1. The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nov 15, 2013 R2. 최하나

2. INTRODUCTION Current guidelines recommend the use of corticosteroids to control airway inflammation in persistent asthma. Clinical studies –Up to 45% of patients responding suboptimally to inhaled corticosteroids –Up to 25% of patients do not respond to oral corticosteroids Corticosteroid-resistant (CR) patients –Airway inflammation and remodeling –Severe asthma phenotype –Alternative treatment strategies are needed to improve asthma control

3. 16S rRNA gene sequence analyses of airway specimens → diversified microbial communities in the airways of subjects with asthma Compared with healthy patients –Asthma patients : significantly higher bacterial burden and diversity caused by expansion of pathogenic bacteria. Moreover, airway microbiome composition and diversity correlate with bronchial hyperresponsiveness. CR asthma : pathogenic microbial communities residing in the airways →inhibit cellular responses to corticosteroids

4. METHODS Study Subjects prednisone 20mg bid for 7days CR : FEV1 15% baseline FEV1 < 85%

5. Specimen Collection :BAL BAL Differential Analysis Bacterial DNA Extraction, Quantitative PCR, and Sequencing Bacterial Cultures Cell Cultures

6. RESULTS Clinical Characteristics Macrophages are the major cell type in the airway lumen, and produce an array of proinflammatory mediators that control responses of various cell types, including T cells and airway epithelium that are involved in host defense, airway inflammation, tissue remodeling, and repair.

7. Airway Microbiome in Subjects with Asthma

10. Subjects with CR asthma with microbial expansions (24 of 29 patients) Subjects with CS asthma with bacterial expansions (9 of 10 patients)

11. Unique Bacterial Genus Expansions in the Airways of CR and CS Subjects with Asthma

12. Effects of Bacteria from the Airways on Cell Activation and Response to Corticosteroids in Airway Macrophages

13. 2uM 10uM

14. DISCUSSION

19. CONCLUSION A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.