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

 描述(申请人提供)：患有阻塞性睡眠呼吸暂停(OSA)的人，一种在睡眠中上呼吸道反复塌陷导致呼吸暂停的情况，有发展和/或加速脑血管疾病发展的风险。其中一种疾病是脑部小血管疾病(CSVD)，它由大脑小血管的病理改变组成，并与皮质下白质和灰质的损伤有关。在这项提案中，我们将提出这样的观点，即CSVD是由OSA导致的肠道微生物群失衡(生物失调)加速的。有证据表明，OSA改变了肠道微生物群，并增强了自发性高血压卒中易感(SHRSP)大鼠的血脑屏障(BBB)破坏和脑炎症，SHRSP是CSVD的模型。重要的是，血脑屏障的破坏和脑部炎症是与CVSD发展相关的条件。还将提供证据表明，在OSA过程中，肠道微生物组可以改变，以减弱血脑屏障的破坏和小胶质细胞的激活。在拟议的研究中，将检验两个假设，每个假设都包含一个特定的目标。(1)阻塞性睡眠呼吸暂停导致肠道生物失调，加速脑小血管病血脑屏障的破坏和小胶质细胞的激活。(2)停止呼吸暂停以模拟治疗可恢复健康的肠道微生物区系，并减轻脑小血管疾病的血脑屏障破坏和小胶质细胞激活。这些假设将通过SHRSP大鼠和OSA模型进行验证，SHRSP大鼠是治疗CSVD的较好动物模型之一，OSA模型中植入的气管气囊可以在睡眠期间远程充气以产生呼吸暂停。OSA前后肠道的细菌多样性和组成将通过元基因组分析确定。这些分析可以将细菌鉴定到属或种的分类水平。通过将供体大鼠的盲肠内容物灌胃到受体大鼠的盲肠内容物中，肠道微生物区系将发生改变。如果第一个假设是Vald，那么在没有进行OSA的大鼠中制造生物失调，应该会加速血脑屏障的分解，并激活小胶质细胞。相反，通过盲肠移植维持OSA大鼠健康的肠道微生物群应该可以防止或减弱血脑屏障的破坏和小胶质细胞的激活。OSA唯一有效的治疗方法是持续正压(CPAP)，通过戴在鼻子或鼻子和嘴巴上的面罩提供压力来保持呼吸道开放。CPAP治疗将通过停止大鼠OSA来模拟。AIM 2的研究将确定停止呼吸暂停是否可以恢复SHRSP大鼠健康的肠道微生物区系，并减弱SHRSP大鼠的血脑屏障破坏和小胶质细胞激活。如果这些假设成立，那么肠道生物失调可能会影响大脑的健康。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追踪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.