In this YouTube explainer, the presenter reviews a newly published Nature Metabolism paper (July 19, 2024) that uncovers a causal gut‑microbiome pathway linking Western‑style diets to reduced levels of the anti‑obesity hormone GLP‑1. The study shows that an obesogenic diet expands the hydrogen‑sulfide‑producing bacterium Desulfovibrio, which damages mitochondria in intestinal L‑cells, lowering ATP production and GLP‑1 secretion. The researchers demonstrate that the over‑the‑counter drug bismuth subsalicylate (the active ingredient in Pepto‑Bismol) blocks hydrogen sulfide accumulation, prevents Desulfovibrio overgrowth, restores GLP‑1, and reduces weight gain in mice. Human data corroborate higher Desulfovibrio and lower GLP‑1 in metabolic‑syndrome patients. The presenter also cites a 2015 inulin‑fiber trial that cut Desulfovibrio abundance by 42% in three weeks, suggesting dietary fiber could similarly boost GLP‑1. He concludes by speculating on broader fiber‑based or microbiome‑targeted therapies for metabolic syndrome, expressing optimism that future research will clarify these avenues.
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This paper I just read blew my mind. Whoa. It answered several questions that have been floating around in my synapses. And like any good paper should, it raised some more questions. In this video, I promise you I will do 3 things. First, I'm gonna show you new data on how, yes, how a poor diet can deplete levels of the anti-obesity hormone GLP-1, which is the natural form of the hormone that drugs like Ozempic try to mimic. Two, I'm gonna share with you preclinical data on how to target a microbiome intestinal cell axis to augment, to raise GLP-1 hormone production to prevent metabolic syndrome. And 3, I'm going to speculate about a potentially novel benefit of certain specific fibers, fibers in food. So the paper in question was published just 8 days ago as I record this in Nature Metabolism on July 19th, 2024. And first, for a tiny bit of background, it's already known that this hormone GLP-1 is depleted, is decreased in various insulin resistance related disorders. This includes obesity, polycystic ovarian syndrome, which I did a different video on, and metabolic syndrome, which is a constellation of clinical features that includes low HDL cholesterol, high triglycerides, high blood pressure, excess abdominal fat, and high blood sugar. But how this occurs, how GLP-1 is reduced in insulin resistance related disorders, really hasn't been clear until now. What the researchers found, starting in a mouse model, is that levels of a bacteria in the intestines— this bacteria called Desulfovibrio— were elevated, and that elevated levels of this Desulfovibrio bacteria negatively correlated with GLP-1 levels. So higher Desulfovibrio, lower GLP-1 levels. And they also found that a diet, a westernized diet, obesogenic westernized diet, although I guess that's kind of synonymous, was sufficient to increase desulfovibrio levels. So this relationship appears in humans as well. It's not just mice. In humans with metabolic syndrome, desulfovibrio levels are elevated in the intestines and GLP-1 levels are reduced. And I want to reinforce, they show in this paper causality. The researchers do find that Desulfovibrio is sufficient to reduce GLP-1 production, and they also discover how this occurs, what the mechanism is, and I think it's absolutely fascinating. Basically, here's how it works. Desulfovibrio has a hydrogen sulfide-based metabolism, and Desulfovibrio generates enough hydrogen sulfide to overwhelm the detoxification systems of the gut to the point that the hydrogen sulfide will actually damage mitochondria in intestinal L cells. L cells being the cells in the intestines that produce the incretin hormone GLP-1. Basically, the hydrogen sulfide damages the mitochondria, so there's a decrease in ATP production, disruption of mitochondrial membrane potential, and because there's an energy deficit in these L cells, they're unable to produce enough GLP-1, and GLP-1 levels go down. Now, here is where things kind of get extra crazy. There's a way to reduce hydrogen sulfide using an over-the-counter medication that you've probably heard of, bismuth subsalicylate, which is the active ingredient in Pepto-Bismol. Yeah, Pepto-Bismol. And in fact, when they treated Western diet-fed mice with this bismuth compound, they found that it did indeed prevent weight gain. It reduced hydrogen sulfide in the feces of these mice. It reduced fat mass pretty impressively. It prevented the Sulfovibrio expansion, which would otherwise be induced by the Westernized diet, and it increased GLP-1 levels by a lot relative to control. So in summary, these researchers identify a causal, a causal pathway whereby a microbiota, Desulfovibrio, produces hydrogen sulfide. This hydrogen sulfide in the intestines decreases energy production, damages mitochondria in intestinal L cells, thus depleting GLP-1 levels and contributing to insulin resistance disorders like metabolic syndrome. They also found that bismuth subsalicylate in Pepto-Bismol could protect against this effect in an obesogenic diet context. So my takeaway from this is we now have just a better physiologic basis for how poor obesogenic Western diets deplete GLP-1 levels. So I see this as filling out our understanding of the root cause of disease, specifically obesity, metabolic syndrome, and other insulin resistance disorders. And with this better physiologic understanding, we can start to dissect how different metabolic health and dietary interventions may benefit different patients. For example, desulfovibrio levels are known to be higher in patients with metabolic syndrome, as I mentioned, who also have lower levels of GLP-1, presumably as a result. And prior work has suggested that higher fiber diets, potentially through the production of short-chain fatty acids, can decrease desulfovibrio levels. So as a specific example, there was a 2015 randomized controlled trial that found just 21 days, just 3 weeks, of only 5 grams per day of inulin fiber, which is naturally found in foods like asparagus, chicory, and artichokes, and as a kind of joking aside, is found less naturally in AG1. They're not a sponsor, but I'm gonna tease that on the off chance they wanna spend some of their Huberman and Rogan dollars to promote this basic science video. Please. Anyway, that aside, inulin, 3 weeks at 5 grams decreased desulfovibrio levels by 42% in the study. This is a pretty modest dose of this fiber and a rather large drop in this hydrogen sulfide-producing bacteria. I think that's pretty cool. Now, could this have therapeutic efficacy in part through enhancing GLP-1 levels? Possibly. Also, questions that arise: are there other fibers, particular fibers, that might be even more potent? Or are there other foodstuffs that could decrease disulfuvibrio levels, augment GLP-1 production, and shift the microbiome generally in a more favorable way to better balance hydrogen sulfide production and detoxification, to better regulate the GLP-1 incretin hormone system? I think these are just fascinating questions to ask. And honestly, I'm optimistic that they will be answered in the coming years. Stay curious and mind your gut bugs.
