Cerebral small vessel disease, obstructive sleep apnea, and the gastrointestinal system

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 DESCRIPTION (provided by applicant): Individuals suffering from obstructive sleep apnea (OSA), a condition where the upper airway repeatedly collapses during sleep to produce apneas, are at risk for developing and/or accelerating the progression of cerebrovascular diseases. One of these diseases, cerebral small vessel disease (CSVD), consists of pathological alterations in cerebral small vessels and is associated with injury to subcortical white and grey matter. In this proposal, we will develop the idea that CSVD is accelerated by an imbalance in the gut microbiome (dysbiosis) resulting from OSA. Evidence will be presented that OSA alters the gut microbiome, and enhances blood-brain barrier (BBB) breakdown and brain inflammation in spontaneously hypertensive stroke prone (SHRSP) rats, a model for CSVD. Importantly, BBB breakdown and brain inflammation are conditions associated with the development of CVSD. Evidence will also be provided that the gut microbiome can be altered during OSA to attenuate BBB breakdown and microglia activation. Two hypotheses, each consisting of a specific aim, will be tested in the proposed studies. (1) Obstructive sleep apnea produces gut dysbiosis that accelerates BBB breakdown and microglia activation in cerebral small vessel disease. (2) Stopping the apneas to simulate therapy restores a healthy gut microbiota, and attenuates BBB breakdown and microglia activation in cerebral small vessel disease. These hypotheses will be tested using SHRSP rats, one of the better animal models for CSVD, and a model of OSA where an implanted tracheal balloon can be remotely inflated during sleep to produce apneas. Bacterial diversity and composition of the gut will be determined before and after OSA by metagenomic analyses. These analyses can identify bacteria to the taxonomic level of genus or species. The gut microbiota will be altered by gavaging cecal contents from a donor rat into that of recipient rat. If the first hypothesis is vald then creating dysbiosis in rats not undergoing OSA should accelerate BBB breakdown and activate microglia. Conversely, maintenance of a healthy gut microbiome in OSA rats using a cecal transplant should prevent or attenuate BBB breakdown and microglia activation. The only effective therapy for OSA is continuous positive airway press (CPAP), which holds the airway open by pressure provided by a mask that fits over the nose or nose and mouth. CPAP therapy will be simulated by stopping OSA in the rats. Studies in Aim 2 will determine if stopping apneas can restore a healthy gut microbiota, and attenuate BBB breakdown and microglia activation in the SHRSP rats. If these hypotheses are valid, then gut dysbiosis can affect the health of the brain. Establishing this link could dramatically refocus our attention on the gastrointestinal trac as a potential cause for brain injury as well as provide a target for therapeutic intervention.