TMAO, produced in the gut when red meat and high-fat dairy are broken down, identified patients with rapidly growing AAAs.
Circulating levels of trimethylamine N-oxide (TMAO), a metabolite generated by the gut microbiome, is associated with an increased risk of abdominal aortic aneurysm (AAA) independent of other traditional risk factors, a new study shows.
Higher levels of TMAO also were associated with an increased risk for fast-growing AAAs and aneurysms usually recommended for surgery.
“Essentially, your gut microbiome is controlling the growth of the aorta in terms of the aneurysm,” lead investigator Scott Cameron, MD, PhD (Cleveland Clinic, OH), told TCTMD. “Not only can we potentially block that and stop that pathological process from happening, but we can also use that clinically. I’ve been using it for the last 2 or 3 years actually.”
For example, in one patient with TMAO levels exceeding 30 µM—6.5 µM or greater is considered elevated—Cameron inquired about what they were eating. It turned out the patient was supplementing their diet with L-carnitine to boost muscle mass. “Unfortunately, if you carry this type of bacteria in your gut, you’re more likely than not going to take [L-carnitine] and convert it to TMAO.”
TMAO is formed when gut bacteria break down choline and carnitine, which are found in animal foods, such as red meat, eggs, and full-fat dairy products, and release trimethylamine (TMA) into the blood stream. TMA is then oxidized into TMAO in the liver. The compound has been widely studied and linked to the onset and progression of cardiovascular disease, as well as kidney disease, metabolic disorders like diabetes, and neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease.
Two years ago, investigators, including Cameron, published research showing that increasing TMAO levels accelerated the growth of aneurysms in a mouse model. They also showed that the suppression of gut-microbial TMAO halted the progression of AAA growth.
“At that point, it became clear that TMAO was actually something damaging the blood vessel wall and changing the signaling properties of the muscle in the blood vessel wall [and] causing the [arterial] weakening,” said Cameron.
From Mice to (Mostly) Men
In the current study, published today in JAMA Cardiology, the investigators looked into whether circulating levels of TMAO at baseline could identify patients at heightened risk for AAA as well as those with a rapidly expanding aneurysm. The analysis included 237 patients (mean age 65 years; 11% female) with AAA or ectasia (aortic diameter 2.5 to 2.9 cm) from Europe, as well as a US cohort that included 658 patients (mean age 63 years; 20.5% female) from the Cleveland Clinic, of whom 15.7% had AAA and the rest served as controls.
In each cohort, patients with AAA had significantly higher plasma TMAO levels than controls. European patients with elevated TMAO levels had a more than threefold increased risk of AAA, with similar risks observed in the US cohort (OR 2.74; 95% CI 1.78-4.23), when compared with those with normal TMAO levels. After adjusting for cardiovascular risk factors, elevated TMAO remained an independent predictor of AAA in the European, US, and combined cohorts. Adding TMAO as a clinical measure also improved risk estimation for AAA beyond traditional risk factors.
In addition, TMAO identified patients with rapidly progressing AAA, which was defined as a growth rate of 4 mm or more per year. After adjusting for various cardiovascular risk factors, elevated TMAO was associated with a risk of rapidly progressing AAA in the European (OR 2.75; 95% 1.20-6.79), American (OR 2.71; 95% CI 1.53-4.80), and combined (OR 2.30; 95% CI 1.47-3.62) cohorts.
Finally, researchers showed that elevated TMAO was associated with an increased risk for recommended surgical intervention, which was defined as AAA diameter ≥ 5.5 cm or AAA growth rate ≥ 4 mm per year. The heightened risk for surgery with elevated TMAO was significant after adjusting for cardiovascular risk factors. Again, when TMAO was added to a risk model, it helped improve risk prediction for surgery.
Blocking TMAO and Avoiding Surgery
To TCTMD, Cameron said that the microbiome-derived TMAO has been shown to bind to a receptor in the vascular smooth muscle cells of the aorta. Developing drugs that block its production could be a “game changer” in that it could halt the progression of AAA and help some patients avoid surgery, he said.
TMAO is not the only biomarker that may prove useful in caring for patients with AAA. In a study published in 2024, researchers, including Cameron, showed that soluble glycoprotein VI (GP-VI), which is a marker of platelet activity, also was predictive of AAA diagnosis and linked to the growth of the aneurysms. In an animal model, blocking GP-VI also reduced the progression of the AAA.
“What we’ve done with TMAO now is shown the same thing,” said Cameron.
While serial imaging is currently used to follow patients with AAA, Cameron said it doesn’t tell doctors everything they need to know about the patient’s risk for rupture. “It doesn’t tell you about the properties of the blood vessel wall,” he said. For that reason, biomarkers, such as TMAO and GP-VI, can better highlight at-risk patients where there’s accruing biological damage to the arterial wall.
For patients with AAA and elevated TMAO, Cameron currently recommends dietary changes, the biggest of which is limiting L-carnitine and choline supplements. Cutting back on full-fat dairy products and red meat, particularly processed meat, and increasing plant-based foods are also recommended. There is limited, high-quality evidence for taking probiotics, but there is some basic science data showing that bioactive yogurts can decrease TMAO production. Aerobic exercise is another way to lower TMAO levels, although the mechanism is unclear, said Cameron.
Right now, one of the biggest questions around TMAO is whether the findings are the same in women, said Cameron. The present study included few women because AAA is a disease that largely affects men. Women do develop aortic aneurysms, although the growth trajectory differs and tears/ruptures occur at smaller diameters.
“We need to focus on women and see does this thing [hold] or similarly find biomarkers for women,” he said.