecule that has this hormetic effect, increases mitochondria biogenesis, it increases all these genes involved in dealing with stress there's lot of benefits You know, endotoxin release from the gut, one, it causes more VLDL production because VLDL sucks soaks it up So that's part of the reason why inflammation is also correlated with an increase in LDL number It also binds to ApoB, it binds to the part, it binds to where the LDL receptors bind so that LDL can't be recycled as well

So it, kind of, prevents There's a lot of bad things about endotoxin being released Now I don't know, maybe there is some, sort of, slight benefit from endotoxin being released You know, I don't want to get too into the endotoxin world I'm just saying there is, in my

I'm trying to, like, understand in my mind how [Dom]: So you might be a little biased because some of the high-fat diet work has endotoxin I'm a little bit, I need to get educated, I mean, I understand endotoxin from, kind of, like a basic science point of view [Rhonda]: Right, like, "sepsis, bad" [Dom]: Yeah, from "sepsis, bad," but I do know when your body is challenged, even things like radiation

I mean, there are some thingsyou know, I don't know of any case where an auto antibody is a good thing, but I know most of the things that are bad out there do have some benefits, it's the level it's the level [Rhonda]: Absolutely, dose is very important

[Dom]: And the phenotype's ability to adapt to that chemical, that stimulus is really important Like, old people don't adapt to older phenotypes don't adapt to an oxidative stress stimulus as robust So I would be interested, and there's ways to simulate endotoxin, right? Experimental models and that's something we can do, challenge, perhaps run an experiment where we have animals on different diets where we can challenge them and look at inflammatory cytokines We're doing a lot of that work now [Rhonda]: And gut health in general, gut permeability

I would love to see some ketogenic research go in that direction because there's so many unanswered questions in my mind And there's a lot of bad data out there, like so from the high-fat diet and the effects on the gut because when you look at controlled diets and the high-fat diet, well, the controlled diets have, like, 50% more fiber, and it's like, "Well, that's not really the same thing if you're just changing fat" So there's, you have sift through all sorts of crap, and it's, like, there's lots of data you just have to throw out, but still at the end of the day, I'm uncertain and I'm weary about me, eating a high-fat diet Not not mention the fact that I have certain gene polymorphisms that may not be as compatible, but because of that, because of gut health, that's my major, the limiting factor for me is gut health and I like to see more research on ketogenic diets and gut health, like, that's something that I think is important [Dom]: How to optimize it

[Rhonda]: Yeah, or just what the effects are, like maybe they're for one, we're starving out probably a lot of the pathogenic sugar-eating bacteria So there's probably some good things going on And then there's, well, what effect does medium-chain triglycerides has? Is it the same as long-chain fats? Maybe not So maybeso there is different types of fat there's studies that had been coming out very recently showing the effects of polyunsaturated fat on the gut biome, and how it has a positive effect So maybe if you eat certain types of fat, more of these types of fat versus the others There's lot of things out there to be explored [Dom]: Undoubtedly shifts it, yeah

It shifts it I mean, your gut microbiome has an appetite for whatever you're feeding it and that probably influences profoundly your own appetite So I think if you have sugar-eating gut microbes, you're probably going to be craving sugar if you go a few hours without having sugar And I think I would be very interested in not only, like, shifting someone from a high-carb diet to two or three different types of ketogenic diets, I think, would be important with specific fatty acid compositions and fiber compositions And I think it's the diversity of the fiber that's incorporated

[Rhonda]: Diversity, yes, it is very important There have been there's lots of different types of bacteria and they're eating different precursors to generate a lot of these other signaling molecules, short chain fatty acids and things like that that are regulating your immune system, that are regulating literally hematopoiesis, Tregs, natural killer cells lots ofand this is a whole blooming field of research

That's also another reason I've been a little hesitant to experiment with this because I'm so, fiber is so important for me, fiber from vegetables You know, I'm not adverse to fiber from fruits, so fiber from fruits, legumes, beans, like, I like to get a lot of fiber in my diet, and so I don't know if that, is that compatible with it? [Dom]: I get more fiber on a ketogenic diet You know, and we're talking about a well-formulated ketogenic diet, as Jeff Volek likes to And because that is really important because you talk to people that you eat ketogenic diets and it's all over the board But I think a well-formulated ketogenic diet would have an abundance of fiber sources, everything from green vegetables, of course, but would include a salad, and I think it's really important from a gut microbiome perspective to get in raw vegetables, I think, from what I've known and a half-dozen individuals that I talk to that are, kind of experts in this field They think that that has a pretty profound effect, and I have always done that and I would say my gut health has not It may be due to what I eliminated in my diet I grew up in an Italian family eating a lot of pasta, bread, so they were the staple foods, and I gravitated toward a Paleo diet mid-90s, early 2000s and then the ketogenic diet, and I have never had better gut health than when on a ketogenic diet, but my diet is, like I said, more of a modified Atkins and has a pretty liberal amount of vegetables in it And I think the benefit to including the vegetables, they're just carriers for the fat and they also slow protein digestion, which helps minimize the insulin spike that you can get from protein and helps keep me in ketosis But, I mean, getting back to your question about the ketogenic diet or high-fat diet influencing endotoxin or factors, I would think that would show up in the literature that if some, and maybe it does, but it usually, a high-fat diet is in the context of a high-carbohydrate diet, too So that's what we don't know when we talk about LDL particles being elevated, like, even skyrocketed, LDL, little peak

That is only understood in the context of a high-fat diet, which also includes also sugar like a western diet So we don't yet understand lipidomics and the shifts in lipid profile of the ketogenic diet, LDL(p), specifically, we don't understand it in the context of ketoadaptation

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