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.