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New Research Identifies Link Between Gut Microbes and Stroke

Drs. Hazen and Zhu found that elevated levels of blood TMAO are associated with larger infarct volume and poorer functionality following injury in preclinical stroke models, offering the first evidence that the gut microbiome directly modulates stroke severity.


New preclinical findings from Cleveland Clinic researchers show for the first time that the gut microbiome impacts stroke severity and functional impairment following stroke. The results, published in Cell Host & Microbe, lay the groundwork for potential new interventions to help treat or prevent stroke.

The research was led by Weifei Zhu, PhD, and Stanley Hazen, MD, PhD, researchers in the Department of Cardiovascular & Metabolic Sciences. The study builds on more than a decade of research spearheaded by Dr. Hazen related to the gut microbiome’s role in cardiovascular health and disease, including the adverse effects of TMAO (trimethylamine N-oxide)—a byproduct produced when gut bacteria digest certain nutrients abundant in red meat and other animal products, including choline, lecithin and carnitine.

The latest phase of TMAO research at Cleveland Clinic

“The present study expands on our earlier 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,” said Dr. Hazen, who directs Cleveland Clinic’s Center for Microbiome & Human Health.

Previously, Dr. Hazen and his team discovered that elevated TMAO levels can lead to the development of cardiovascular disease-related events. In clinical studies involving thousands of patients, his team has shown that blood levels of TMAO predict future risk of heart attack, stroke and death—findings that have been replicated around the world. Earlier studies, also led by Drs. Zhu and Hazen, were the first to show a link between TMAO and increased risk for blood clotting.

“In this study we found that dietary choline and TMAO produced greater stroke size and severity, and poorer outcomes in preclinical models,” said Dr. Hazen. “Remarkably, simply transplanting gut microbes capable of making TMAO was enough to cause a profound change in stroke severity.”

The effects of transplanting patient-derived and engineered microbes on stroke

The researchers transplanted fecal material from patients with high and low TMAO levels into germ-free mice. They also performed parallel experiments using defined microbial communities genetically engineered with or without the ability to make the precursor of TMAO. Over time, the recipients of the microbes from patients with elevated TMAO levels (or synthetic communities that can make the TMAO precursor) were found to have significantly more TMAO in their blood. Higher blood TMAO levels were associated with more extensive brain damage in multiple stroke models and a greater degree of motor and cognitive functional deficits following stroke. Researchers also found that dietary manipulations that alter TMAO levels impacted stroke severity, where higher levels of TMAO in the blood was associated with larger stroke sizes.

“Functionality after a stroke—which occurs when blood flow to the brain is blocked—is a major concern for patients,” said Dr. Hazen, who is also a practicing physician and co-section head of Preventive Cardiology & Cardiac Rehabilitation in the Miller Heart, Vascular & Thoracic Institute. “To understand if choline and TMAO modulate post-stroke functionality, in addition to stroke severity, we compared performance on various tasks pre-stroke, and then both in the short- and long-term following stroke.”

The team found that transplanting microbes that harbor an enzyme critical to dietary choline-related TMAO production in the gut, called CutC, was enough to drive heightened stroke severity (over two-fold larger stroke) and worsened outcomes (20-30% reduction in multiple functional outcome measures).

Next steps

According to Dr. Zhu, targeting the gut microbe enzyme may be a promising approach to prevent diet-associated stroke. “When we genetically silenced the gut microbe gene that encodes CutC, stroke severity significantly diminished. Ongoing research is exploring this treatment approach, as well as the potential for dietary interventions to help reduce TMAO levels and stroke risk, since both a Western diet and a diet rich in red meat are known to elevate TMAO levels.”

The team’s next goal will be to test whether inhibiting the microbial step involved in TMAO production provides therapeutic benefits in preclinical models.

Dr. Hazen is chair of Lerner Research Institute’s Department of Cardiovascular & Metabolic Sciences. He is an elected member of the National Academy of Medicine and holds the Jan Bleeksma Chair in Vascular Biology and Atherosclerosis and the Leonard Krieger Chair in Preventive Cardiology at Cleveland Clinic. His seminal discoveries related to TMAO have been replicated around the world and TMAO testing has been widely adopted in clinical practice.

This study was supported in part by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.


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