Disruption of the endogenous microbiota leads to the development of chronic rhinosinusitis in mice.

Abstract

Chronic rhinosinusitis is a non-invasive, inflammatory disease of the upper airways that affects approximately 37 million people per year. Currently the etiology of chronic rhinosinusitis is unknown. Hypersensitivity responses to inhaled fungal elements in the nasal cavity have been proposed as a possible etiology because fungi such as <italic>Aspergillus, Alternaria</italic> and <italic> Candida</italic> can be routinely isolated from patients with the disease. Since fungi can also be isolated from the nasal cavities of healthy individuals, this suggests that fungi are not the primary etiologic agents, and that there may be an underlying pathology in these patients predisposing them to chronic nasal inflammation. Many studies have now shown altered microbiota, caused in part by antibiotic usage, can account for the escalating rates of inflammatory diseases. Based on clinical, epidemiological and laboratory observations, we sought to determine whether antibiotic-induced alteration of the gastrointestinal (GI) microbiota, including colonization by <italic>C. albicans</italic>, could lead to the development of chronic nasal inflammation in mice. Following alterations in their microbiota, mice in these studies developed inflammation in the lamina propria of the respiratory epithelium, which is characteristic of chronic rhinosinusitis. When additionally exposed to a common aeroallergen, treated mice had an exacerbated, chronic response, suggesting a heightened hypersensitivity to inhaled antigens. Furthermore, the disease proved to be a Th2 mediated process, which developed independently of host genetic predisposition, and was dependent on the alteration of the endogenous microbiota itself. Since the majority of chronic rhinosinusitis cases have an unknown etiology, these studies offer a new mechanism to consider in development of this disease. All the characteristics of human chronic rhinosinusitis were replicated in our murine model without systemic immunization and without exposure to exogenous antigens. While we have not yet identified the target of the inflammatory response, we postulate that the microbiota alterations cause a break in mucosal tolerance mechanisms. The result of this break is the development of a Th2 hypersensitivity response in the nasal mucosa to either an inhaled environmental antigen or a constituent of the endogenous microbiota.