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.

项目概要： 慢性鼻窦炎（CRS）是一种慢性气道疾病，定义为鼻窦持续炎症和感染。 鼻和鼻窦粘膜。越来越多的证据表明微生物失衡（生态失调）与 疾病发病机制，但鼻窦微生物群与宿主环境（包括 粘膜纤毛清除功能障碍（MCC））目前尚不清楚。此外，尚不清楚当地环境如何 通过无效的粘液运输产生的支持和维持体内细菌的生长。基本的 该提案的假设是，CRS 通过一系列定义的相关事件而发展：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 碳源营养物，4) 鼻窦病原体的增殖。提出以下具体目标 检验这个假设： (1) 评估粘蛋白发酵厌氧菌对顽固性 CRS 进展的贡献。我们的 具体的假设是，丰富的碳源营养物质（来自丰富的碳源营养物质） 患有假单胞菌的 CRS 患者中粘液发酵厌氧菌）与 CRS 严重程度的标志物相关。 (2) 确定碳源养分（乙酸盐）对假单胞菌发育的影响 鼻窦炎。我们的具体假设是，接种野生型铜绿假单胞菌的兔子将表现出 当有醋酸盐时，鼻窦炎最为严重。 (3) 评估健康粘液的转移是否具有基线粘蛋白代谢物和共生体 微生物群可以逆转疾病进展。我们的具体假设是粘液的转移 含有基线短链脂肪酸和健康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 发病机制的批判性理解并建立新的 以及有关厌氧菌在疾病进展中的重要知识。我们相信创新兔子 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 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导致气道疾病，进而为病原体提供营养 否则无法获得在窦内生长的碳源。针对发酵粘蛋白的厌氧菌和 它们的代谢物是治疗 CRS 的一种新的治疗策略。恢复微生物群落 通过粘液转移治疗患病鼻窦是一种非常有价值、廉价且安全的慢性鼻窦炎治疗方法。这样一个 治疗可以减少抗生素处方并对抗不断上升的抗生素耐药性发生率。

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