Nick Norwitz breaks down how ketogenic diets trigger weight loss through a gut bacteria mechanism. When you eat keto, a bacterium called Lactobacillus murinus depletes, causing bile acids TDCA and TUDCA to accumulate and block fat absorption in the intestines. The effect shows up in humans: a study of 416 people found those with higher taurine-conjugated bile acids had lower BMI.
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-ketone 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. Welcome to my channel. Stay curious. 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 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-DCA 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 absorptive effect? Well, towering conjugated bile acids, the TDCA and the TUDDCA, 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, particularly 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 TUDCA. 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 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 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.
