Rationale: Idiopathic pulmonary fibrosis (IPF) causes considerable global morbidity and mortality, with poorly understood mechanisms of disease progression. Recent observational studies have reported associations between lung dysbiosis, mortality and altered host defense gene expression, supporting a role for lung microbiota in IPF. However, the causal significance of altered lung microbiota in disease progression is undetermined.
Objective: To examine the effect of microbiota on local alveolar inflammation and disease progression using both animal models and human IPF subjects.
Methods: For human studies, we characterized lung microbiota in bronchoalveolar lavage fluid from 68 IPF patients. For animal modeling, we used a murine model of pulmonary fibrosis in conventional and germ free mice. Lung bacteria were characterized using 16S rRNA gene sequencing with novel techniques optimized for low biomass sample load. Microbiota were correlated with alveolar inflammation, measures of pulmonary fibrosis and disease progression.
Main Measurements and Results: Disruption of the lung microbiome predicts disease progression, correlates with local host inflammation, and participates in disease progression. In IPF patients, lung bacterial burden predicts fibrosis progression, and microbiota diversity and composition correlate with increased alveolar pro-fibrotic cytokines. In murine models of fibrosis, lung dysbiosis precedes peak lung injury and is persistent. In germ-free animals, the absence of a microbiome protects against mortality.
Conclusion: Our results demonstrate that lung microbiota contribute in the progression of IPF. We provide biologic plausibility for the hypothesis that lung dysbiosis promotes alveolar inflammation and aberrant repair. Manipulation of lung microbiota may represent a novel target for the treatment of IPF. Less...