Interactions between Pulmonary Inflammation, Airway Hyperresponsiveness, and the Lung Bacterial Microbiome in Horses with Inflammatory Airway Disease

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Background: A pulmonary inflammatory condition suffered by horses, Inflammatory Airway Disease (IAD) is associated with cough, exercise intolerance, and lung function impairment. IAD is significant in the context of animal welfare and the horse industry, as it is associated with loss of value and the early retirement of otherwise healthy animals. Along with other respiratory diseases, it is second only to myoarthroskeletal injuries when it comes to performance-limiting conditions for sport horses. In 2007, a panel of experts from the American College of Veterinary Internal Medicine concluded that airborne dust particles present in barns were likely contributing to the disease, but there was no clear evidence of an allergic-type response. Based on studies that link exercise intolerance and cough to a high bacterial load in the trachea and bronchi, we propose that lower airway bacterial communities contribute to the perpetuation of inflammation and lung function impairment in IAD. This is also supported by new evidence that bacteria play a role in lung diseases not considered primarily infectious, such as asthma. Conventional culture-dependent techniques can only detect a third or fewer of the bacterial populations, and are no longer considered the ideal tool to investigate lung bacterial communities. The development of molecular techniques that can readily sequence the genome of entire bacterial populations-called microbiome-has led to the discovery that even healthy lungs are not sterile. This is a unique opportunity to revisit the potential aetiology of IAD. **Objectives: The main goal of this program is to elucidate the role of lung bacterial microbiome in IAD. The general underlying hypothesis is that horses with IAD have an altered lung microbiome that varies in time and contributes to perpetuating inflammation and lung function impairment. The specific objectives are 1) To develop sampling techniques of the lower airways that effectively bypass the upper airway bacterial flora; 2) To define normal lung bacterial microbiome in different housing conditions; 3) To determine the variation over time of the lung bacterial microbiome in healthy and IAD-affected horses; and 4) To determine the effect of antimicrobials on the lung bacterial microbiome and pulmonary inflammation and function in horses with IAD.**Scientific approach: The lung bacterial microbiome will be studied by mass sequencing, using a portion of bacterial DNA called the 16S rRNA gene, which has both highly conserved sections and hypervariable sections, used for quantification and identification, respectively. The lung microbiome will be studied in bronchoalveolar lavages and lung biopsies, and correlated to airway inflammation and lung function measured by impulse oscillometry and methacholine bronchoprovocation. The stability over time in the same individuals, the effects of housing, and the effects of antimicrobial treatment will be measured and correlated to inflammation in healthy and IAD-affected horses. **Novelty and expected significance: To our knowledge, the lower airway bacterial populations of horses with IAD have not been investigated with advanced molecular techniques. This program will provide valuable information on the stability of the pulmonary bacterial microbiome over time, its change with housing environment, and its response to intervention with antimicrobials. It is anticipated that this research program will demonstrate that horses with IAD have altered lung bacterial populations and that this contributes to perpetuating airway inflammation and function impairment. It may eventually be beneficial to refocus our therapeutic interventions to include the restoration of the normal lung microbiome.