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

脑小血管疾病、阻塞性睡眠呼吸暂停和胃肠系统

• 批准号: 9013193
• 负责人: ROBERT M BRYAN
• 金额: $ 23.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013193
• 关键词: Acceleration; Affect; Animal Model; Apnea; Attention; Attenuated; Bacteria; Blood - brain barrier anatomy; Brain; Brain Injuries; Cerebrovascular Disorders; Cerebrum; Development; Disease; Encephalitis; Feces; Gastrointestinal tract structure; Health; Implant; Individual; Infarction; Injury; Link; Maintenance; Masks; Metagenomics; Microaneurysm; Microglia; Microvascular Dysfunction; Modeling; Nose; Obstructive Sleep Apnea; Oral cavity; Positioning Attribute; Rattus; Risk; Sleep; Stroke; Testing; Therapeutic Intervention; Transplantation; effective therapy; gastrointestinal; gastrointestinal system; gray matter; gut microbiota; microbiome; pressure; prevent; public health relevance; rRNA Genes; white matter

 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.

 描述（由申请人提供）：患有阻塞性睡眠呼吸暂停（OSA）（一种上呼吸道在睡眠期间反复塌陷而产生呼吸暂停的疾病）的个体有患脑血管疾病和/或加速脑血管疾病进展的风险。脑小血管疾病（CSVD）由脑小血管的病理改变组成，与皮质下白质和灰质损伤有关。在本提案中，我们将提出这一想法。 OSA 引起的肠道微生物组失衡（生态失调）会加速小脑血管病（CSVD）。有证据表明，OSA 会改变肠道微生物组，并增强血脑屏障 (BBB) 的破坏和易患自发性高血压中风的脑部炎症。 SHRSP）大鼠，一种 CSVD 模型，重要的是，BBB 破坏和脑部炎症是与 CVSD 发展相关的疾病，证据表明肠道微生物组在 OSA 期间可能发生改变。减弱 BBB 分解和小胶质细胞激活。拟议的研究将测试两个假设，每个假设都有一个特定目标 (1) 阻塞性睡眠呼吸暂停会导致肠道菌群失调，从而加速脑小血管疾病中的 BBB 分解和小胶质细胞激活。停止呼吸暂停以模拟治疗可恢复健康的肠道微生物群，并减弱脑小血管疾病中的血脑屏障破坏和小胶质细胞激活。这些假设将使用 SHRSP 大鼠（更好的动物模型之一）进行测试。用于 CSVD 的模型，以及 OSA 模型，其中植入的气管球囊可以在睡眠期间远程充气以产生呼吸暂停。将通过宏基因组分析确定 OSA 之前和之后的肠道细菌多样性和组成。这些分析可以在分类水平上识别细菌。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，肠道微生物群将会发生改变。如果第一个假设成立，则会在大鼠中造成菌群失调。未接受 OSA 的患者会加速 BBB 分解并激活小胶质细胞，使用盲肠移植维持 OSA 大鼠健康的肠道微生物组应预防或减弱 BBB 分解和小胶质细胞激活，治疗 OSA 的唯一有效疗法是持续气道正压通气 (CPAP)。目标 2 中的研究将通过停止大鼠的 OSA 来模拟 CPAP 治疗，从而通过适合鼻子或鼻子和嘴巴的面罩提供的压力来保持气道开放。呼吸暂停可以恢复健康的肠道微生物群，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，那么肠道菌群失调会影响大脑的健康，从而可以极大地重新将我们的注意力集中在胃肠道上。脑损伤的潜在原因，并为治疗干预提供目标。