Dysbiosis of the Sinus Microbiota in Chronic Rhinosinusitis

项目总结： 慢性鼻-鼻窦炎(CRS)是一种慢性呼吸道疾病，定义为持续性炎症和感染 鼻腔和鼻窦粘膜。越来越多的证据表明，微生物失衡(生物失调)与 疾病发病机制，但鼻窦微生物区系与宿主环境(包括 粘液纤毛清除功能障碍(MCC)对此知之甚少。此外，还不清楚当地的环境是如何 通过无效的粘液运输产生，支持和维持细菌在体内的生长。最基本的 这一建议的假设是CRS通过一系列确定的依赖事件发展：1)受损 粘液清除，2)产生生物失调(主要是厌氧细菌生长)，3)粘蛋白降解 对碳源营养的影响；4)鼻窦病原体的增殖。提出了以下具体目标： 验证这一假设： (1)评价粘蛋白发酵厌氧菌在顽固性CRS进展中的作用。我们的 具体的假设是碳源营养素的丰富(产生于丰富的 假单胞菌感染的CRS患者中的厌氧菌与CRS严重程度的标志物相关。 (2)测定碳源营养(醋酸盐)对假单胞菌生长的影响 鼻窦炎。我们的特定假设是，接种野生型铜绿假单胞菌的兔子将证明 当有醋酸盐时，最严重的鼻窦炎。 (3)评估健康粘液的转移是否与基线粘蛋白代谢物和共生体有关 微生物区系可以逆转疾病的发展。我们的具体假设是粘液的转移 含有基础单链脂肪酸和健康微生物区系将恢复鼻窦健康和逆转兔鼻窦炎 疾病的发展。 总体而言，我们预计这项建议将产生对CRS发病机制的批判性理解，并建立新的 以及关于厌氧菌在疾病进展中的重要知识。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，并将解锁 CRS慢性炎症和感染的致病机制。生物体通常被定义为 共生菌可能通过降解粘蛋白而导致呼吸道疾病，进而为病原体提供营养。 否则无法获得鼻窦生长所需的碳源。针对发酵粘液的厌氧菌和 其代谢产物是治疗CRS的一种新的治疗策略。恢复中的微生物群落 鼻窦粘液转移是治疗慢性阻塞性肺疾病的一种非常有价值的、廉价和安全的治疗方法。这样的一个 治疗可以减少抗生素处方，对抗不断上升的抗生素耐药性。

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.