The NEW Microbial Molecule Linking Diabetes and Heart Disease

In the days after a new major paper dropped in the journal Nature about the microbiome and heart disease, my social media algorithm went into a frenzy. On the one hand, there were people e-shouting that "Eureka! Heart disease isn't about cholesterol!" And on the other hand, people were claiming "meat causes heart disease!" And in the middle? Well, let's be real, on short-form social media, there's less middle than Oreo Thins. But Here we like triple stuffed, figuratively speaking. So, let's do this. What if one molecule made by bacteria in your gut could quietly sabotage your blood sugar and clog your arteries? Meet imidazolepropionate, a microbial molecule made by gut bacteria from the essential amino acid histidine, now deeply linked to both diabetes and heart disease. I wanna start with this new recent publication. A 2025 paper published in Nature finding that imidazole propionate, or IMP for short, was associated with atherosclerosis in two independent human cohorts, the PSA cohort and the IGD cohort, and was shown to cause atherosclerosis in animal models. Looking first at the human data, in both cohorts I mentioned, higher IMP levels correlated with higher fasting glucose, increased markers of inflammation, like high sensitivity C-reactive protein, more visceral fat, and lower HDL cholesterol—all signs of metabolic dysfunction. And what's more, IMP levels directly correlated with the degree of atherosclerosis in humans as measured by vascular ultrasounds and coronary artery calcium scores. Now, these are interesting associations, but of course, we must ask, what came first, the chicken or the egg? In this case, the IMP or the metabolic dysfunction and atherosclerosis? To answer that question, the causal question, we need animal models. So the researchers injected mice with IMP or a control solution to see what would happen. They used two different mouse models to improve the generalizability of their findings, and indeed, IMP treatment caused atherosclerosis in both animal models. So, how? What is the causal mechanism? Turns out IMP did not affect cholesterol levels, so I suppose the one half of the internet was partly right. Instead, IMP increased the expression and activation of several inflammatory proteins and signaling pathways, including TNF-alpha cytokine signaling, NF-kappa-B signaling, and the expression and expansion of pro-inflammatory Th17 immune cell population. So in short, in a nutshell, IMP heightened the inflammatory atherogenic environment in a cholesterol-independent manner. They also found, the researchers found, or more accurately confirmed, that a key player in this IMP pathway was a protein complex you may have heard of called mTOR. And I say confirmed because this link was actually first identified years prior in a 2018 publication in the journal Cell when researchers discovered that IMP is elevated in people with type 2 diabetes and that it causes insulin resistance. Now, in this earlier study, researchers observed significantly higher IMP levels in people with type 2 diabetes and insulin resistance as compared to BMI-matched controls. Again, they turned to mice to demonstrate causality, and they found that IMP treatment impaired glucose metabolism, increased hepatic production of glucose, the liver's production of glucose, by upregulating rate-limiting enzymes in gluconeogenesis—I know, a lot of words—reduced energy expenditure, and caused insulin resistance by disrupting insulin signaling specifically near the level of the insulin receptor. As I mentioned earlier, all of this was mediated by the metabolic control switch, mTOR. So I've said a lot, I've thrown a lot of jargon at you, I know you can handle it, consider it progressive mental overload. But anyway, to summarize: imidazolepropionate is a metabolite produced by gut bacteria that has emerged as a key player in both type 2 diabetes and cardiovascular disease. It is elevated in individuals with metabolic dysfunction, and has been shown to directly cause insulin resistance and cause atherosclerosis in animal models. The mechanism involves increased inflammation and disrupted insulin signaling, largely or at least in part mediated through the mTOR pathway. Alright, does that make sense? Are we together? Of course, I now figure you're wondering, "What can I do, what can you do to lower your IMP levels and protect your metabolic and cardiovascular health?" Well, the truth I have to tell you is the research is not yet at the point where we can manipulate IMP levels with precision or specificity. But I can make some, hopefully, useful informed input. First and foremost, it's important to acknowledge what probably will not work. You might imagine that because IMP is derived from the amino acid histidine, that essential amino acid, that restricting histidine would be an effective way to reduce IMP. Sounds logical. Now that's what the internet thought too. But it's not effective. Sorry plant-based evangelical influencer guy, but restricting histidine won't help. When you compare people with high versus low levels of IMP in their body, there is no difference in histidine intake. Rather, instead, the presence of specific bacterial enzymes is what determines IMP levels. And the presence or absence of these enzymes is determined by the composition of your gut microbiome. So the good news is I see no reason for you to restrict protein based on these data. The slightly less good news is that we don't yet know exactly how to shift the microbiome to a low IMP-producing state. We just don't know. It is true there are associations between intake of certain foods including fiber-rich vegetables, and nuts, and certain eating patterns, such as a Mediterranean diet eating pattern, that do correlate with lower IMP levels in humans and better cardiovascular outcomes at a population level. You can take this for what it's worth to you. On the one hand, it's tempting, and honestly it's reasonable to speculate, that eating a whole food-based diet that might be fiber-rich from whole foods shifts the microbiome in a direction that lowers IMP levels and improves heart health. I see nothing wrong with that speculation, with that hypothesis. That said, it's also important to acknowledge that these associational data might give a skewed perception of biological reality given that people who eat what's conventionally considered to be healthy tend to live healthier lives overall. This is called healthy user bias. Now, I'll let you decide what's compelling to you. Are these associational data compelling and do you want to shift your diet based on them? That's totally up to you. That said, I do think it's reasonable and productive to consider that broadly treating your microbiome well— I know that's kind of vague— can lower IMP levels with favorable health effects on your heart health. So here are 3 ways to do just that, treat your microbiome well. First, eliminate ultra-processed foods from your diet. Many of the additives in these foods are microbiome disruptors that can lead to microbiome imbalance or dysbiosis. When it comes to supporting your microbiome, it's as much or more about what you do not eat as what you do eat. You can also introduce low-sugar fermented foods, foods like kimchi, sauerkraut, kefir, and natto. These can improve microbiome diversity, which is linked to lower IMP levels. In fact, research shows that fermented foods are more consistently effective at improving microbiome diversity and lowering inflammation as compared to dietary fiber. So if you have to choose between the broccoli or the kimchi, I'd choose the kimchi. Finally, engage in stress reduction practices. While you might think your microbiome is determined solely by what you eat, your mental state also feeds or starves your microbiome. Literally. In fact, chronic stress can, by way of the vagus nerve, the 10th cranial nerve that connects your brain to your gut and your gut to your brain, it can cause glands in your gut called Brunner's glands to starve off or feed good guy gut bacteria, leaving room for the expansion of bad gut bacteria when you're in a stressed and anxious state. So eat well, but also remember to take a breath, chill out, and cuddle a puppy. For more on that, see this video. Now, the story of IMP it reveals something kind of big. Metabolism? It doesn't live in silos. What happens in your gut can ripple through your liver, immune system, blood vessels, and even your brain. The microbiome, mTOR, inflammation, glucose, and cardiovascular health are all part of one interconnected web. That is the big point I want to communicate to you today. Metabolism? It's not just about calories in, calories out. It's about communication between organs, microbes, molecules. And an ecosystem that thrives or breaks down together. Imidazole propionate, it's not just one molecule, it tells a bigger story. And if you want a glimpse of that bigger story, I have a challenge for you. Below, I'm linking 6 of my most popular newsletters on heart health, including those covering the gut-heart axis, Lp, vitamin C, how the heart talks to the brain with exosomes and microRNA, and more. If you're truly committed to learning the deeper nuances of heart health, I promise these reads will be worth your time. Stay curious, let me know what you thought of this video and what you want to learn next. Bye!