A chemical that gut bacteria help make from nutrients in foods like red meat and eggs is linked to atrial fibrillation, the most common lasting heart rhythm problem, according to research from Cleveland Clinic1. The chemical is called TMAO, short for trimethylamine N-oxide. In blood samples from 5,090 heart patients, people with the most TMAO were more likely to have the condition1. In mice, extra TMAO brought the rhythm problem on sooner, and an experimental gut-targeted compound that cut TMAO production delayed it1.
The work was published online in the Journal of Clinical Investigation on July 24, 20261, and Cleveland Clinic described it on October 29 as showing that TMAO is a “modifiable” risk factor, meaning one that could in principle be changed1. That claim rests on the mouse experiments. No one has yet tested whether lowering TMAO prevents atrial fibrillation in people.
What the researchers found
Atrial fibrillation, often called AFib, happens when the heart’s upper chambers beat fast and irregularly. It affects more than 10 million adults in the US and can lead to blood clots, stroke and heart failure if left unchecked2.
TMAO starts in the gut. Bacteria break down nutrients such as choline and L-carnitine1 into a compound called trimethylamine, which the liver then turns into TMAO2. Red and processed meat, eggs, high-fat dairy and some supplements are the main food sources of the starting nutrients2.
The team, led by cardiologist Robert Koeth with co-author Stanley Hazen, measured TMAO and related compounds in blood from patients having a planned heart catheter procedure at Cleveland Clinic1. After accounting for age, sex, diabetes, heart disease, body weight, kidney function and other factors, people in the top third for TMAO had 1.7 times the odds of having AFib compared with people in the bottom third1. Some news coverage described this as a 70% increased risk2.
“Our study is the first that puts the connection between TMAO and AF together using a bench-to-bedside approach, and we fulfilled our goal to establish a clear, probable mechanism,” said Koeth1.
What happened in the mice
To go beyond a link in people, the researchers used two kinds of mice1. One is a genetically altered strain that develops AFib on its own, first in bursts and then permanently1. The other is ordinary lab mice, whose hearts were stimulated with a small electrical probe to see how easily AFib could be set off1.
- In the AFib-prone mice, adding choline or TMAO to the diet made the first AFib episode come sooner and sped the move to permanent AFib1.
- In ordinary mice, extra TMAO led to an 11-fold increase in how often AFib could be triggered during the electrical tests1.
- Mice on a high-choline diet developed an enlarged upper left heart chamber, a structural change linked to the condition1. Measurements of the heart’s electrical signals showed changes that make abnormal rhythms easier to start and keep going3.
The team also tested iodomethylcholine, an experimental compound that stays mostly in the gut and blocks the bacterial enzyme that does the first step of TMAO production1. In the AFib-prone mice, it lowered TMAO and clearly delayed the rhythm problem1. It also largely prevented the chamber enlargement seen with high choline1. The mix of gut bacteria shifted, and the researchers reported no notable harm to the liver2.
As for how TMAO might act, the study points to the automatic nervous system that helps set the heart’s pace. The researchers report that TMAO blocks a receptor on heart cells, known as the M2 muscarinic receptor, that responds to a nerve signaling chemical3. They argue this throws the nervous system’s control of the heart off balance and promotes AFib3.
What it does not show yet
The human part of the study looked at who already had AFib when their blood was drawn3. That kind of snapshot can show a link, but it cannot show which came first, the high TMAO or the rhythm problem. The patients were also people already having heart procedures for known or suspected heart disease2, so the results may not apply to the general population.
The cause-and-effect evidence, including the enlarged heart chambers and the delay from blocking TMAO, comes only from mice1. Mouse hearts and gut bacteria differ from human ones, and many results in mice do not carry over to people. The compound used here is experimental, and the sources describe no human testing of it for AFib.
Koeth said that “further study will help refine an effective therapeutic approach”1. The study did not test whether changing diet lowers AFib risk, and nothing in it tells people how to eat.
Who is behind it
The study’s authors are mostly from Cleveland Clinic, with collaborators at Case Western Reserve University4. Robert Koeth is the corresponding author4. Hazen, who co-leads Preventive Cardiology at the clinic, said TMAO “opens up a novel preventative paradigm”1.
The paper lists financial ties. Hazen and co-author Zeneng Wang are named as co-inventors on Cleveland Clinic patents related to heart tests and treatments3. They have the right to receive royalties from Cleveland Heart Lab, a subsidiary of Quest Diagnostics, and from Zehna Therapeutics3. Hazen also reports being paid as a consultant for Zehna Therapeutics and receiving research funds from it3. The sources reviewed for this article do not say who funded the AFib study itself.
How it fits the field
Hazen’s team was the first to show that gut bacteria make TMAO from nutrients in animal foods5. Over the past 15 years, studies by his lab and others have tied TMAO to hardened arteries, blood clots, bulging of the body’s main artery and heart failure1. A 2024 study with Tufts University followed nearly 12,000 people who were healthy at the start for almost 16 years. Higher TMAO predicted later heart failure, after accounting for other risk factors6. A TMAO blood test was already in clinical use by 20185.
The idea of blocking TMAO in the gut is also not new. In 2018 the same group reported a class of compounds that stop bacteria from making TMAO without killing them5. In mice, one dose lowered blood TMAO for up to three days and reversed signs of excess clotting5. Procter & Gamble researchers took part in some of that work, and Hazen reported consulting for and receiving research funds from the company5. Hazen said then that the team looked forward to taking the approach into people5.
The new study adds AFib to that list. The researchers say ordinary risk factors such as high blood pressure and obesity do not fully explain who gets it1.
What to watch next
- Whether studies that follow people over time show that high TMAO comes before new AFib, rather than only appearing alongside it.
- Whether any TMAO-blocking compound enters human trials, and whether AFib is one of the conditions tested.
- Whether other research groups, outside the labs with patents and company ties, find the same link.
