Table of Contents

What is already known on this topic
Elevated levels of the microbiota-derived metabolite trimethylamine N-oxide (TMAO) can lead to the development of cardiovascular disease, and blood levels of TMAO predict future risk of heart attack, stroke, and death. However, it’s unclear whether gut microbes could contribute to cause stroke.

What this research adds
Working in mice, researchers found that dietary choline and TMAO resulted in greater stroke size and severity, and poorer post-stroke outcomes. Transferring microbes able to produce TMAO to the guts of control mice was enough to increase stroke severity. This suggests that gut microbes could affect stroke severity or post-stroke outcome through the production of TMAO.

Conclusions
The findings could help to develop new interventions to treat or prevent stroke.

A stroke is a life-threatening medical condition caused by a blocked blood vessel or bleeding in the brain. Now, a new study suggests that gut microbes could affect stroke severity or post-stroke outcome through a metabolite produced from the digestion of certain nutrients abundant in red meat and other animal products.

The findings, published in Cell Host & Microbe, could help to develop new interventions to treat or prevent stroke.

Elevated levels of the microbiota-derived metabolite trimethylamine N-oxide (TMAO) can lead to the development of cardiovascular disease, and blood levels of TMAO predict future risk of heart attack, stroke, and death. “This new study expands on these findings, and for the first time provides proof that gut microbes in general — and through TMAO specifically —  can directly impact stroke severity or post-stroke functional impairment,” says study senior author Stanley Hazen at Cleveland Clinic.

To assess whether gut microbes could contribute to cause stroke, Hazen, Weifei Zhu and their colleagues analyzed brain damage in mouse models of stroke. 

Stroke impact

First, the researchers compared brain damage between mice with elevated TMAO levels and those with reduced TMAO levels. Following stroke, animals with higher levels of TMAO had greater brain damage. 

Next, the team assessed some of the animals’ performance on various tasks before they had a stroke, and then in the short- and long-term after the stroke. “Functionality after a stroke —  which occurs when blood flow to the brain is blocked —  is a major concern for patients,” Hazen says. Animals with higher levels of TMAO had more serious deficits in movement and cognition than those with lower levels of TMAO, the team found.

Giving mice either TMAO or choline, which raises TMAO levels in the blood, increased stroke size and post-stroke deficits in motor function. The team also found that transferring gut microbes able to produce TMAO from people into the intestines of germ-free mice was enough to increase stroke severity in the rodents. This shows that both TMAO production and stroke severity are transmissible traits, the researchers say. 

Diet effect

Finally, the team found that a microbial enzyme called CutC, which is critical to TMAO production, appears to be responsible for the increased severity of strokes and the worsened outcomes

“It is notable that both a Western diet and a diet rich in red meat are known to significantly elevate TMAO levels, and numerous epidemiological studies have shown a significant association between these diets and stroke risk,” the researchers say. “The present studies, when combined with previous clinical studies associating TMAO with stroke risk, suggest dietary interventions in subjects at heightened risk of stroke merit further investigation.”

While the findings add to the growing body of data linking gut microbiota to human health and disease, more work is needed to determine whether the gut microbial TMAO pathway could be a therapeutic target for treating or preventing stroke. “A better understanding of the underlying mechanisms contributing to TMAO-driven stroke risk is an area of intense interest,” the authors say.