Stroke remains the leading cause of serious, long-term adult disability, with hundreds of thousands rendered disabled in the U.S. each year. This disability translates into billions of dollars in health care costs, lost productivity, and long-term care. Thus, finding ways to reduce stroke morbidity and improve outcomes is a priority. Age, known co-morbidities such as diabetes, and the size and location of the infarct strongly influence stroke outcome. Even after accounting for these recognized factors, much of the variability in recovery after stroke remains unexplained. Inflammation contributes to pathophysiology of both acute ischemic injury and more delayed injury that affects the outcomes in cerebral ischemia. One major effort in characterizing immune mechanisms in disease and immune response to injury focuses on the human microbiome. Recent data in mouse models of stroke have established a relationship between gut microbiota, neuroinflammatory response to ischemic infarct, and outcomes. These animal studies, if recapitulated in human disease, could open an entirely novel and dramatic avenue of treatment in ischemic stroke. To date, the limited microbiome studies in human cerebrovascular disease have not focused on stroke outcome. We hypothesize that recovery after ischemic stroke is influenced by gut microbial composition. A secondary hypothesis is that gut microbial composition influences neurocognitive function after stroke. To test these hypotheses we propose using microbial surveys of gastrointestinal microbiota from individuals presenting with ischemic stroke.
Aim 1 will investigate the relationship of baseline intestinal microbial community composition with ischemic stroke outcomes at 3 months, comparing the composition and diversity of gut microbiota in those with a) excellent (NIHSS<1) versus non-excellent outcomes and b) devastating (NIHSS>20) versus non-devastating outcomes.
Aim 2 will investigate the relationship of baseline intestinal microbial community composition in those with specific neurocognitive deficits after ischemic stroke, to determine whether microbiota composition and diversity influence neurocognitive function after stroke. Upon successful completion of this project, in addition to testing our hypotheses, we will have collected the necessary clinical/phenotypic data and biological samples to extend our investigations to subsequent metagenomic and mechanistic studies, as well as examine the interplay between host factors and the gut microbiome on stroke outcome and cognitive function , thus paving the way for future novel strategies to reduce stroke morbidity.

Public Health Relevance

Despite substantial reduction in deaths from stroke, stroke remains the #1 cause of adult disability in the U.S.; we lack reliable predictors of outcome ? two patients with identical strokes can have radically different recoveries with one returning to work and another severely disabled and requiring constant care. The interplay between the microbes that live on and in us (our ?microbiome?) and our immune system is increasingly recognized as influencing brain and vascular disease, with recent animal data suggesting the gut microbiome can alter stroke risk factors (e.g. high blood pressure), responses to treatment, and stroke outcomes. In this proposal we will collect and analyze fecal samples from 300 stroke patients as a crucial first step towards exploring the relationship between the gut microbiome and (1) stroke severity and (2) recovery at 3 months.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Bosetti, Francesca
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University of Virginia
Schools of Medicine
United States
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