Dysbiosis of the Sinus Microbiota in Chronic Rhinosinusitis

慢性鼻窦炎中鼻窦微生物群的失调

• 批准号: 10165486
• 负责人: Do-Yeon Cho
• 金额: $ 15.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165486
• 关键词: Acetates; Acute; Adult; Affect; Airway Disease; Anaerobic Bacteria; Antibiotic Resistance; Antibiotics; Bacteroides; Bacteroides fragilis; Bioavailable; Carbon; Chronic; Chronic Obstructive Airway Disease; Clinic Visits; Clinical; Coculture Techniques; Complex; Congestive Heart Failure; Data; Development; Disease; Disease Progression; Drainage procedure; Energy-Generating Resources; Environment; Event; Fermentation; Functional disorder; Funding; Generations; Gram-Negative Bacteria; Growth; Guidelines; Health; Health Expenditures; Impairment; In Vitro; Incidence; Infection; Inflammation; Isocitrate Lyase; Knowledge; Laboratories; Medical; Metronidazole; Microbe; Modeling; Mucins; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Nasal cavity; Nose; Nutrient; Operating Rooms; Operative Surgical Procedures; Organism; Oryctolagus cuniculus; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Population; Probiotics; Proliferating; Pseudomonas; Pseudomonas aeruginosa; Pyruvate synthase; Quality of life; Resolution; Respiratory System; Role; Series; Severities; Severity of illness; Sinus; Sinusitis; Social Functioning; Source; Symptoms; Testing; Therapeutic; Training; Virulence; Virulence Factors; Volatile Fatty Acids; Work; care burden; chronic rhinosinusitis; combat; commensal bacteria; commensal microbes; cost; dysbiosis; feeding; gastrointestinal system; glyoxylate; health care economics; in vivo; innovation; microbial community; microbiome; microbiota; mucus clearance; mutant; novel therapeutic intervention; opportunistic pathogen; pathogen; pathogenic bacteria; preclinical study; skills; treatment effect; treatment strategy

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.

项目摘要： 慢性鼻塞炎（CRS）是一种慢性气道疾病，定义为持续的炎症和感染 鼻和鼻窦粘膜。越来越多的证据表明，微生物失衡（营养不良）与 疾病的发病机理，但是鼻窦微生物群和宿主环境之间的复杂相互作用（包括 功能失调的粘膜纤毛清除率（MCC）鲜为人知。此外，目前尚不清楚当地的环境如何 通过无效的粘液转运支持并维持体内细菌生长。基本 该建议的假设是CRS通过一系列定义的依赖性事件而发展：1）受损 粘液清除率，2）产生营养不良（主要是厌氧细菌生长），3）粘蛋白降解 到碳源营养素，4）窦病原体的增殖。提出以下具体目标 检验此假设： （1）评估粘蛋白发酵厌氧菌对顽固的CRS进展的贡献。我们的 具体假设是丰富的碳源营养素（由丰富产生 CRS患者的粘膜厌食症）与CRS严重程度的标记相关。 （2）确定碳源营养素（乙酸）对假单胞菌发展的影响 鼻窦炎。我们的具体假设是，接种野生型P.铜绿假设将证明 乙酸盐可用时最严重的鼻窦炎。 （3）评估健康粘液与基线粘蛋白代谢产物和共生的转移是否转移 微生物群可以逆转疾病的进展。我们的具体假设是粘液的转移 含有基线SCFA和健康的微生物群将恢复鼻窦健康并逆转兔鼻窦炎 疾病进展。 总体而言，我们预计该提案将产生对CRS发病机理的批判性了解并建立新的 以及有关疾病进展中厌氧菌细菌的重要知识。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 致病机制导致CRS慢性炎症和感染。有机体通常定义为 共生可能通过降解粘液来导致气道疾病，进而为病原体提供营养 否则无法获得窦中生长的碳源。靶向粘蛋白发酵厌氧菌和 他们的代谢产物是治疗CRS的新型治疗策略。恢复微生物社区 粘液转移的疾病鼻窦代表了对CRS的高度价值，廉价且安全的治疗。这样的 治疗可以减少抗生素处方并打击抗生素耐药性的上升。

项目成果

Unilateral Intervention in the Sinuses of Rabbits Induces Bilateral Inflammatory and Microbial Changes.

• DOI: 10.3389/fcimb.2021.585625
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Lux CA;Johnston JJ;Waldvogel-Thurlow S;Dassi C;Douglas RG;Cho DY;Taylor MW;Biswas K
• 通讯作者: Biswas K