In a publication in the journal, Cell Host & Microbe, Zhu et al used knowledge from previous studies that have demonstrated a correlation between circulating levels of the gut microbiota–derived metabolite trimethylamine-N-oxide (TMAO) and stroke-incident risk. The research was led by Weifei Zhu, PhD, and Stanley Hazen, MD, PhD, of Cleveland Clinic's Lerner Research Institute. The study builds on more than a decade of research led by Dr. Hazen and his team related to the gut microbiome's role in cardiovascular health and disease, including the adverse effects of TMAO–a byproduct created when gut bacteria digest certain nutrients abundant in red meat and other animal products.
In earlier studies, Dr. Hazen and his team revealed that higher TMAO levels can lead to the development of cardiovascular disease. In clinical studies involving thousands of patients, researchers demonstrated that blood levels of TMAO predict future risk of myocardial infarction, stroke, and mortality—findings that have been duplicated around the world. Earlier studies, also led by Drs. Zhu and Hazen, were the first to demonstrate a connection between TMAO and enhanced risk for blood clotting. In this study, researchers examined whether gut microbiota in general or either TMAO or a functioning gut microbial cutC gene can impact stroke severity using multiple rodent models of stroke.
In an interview, Dr. Hazen, chair of the Department of Cardiovascular & Metabolic Sciences and director of Cleveland Clinic's Center for Microbiome & Human Health, stated, "In this study we found that dietary choline and TMAO produced greater stroke size and severity, and poorer outcomes in animal models. Remarkably, simply transplanting gut microbes capable of making TMAO was enough to cause a profound change in stroke severity."
In the study, researchers compared brain damage in preclinical stroke models between those with elevated or diminished TMAO levels. Over time, those with greater levels of TMAO had more extensive brain damage and a greater degree of motor and cognitive functional deficits following stroke. The researchers also discovered that dietary adjustments that modify TMAO levels, such as eating less red meat and eggs, impacted severity of stroke. The research team also indicated that a gut microbe enzyme critical to TMAO production called CutC drove heightened stroke severity and exacerbated outcomes.
Dr. Hazen, who is also co-section head of Preventive Cardiology & Cardiac Rehabilitation in Cleveland Clinic's Miller Heart, Vascular & Thoracic Institute stated, "Functionality after a stroke—which occurs when blood flow to the brain is blocked—is a major concern for patients. To understand if choline and TMAO affect 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." Additionally according to Dr. Zhu, pursuing this gut microbe enzyme may be an encouraging approach to prevent stroke. Dr. Zhu stated, "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. Switching to plant-based protein sources helps to lower TMAO.
The researchers indicated that the results from the new study expand on findings from previous studies and for the first time provide evidence that gut microbes in general—and through TMAO specifically—can directly influence stroke severity or post-stroke functional impairment. They concluded that the differences in cerebral infarct volumes and functional outcomes noted in low versus high TMAO states is incredible, and a better understanding of the underlying mechanisms contributing to TMAO-driven stroke risk is an exciting area of intense interest.
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