CRS Microbiome: Multi-omic Integrative Longitudinal Experimental (CRS-MILE) study - SUMMARY: Chronic rhinosinusitis (CRS) is a highly prevalent disease that inflicts a severe quality-of- life (QOL) impairment. QOL-measures have ranked CRS among severe ailments such as congestive heart failure, chronic obstructive pulmonary disease, and end-stage renal disease. Its high prevalence, chronic duration, and extensive antibiotic use, result in a large personal and societal burden that places it among the top ten most costly medical conditions. Although often considered an infectious disease, many now view CRS as a chronic inflammatory disorder where host-microbial interactions play a role. Current data suggest that microbiota alterations (dysbiosis) exist in CRS, and that loss of protective organisms with acquisition of pathogens may contribute to the refractory nature of the disease. Our long-term goal is to determine the functional role(s) of the sinus microbiome in health and disease, and to translate these novel insights into the CRS management algorithm with new therapeutic objectives and targets for intervention. Our central hypothesis is that dysbiosis in CRS promotes chronic mucosal inflammation and compromises response to therapy. This hypothesis has been formulated on the basis of publications and preliminary data produced in the applicants' laboratories and clinical practice, and will be tested by pursuing three specific aims: 1) Evaluate the functional capacity of microbiome alterations observed in CRS using an integrative multi-`omics approach; 2) Determine the relationship between microbiome alterations and CRS disease severity and therapeutic outcomes in a longitudinal multi-institutional human intervention study; 3) Determine how CRS-associated microbes alter sinonasal mucosal core functions to drive disease chronicity, through in vitro experimentation. We will use innovative technologic and analytic approaches to examine sinus biospecimens and health outcomes, seeking to transform current clinical and research understanding of the role of microbes in CRS. This study moves beyond prior small, cross-sectional, observational human CRS microbiome association studies by defining molecular, cellular, and immunological processes using a multi-`omics approach. Our study is unique in its examination of both control and CRS subjects, longitudinal sampling from an intervention study, well-defined clinical outcomes, and delineation of mechanisms of host-microbial crosstalk in the airway. The proposed research is significant because it is expected to advance understanding of how the microbiome, including specific microbial species, impacts mucosal immunity and barrier function in CRS. Ultimately, such knowledge will change the current treatment paradigm in CRS, decrease antibiotic overuse, and direct development of new therapeutic goals and treatment strategies for CRS patients.
