Dysbiosis of the Sinus Microbiota in Chronic Rhinosinusitis

项目概要： 慢性鼻窦炎（CRS）是一种慢性气道疾病，定义为持续性炎症和鼻窦炎感染。 鼻和鼻窦粘膜。越来越多的证据表明，微生物失衡（生态失调）与 疾病的发病机制，但窦微生物群和宿主环境（包括 功能障碍性粘膜纤毛清除（MCC））的研究知之甚少。此外，目前还不清楚当地环境如何 通过无效的粘液运输产生，支持并维持细菌在体内的生长。根本 该建议的假设是CRS通过一系列定义的相关事件发展：1）受损 粘液清除，2）生态失调的产生（主要是厌氧细菌生长），3）粘蛋白降解 碳源营养素，和4）窦病原体的增殖。提出了以下具体目标， 测试这个假设： (1)评估粘蛋白发酵厌氧菌对慢性CRS进展的贡献。我们 具体假设是碳源营养物丰富（由丰富的 假单胞菌感染的CRS患者中的粘液分泌性厌氧菌（mucinfermenting anaerobes）与CRS严重程度的标志物相关。 (2)确定碳源营养物（乙酸盐）对假单胞菌生长发育的影响 鼻窦炎我们的具体假设是，用野生型铜绿假单胞菌接种的兔子将证明 最严重的鼻窦炎时，醋酸是可用的。 (3)评估是否转移健康粘液与基线粘蛋白代谢产物和唾液酸 微生物群可以逆转疾病进展。我们的假设是粘液的转移 含有基线SCFA和健康微生物群的药物将恢复鼻窦健康并逆转兔鼻窦炎 疾病进展。 总的来说，我们预计这一建议将产生对CRS发病机制的批判性理解，并建立新的 和重要的知识厌氧菌在疾病的进展。我们相信创新的兔子 我们实验室创建的CRS模型非常适合拟议的临床前研究， 导致CRS慢性炎症和感染的致病机制。生物体通常定义为 共生体可能通过降解粘蛋白而为病原体提供营养，从而导致呼吸道疾病 否则无法获得碳源在窦中生长。靶向粘蛋白发酵厌氧菌， 其代谢物是治疗CRS的新的治疗策略。恢复微生物群落 通过粘液转移的患病鼻窦代表了用于CRS的高度有价值的、廉价的和安全的疗法。这样的 治疗可以减少抗生素处方并对抗抗生素耐药性的上升。

PROJECT SUMMARY: Chronic rhinosinusitis (CRS) is a chronic airway disease defined as persistent inflammation and infection of the nasal and sinus mucosa. Mounting evidence suggests that a microbial imbalance (dysbiosis) is associated with disease pathogenesis, yet the complex interaction between the sinus microbiota and host environment (including dysfunctional mucociliary clearance (MCC)) is poorly understood. Additionally, it is unclear how the local milieu created through ineffective mucus transport supports and sustains bacterial growth in vivo. The fundamental hypothesis of this proposal is that CRS develops through a defined series of dependent events: 1) impaired mucus clearance, 2) generation of dysbiosis (predominantly anaerobic bacterial growth), 3) mucin degradation to carbon-source nutrients, and 4) proliferation of sinus pathogens. The following specific aims are proposed to test this hypothesis: (1) Evaluate the contribution of mucin-fermenting anaerobes to recalcitrant CRS progression. Our specific hypothesis is that abundance of carbon-source nutrients (generated from abundant mucinfermenting anaerobes) in CRS patients with Pseudomonas correlates to markers of CRS severity. (2) Determine the impact of the carbon-source nutrient (acetate) on the development of Pseudomonas sinusitis. Our specific hypothesis is that rabbits inoculated with wild type P. aeruginosa will demonstrate the most severe sinusitis when acetate is available. (3) Assess whether the transfer of healthy mucus with baseline mucin metabolites and commensal microbiota can reverse disease progression. Our specific hypothesis is that transfer of mucus containing baseline SCFAs and healthy microbiota will restore sinus health and reverse rabbit sinusitis disease progression. Overall, we anticipate that this proposal will yield critical understanding of CRS pathogenesis and establish new and important knowledge regarding anaerobic bacteria in disease progression. We believe the innovative rabbit model of CRS created by our laboratory is ideally suited for the proposed pre-clinical studies and will unlock the pathogenic mechanism leading to chronic inflammation and infection in CRS. Organisms typically defined as commensals may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to obtain a carbon source for growth in the sinus. Targeting mucin-fermenting anaerobes and their metabolites is a novel therapeutic strategy for the treatment of CRS. Restoring the microbial community in diseased sinuses by mucus transfer represents a highly valued, inexpensive and safe therapy for CRS. Such a therapy could reduce antibiotic prescriptions and combat the rising incidence of antibiotic resistance.