Microbial Dysbiosis Among Veterans Following Deployment-Related Airborne Exposures

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This is an application for a Merit Award to Dr. Alexa A. Pragman, M.D., Ph.D., a Staff Physician in Infectious Disease at the Minneapolis VA and an Assistant Professor at the University of Minnesota. Dr. Pragman’s current work on the chronic obstructive pulmonary disease lung microbiota is funded by a 5-year Career Development Award-2 from the VA Office of Research and Development. Dr. Pragman has established a record of accomplishments and publications related to her patient-oriented work on the lung microbiota in chronic inflammatory pulmonary diseases. This Merit Award will provide the resources necessary to study the effects of fine particle airborne pollution on the lung microbiota of veterans following deployment to southwest Asia (Iraq, Afghanistan, or neighboring countries). Following deployment to southwest Asia, veterans are disproportionately affected by chronic lung problems including coughing, wheezing, and shortness of breath. While deployed, these veterans were exposed to excessive concentrations of airborne particulate matter of ≤2.5 μm in size (PM2.5) as a result of seasonal dust storms, burn pit smoke, and industrial pollution. PM2.5 exposure causes acute and chronic respiratory problems, and may lead to diseases such as asthma and chronic obstructive pulmonary disease. PM2.5 exposure has been linked to airway and gut microbiota dysbiosis in humans and rodent models, suggesting that dysbiosis is a potential mediator for the inflammation, symptoms, and lung tissue destruction that continue long after excessive PM2.5 exposure has stopped. Dysbiosis is defined as an imbalance or maladaptation in the community of micro-organisms inhabiting a particular site. In this Merit Award application, Dr. Pragman proposes a prospective case-control study to assess the relationships between PM2.5 exposure, microbiota dysbiosis, and inflammation. This will be accomplished in collaboration with VA Cooperative Study #595, Service and Health Among Deployed Veterans (SHADE), which aims to understand the association between PM2.5 exposures during deployment and subsequent respiratory symptoms. Dr. Pragman’s study will recruit 140 SHADE participants with chronic lung symptoms (coughing, shortness of breath, or wheezing) and 140 SHADE participants without chronic lung symptoms. All subjects will provide saliva and stool samples for microbiota analyses on an annual basis for 3 years. Sputum samples for microbiota analysis will also be obtained from a subset of subjects on the same schedule. We will assess microbiota dysbiosis and tissue-specific and systemic markers of inflammation. Our analysis will take into account PM2.5 exposure levels (obtained from the SHADE study), tissue or site-specific effects, and incorporate other risk factors for microbial dysbiosis. In Aim 1, Dr. Pragman will determine associations between deployment-related PM2.5 exposure and site-specific dysbiosis. In Aim 2, Dr. Pragman will determine associations between site-specific dysbiosis and respiratory symptoms. In Aim 3, Dr. Pragman will determine site-specific associations between dysbiosis and inflammation. Our overall objective is to establish microbial dysbiosis as a mediator between PM2.5 exposure and respiratory symptoms. Our central hypothesis is that deployed veterans’ PM2.5 exposures place them at increased risk for dysbiosis, which in turn increases risk of developing chronic respiratory symptoms and disease. These findings may identify veterans at high risk for developing lung disease, and may identify a new treatment target—the microbiota—for primary and secondary prevention of lung disease in this high-risk veteran population.