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Abstract
Environmental factors, such as cigarette smoking or lung infections, may influence chronic obstructive pulmonary disease (COPD) progression by modifying the respiratory tract microbiome. However, whether the disease itself induces or maintains dysbiosis remains undefined. In this longitudinal study, we investigated the oropharyngeal microbiota composition and disease progression of mice (in cages of 5–10 mice per cage) before, during and up to 3 months after chronic cigarette smoke exposure or exposure to room air for 6 months. Cigarette smoke exposure induced pulmonary emphysema measurable at the end of exposure for 6 months, as well as 3 months following smoke exposure cessation. Using both classical culture methods and 16S rRNA sequencing, we observed that cigarette smoke exposure altered the relative composition of the oropharyngeal microbiota and reduced its diversity (P <0.001). More than 60 taxa were substantially reduced after 6 months of smoke exposure (P <0.001) However, oropharyngeal microbiota disordering was reversed 3 months after smoke exposure cessation and no significant difference was observed compared to age-matched control mice. The effects of lung infection with Streptococcus pneumoniae on established smoke-induced emphysema and on the oropharyngeal microbiota were also evaluated. Inoculation with S. pneumoniae induced lung damage and altered the microbiota composition for a longer time compared to control groups infected but not previously exposed to smoke (P=0.01). Our data demonstrate effects of cigarette smoke and pneumococcus infection leading to altered microbiota and emphysema development. The reversal of the disordering of the microbiota composition, but not lung damage, following smoke exposure cessation and after clearance of infection suggest that changes in lung structure are not sufficient to sustain a disordered microbiota in mice. Whether changes in the airway microbiota contribute to inducing emphysema requires further investigation.
Highlights
With one billion active smokers worldwide, cigarette smoking remains a leading risk of mortality and disease burden for cardiovascular disease, lung cancer and chronic obstructive pulmonary disease (COPD) [1]
Since bacterial infections are the most frequent cause for exacerbations in COPD, we evaluated the impact of Streptococcus pneumoniae infection on the microbiota composition and disease progression in mice with established smoke-induced emphysema
We found that: (i) chronic cigarette smoke exposure causes emphysema and alters the composition of the oropharyngeal microbiota, as determined by 16S rRNA sequencing and by bacterial culture; (ii) lung infection with S. pneumoniae disrupts lung structure in air- and smoke-exposed mice, and induces a prolonged disordering of the microbiota in the oropharynx in mice previously exposed to cigarette smoke compared to controls; (iii) the alterations in microbiota composition induced by cigarette smoke and by pneumococcal infection are reversed after smoke cessation and after resolution of pneumonia, respectively; (iv) an established emphysema after smoking cessation is not sufficient to maintain a disordered oropharyngeal microbiota
Summary
With one billion active smokers worldwide, cigarette smoking remains a leading risk of mortality and disease burden for cardiovascular disease, lung cancer and chronic obstructive pulmonary disease (COPD) [1]. Genetic factors contribute to increasing the risk of developing COPD, as shown in association studies based on human genome sequencing and polymorphism analysis [4,5,6,7,8]. Experimental mouse models have emphasized the importance of genetic background in the extent of destruction of the lung parenchyma induced by cigarette smoke. Neither smoking status nor genetic profiling alone nor combined can accurately predict whether an individual will develop COPD, suggesting additional contributing factors
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