A gut metabolite that drives atherosclerosis, diabetes, and more
Imidazole propionate is adding to our understanding of the effects of the multitude within us.
Cardiovascular disease remains the leading cause of death, and atherosclerosis - plaque in the arteries - plays a big role.
A new study in Nature brings to light a direct connection between atherosclerosis and the gut microbiome, offering possible solutions. Just think: Modifying the gut microbiome could stop plaque in the arteries, insulin resistance, diabetes, heart failure, and more.
The idea that the gut microbiome plays a role in cardiovascular health, metabolic health, and healthy aging is not new. Numerous studies have tried to determine which bacteria are beneficial and which are harmful.
It turns out that a metabolite that is produced by multiple bacterial species may be the culprit. This one metabolite ties together type 2 diabetes, insulin resistance, heart disease, and neurodegenerative diseases. Additionally, this bacterial metabolite is linked to several factors that have been shown to protect against heart disease, such as a Mediterranean diet, magnesium, a healthy gut barrier to prevent autodigestion, dietary fiber, and more.
Let’s dig into the study, look at what is going on with this microbial metabolite, and then explore possible solutions you could implement today.
Imidazole propionate as a cause of atherosclerosis
New study: Imidazole propionate is a driver and therapeutic target in atherosclerosis
Researchers in Spain conducted animal studies and then used two human study groups to show that imidazole propionate (ImP) can cause atherosclerosis. They identified the receptor and then showed that blocking the pathway prevented the development of atherosclerosis.
The researchers used a method called untargeted metabolomics to look at all of the changes occurring in mice at the initial stages of atherosclerosis. Using a mouse strain that is prone to atherosclerosis, they depleted the gut microbiome using antibiotics in part of the mice. Then they fed the mice a high-cholesterol diet.
As expected, the mice with the depleted microbiome didn’t develop much atherosclerotic plaque. Prior studies had also shown that germ-free mice don’t have as much atherosclerosis, even when fed a diet that should cause extensive plaque formation.[ref]
The Spanish researchers then looked at all of the metabolites produced by the mice that were being fed an atherosclerosis-causing diet. The metabolite that popped up was imidazole propionate (ImP). It was found to be high in mice that were not on antibiotics (thus had a microbiome) and were fed either a high cholesterol diet or a high cholesterol plus choline diet. The addition of choline plus cholesterol was to see if TMAO or another choline metabolite was the problem.
The researchers found that ImP abundance correlates with increased aortic arch lesions, which are deposits of atherosclerotic plaque in the curve of the aorta that can lead to heart attacks and strokes.
OK - so imidazole propionate comes from the gut microbiome and causes atherosclerosis in mice. What about humans?
The researchers looked at 400 volunteers who hadn’t been diagnosed with heart disease or diabetes. They found that 3/4 had subclinical atherosclerosis and 1/4 had no signs of atherosclerosis. Using metabolomic testing, they found that people with subclinical atherosclerosis had higher levels of ImP. The researchers reported “Linear and non-linear associations were observed between ImP concentrations and atherosclerosis and extent of atherosclerosis, respectively”.
Next, the researchers used another cohort involving almost 2,000 people, some of whom had no atherosclerosis and some with subclinical atherosclerosis. They replicated the finding that ImP levels correlate with atherosclerotic plaque. The researchers also showed that ImP levels directly correlated with higher glucose, higher BMI, and higher inflammatory markers. After adjusting for all of the traditional risk factors, higher ImP levels were still “independently associated with main atherosclerosis outcomes”.
What is ImP doing to cause inflammation and atherosclerosis?
The researchers found that ImP is sensed by the imidazoline receptors, I1R and I2R. Activation of the receptors increases TNF-alpha, an inflammatory cytokine, and activates the mTOR pathway.
Interestingly, studies dating back a couple of decades show that blocking the imidazoline 1 receptor (I1R) can improve diabetes and blood pressure.[ref] And a recent study showed that Rilmenidine, an I1-imidazoline RA medication for blood pressure, extends lifespan in C. elegans.[ref]
To prove that imidazole propionate is causative and not just a bystander, the researchers fed mice ImP in their drinking water while feeding them a diet that doesn’t cause atherosclerosis. Using a couple of different strains of mice, they showed that ImP increases atherosclerosis development and causes systemic inflammation without affecting cholesterol or blood glucose levels. They then demonstrated that blocking the ImP-I1R axis inhibited the progression of atherosclerosis, even with high ImP levels.
What is Imidazole propionate?
Imidazole propionate is a metabolite of histidine, which is an essential amino acid found in many protein-rich foods, such as meat, fish, and eggs. Histidine is used by the body for protein synthesis, including growth, tissue repair, etc. It is also the precursor for histamine production. However, the amino acids that we eat are also used by bacteria in the gut.
Certain bacteria in the gut microbiome can convert histidine from foods into imidazole propionate. The Spanish researchers found an increased abundance of Veillonella and Acidaminococcus bacterial species. Interestingly, they also found that the study participants who ate a Mediterranean-style diet had lower ImP levels and lower levels of the ImP-producing bacteria.
What else does research show on ImP?
