Abstract
Stroke is a major cause of death and long-term disability affecting seven million adults in the United States each year. Recently, it has been demonstrated that neurological diseases, associated pathology, and susceptibility changes correlated with changes in the gut microbiota. However, changes in the microbial community in stroke has not been well characterized. The acute stage of stroke is a critical period for assessing injury severity, therapeutic intervention, and clinical prognosis. We investigated the changes in the gut microbiota composition and diversity using a middle cerebral artery (MCA) occlusion ischemic stroke pig model. Ischemic stroke was induced by cauterization of the MCA in pigs. Blood samples were collected prestroke and 4 h, 12 h, 1 day, and 5 days poststroke to evaluate circulating proinflammatory cytokines. Fecal samples were collected prestroke and 1, 3, and 5 days poststroke to assess gut microbiome changes. Results showed elevated systemic inflammation with increased plasma levels of tumor necrosis factor alpha at 4 h and interleukin-6 at 12 h poststroke, relative to prestroke. Microbial diversity and evenness were reduced at 1 day poststroke compared to prestroke. Microbial diversity at 3 days poststroke was negatively correlated with lesion volume. Moreover, beta-diversity analysis revealed trending overall differences over time, with the most significant changes in microbial patterns observed between prestroke and 3 days poststroke. Abundance of the Proteobacteria was significantly increased, while Firmicutes decreased at 3 days poststroke, compared to prestroke populations. Abundance of the lactic acid bacteria Lactobacillus was reduced at 3 days poststroke. By day 5, the microbial pattern returned to similar values as prestroke, suggesting the plasticity of gut microbiome in an acute period of stroke in a pig model. These findings provide a basis for characterizing gut microbial changes during the acute stage of stroke, which can be used to assess stroke pathology and the potential development of therapeutic targets.
Highlights
An estimated seven million adults in the United States suffer from stroke each year, making it the fifth leading cause of death and the first leading cause of long-term disability (Benjamin et al, 2019)
We investigated the changes in gut microbial diversity and composition in a middle cerebral artery occlusion (MCAO) stroke pig model developed by our research team (Duberstein et al, 2014; Platt et al, 2014; Baker et al, 2017)
Non-invasive Magnetic resonance imaging (MRI) allows for real-time, longitudinal assessment of stroke pathophysiology and is a critical clinical tool commonly used to differentiate between stroke type and severity (González, 2012; Baker et al, 2017)
Summary
An estimated seven million adults in the United States suffer from stroke each year, making it the fifth leading cause of death and the first leading cause of long-term disability (Benjamin et al, 2019). In a mouse middle cerebral artery occlusion (MCAO) ischemic stroke model, the stroke mouse exhibited an imbalance in microbial communities, resulting in a reduction in intestinal motility and increased protein leakage in the gut (Singh et al, 2016) These changes correlated with increased brain invasion of proinflammatory T cells from the gut and significantly increased brain infarction (Benakis et al, 2016). Recent failures to translate findings in rodent stroke models have led to the desire to study stroke pathophysiology and therapeutic targets in more translational large animal models such as the pig (Fisher et al, 2009; Saver et al, 2009; Albers et al, 2011)
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