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

 描述（由申请人提供）：患有阻塞性睡眠呼吸暂停（OSA）的个体有发生脑血管疾病和/或加速脑血管疾病进展的风险，阻塞性睡眠呼吸暂停是一种在睡眠期间上气道反复塌陷以产生呼吸暂停的病症。脑小血管病（cerebral small vessel disease，CSVD）是脑小血管病变的一种，与皮质下白色和灰质损伤有关。在本提案中，我们将提出这样的观点：阻塞性睡眠呼吸暂停综合症导致的肠道微生物组失衡（生态失调）会加速CSVD。有证据表明，OSA改变了肠道微生物组，并增强了自发性高血压卒中倾向（SHRSP）大鼠（CSVD模型）的血脑屏障（BBB）破坏和脑炎症。重要的是，BBB破坏和脑炎症是与CVSD发展相关的条件。还将提供证据表明，在OSA期间可以改变肠道微生物组以减弱BBB分解和小胶质细胞活化。在拟议的研究中，将检验两个假设，每个假设都有一个具体的目标。(1)阻塞性睡眠呼吸暂停导致肠道生态失调，加速脑小血管疾病中的BBB破坏和小胶质细胞激活。(2)停止呼吸暂停以模拟治疗恢复健康的肠道微生物群，并减弱脑小血管疾病中的BBB破坏和小胶质细胞活化。这些假设将使用SHRSP大鼠（CSVD的较好动物模型之一）和OSA模型（其中植入的气管球囊可在睡眠期间远程充气以产生呼吸暂停）进行测试。通过宏基因组分析确定OSA前后肠道的细菌多样性和组成。这些分析可以将细菌鉴定到属或种的分类水平。通过将来自供体大鼠的盲肠内容物灌胃到受体大鼠的盲肠内容物中，将改变肠道微生物群。如果第一个假设成立，那么在没有经历OSA的大鼠中产生生态失调应该会加速BBB的破坏并激活小胶质细胞。相反，在OSA大鼠中使用盲肠移植维持健康的肠道微生物组应该预防或减弱BBB破坏和小胶质细胞活化。对OSA唯一有效的治疗方法是持续气道正压通气（CPAP），它通过戴在鼻子或鼻子和嘴上的面罩提供的压力保持气道开放。通过停止大鼠中的OSA来模拟CPAP治疗。目标2中的研究将确定停止呼吸暂停是否可以恢复健康的肠道微生物群，并减弱SHRSP大鼠中的BBB破坏和小胶质细胞活化。如果这些假设是有效的，那么肠道生态失调会影响大脑的健康。建立这种联系可以极大地将我们的注意力重新集中在胃肠道作为脑损伤的潜在原因上，并为治疗干预提供靶点。

 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.