In 2018, researchers first identified imidazole propionate as a potentially causal factor in insulin resistance and type 2 diabetes. The study showed that ImP was produced by the gut bacteria found in people with type 2 diabetes, and that higher ImP levels act on mTORC1 and impair insulin signaling.[ref]
A 2020 study showed that increased ImP levels in people with type 2 diabetes were due to altered gut microbiomes that produced more ImP, rather than to the amount of histidine in their diets.[ref] Since then, multiple studies have confirmed the link between ImP and insulin resistance and diabetes. ImP levels progressively increase from people with normal glucose tolerance to those with prediabetes and then to those with type 2 diabetes.[ref]
A preprint published in June 2025 showed that ImP levels are also associated with lower cognitive scores in Alzheimer’s patients.[ref]
Another study involving 155 heart failure patients and a healthy control group showed that heart failure is associated with a shift in the gut microbiota and higher ImP levels.[ref] A large study also found that ImP levels were a significant independent predictor of 5-year mortality in heart failure patients.[ref]
In people who are overweight, serum ImP levels correlate with high blood pressure. The study involved overweight adults who didn’t have type 2 diabetes, and the researchers noted that ImP levels weren’t tied to how much histidine was in the diet.[ref] In HIV patients, obstructive coronary artery disease is associated with higher ImP levels.[ref]
Why is ImP such a problem?
Researchers have found that injecting ImP into the colon of animals causes increased NF-κB, iNOS, and IL-6, decreased gut mucosal barrier, and alterations in microRNAs (miR-146b), leading to intestinal inflammation.[ref]
(Related article on why the gut mucosal barrier is so important in aging.)
Researchers injected germ-free mice with imidazole propionate and found that increasing the ImP levels directly caused glucose intolerance without affecting food intake, body weight, or insulin levels. The researchers were able to determine that ImP increases mTOR activation. [ref - full study is worth reading]
Another new study from Germany on ImP and atherosclerosis showed that long-term exposure to higher ImP levels prevented endothelial cells from being able to repair damage. In addition, higher ImP increased the size of the atherosclerotic plaque and also decreased insulin receptor signaling.[ref]
What can you do about high ImP?
Magnesium glycinate:
A 2022 study found that magnesium intake interacts with the microbial production of imidazole propionate. The double-blind 2 × 2 factorial randomized controlled trial involved 240 individuals who were at high risk of magnesium deficiency, with part of the participants taking magnesium glycinate as a supplement. The results showed that supplemental magnesium reduced ImP by about 40% after 12 weeks. [ref]
Here’s a magnesium supplement in gelatin capsules.* Amazon link as an example. (My article on why I go with gelatin capsules.)
Why would magnesium matter? Some gut microbes rely on magnesium, and a diet that is low in magnesium shifts the composition of the gut microbiome.
Ginseng:
In mice, ginsenoside (a metabolite of ginseng) alters the gut microbiome and reduces ImP levels significantly.[ref]
Get more dietary fiber:
Reduced vegetable intake is correlated with higher ImP in heart failure patients. However, the effect size was small.[ref]
Histidine in the diet:
Foods high in histidine include meat, fish, eggs, and cheese. Essentially, most high-protein foods are going to contain a high amount of histidine. Multiple studies, though, do not show a direct link between that amount of histidine in the diet and the level of ImP in circulation. Instead, it seems that a diet higher in histidine is only a problem when paired with the gut microbes that produce ImP.[ref][ref]
Role of antibiotics:
Researchers can give mice antibiotics, and it reduces ImP levels even with a high histidine diet. However, the same doesn’t seem to hold true for us humans.
Study participants consumed supplemental histidine, and their serum histidine levels went up a little bit. But… when the study participants were given antibiotics for two weeks, their ImP levels rose significantly. This was likely due to gut microbiome changes shifting towards more ImP producers.
Intermittent fasting:
In rats, higher ImP levels have been shown to have a negative effect on healing nerve injuries. Researchers found that intermittent fasting changed the composition of the gut microbiome in a way that quickly reduced ImP.[ref]
Mediterranean diet:
Circling back to the original Nature study on atherosclerosis, the Spanish researchers also found that the participants eating a Mediterranean-style diet had lower ImP levels on average.[ref]
Conclusion and questions
The study showing that ImP plays a causative role in atherosclerosis helps to tie together the “why” for epidemiological studies showing that the gut microbiome impacts cardiovascular disease. It ties together insulin resistance, heart disease, type 2 diabetes, and possibly even neurodegenerative disease.
I’m left with the question, though, of exactly how and why ImP increases inflammation. I understand the link with insulin and mTORC1 activation, but I don’t fully grasp why ImP elevates NF-kB and IL-6 and activates immune cells.
Bigger picture - I’m left wondering if glyphosate, which targets the shikimate pathway and affects bacteria, changes the gut microbiome in a way that increases ImP-producing bacteria. Or maybe something else common to our modern diet, like non-nutritive sweeteners, could be affecting the composition of the gut microbiome. This is pure speculation on my part; I found no research on it.
The connection between supplemental magnesium and lower ImP levels is intriguing and makes me wonder if other supplemental vitamins and minerals are also affecting ImP levels. For instance, does iron and folic acid fortification in foods cause changes in what thrives in our colon? I’m sure there will be more research to come on this interesting topic.
Great share
Thanks for sharing. I did Not know this