The role of the microbiome in exacerbations of chronic lung diseases

Abstract

Culture-independent microbiological techniques have shown a previously unappreciated complexity to the bacterial microbiome of the respiratory tract that forces reconsideration of the interactions between host, bacteria, and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and relative growth rates of its members. All these factors change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack the features of bacterial infections, including increased bacterial burden and decreased diversity of microbial communities. We propose that exacerbations are occasions of respiratory tract dysbiosis--a disorder of the respiratory tract microbial ecosystem with negative effects on host biology. Respiratory tract dysbiosis provokes a dysregulated host immune response, which in turn alters growth conditions for microbes in airways, promoting further dysbiosis and perpetuating a cycle of inflammation and disordered microbiota. Differences in the composition of baseline respiratory tract microbiota might help to explain the so-called frequent-exacerbator phenotype observed in several disease states, and might provide novel targets for therapeutic intervention.

Figure 1. Lack of influence of upper respiratory tract microbiota on BAL microbiota

Though the microbial communities of the mouth and nose differ significantly (A), route of bronchoscope insertion (via mouth or via nose) has no appreciable effect on BAL microbiota (B). A: Ordination generated from the University of Michigan data collected as part of the NHLBI Lung HIV Microbiome Project^, . B: Reproduced from Dickson and colleagues.

Figure 2. Determinants of the respiratory microbiome

The constitution of the respiratory microbiome is determined by three factors: microbial immigration, microbial elimination and the relative reproduction rates of its members. Any alteration detected in disease states must be attributable to some combination of these three factors. In health, community membership is primarily determined by immigration and elimination; in advanced lung disease, membership is primarily determined by regional growth conditions.

Figure 3. Associations between respiratory microbiota and clinical features of asthma

Among asthmatics, respiratory microbial diversity is positively associated both with bronchial hyperresponsiveness (A) and whether bronchial reactivity improved with clarithromycin therapy (B). Bacterial community composition is significantly different among asthmatics whose airway obstruction improves with systemic corticosteroids (C). A, B: Reproduced from Huang and colleagues. C: Reproduced from Goleva and colleagues.

Figure 4. Cystic fibrosis exacerbations lack key features of bacterial infections

A: CF patients' clinical response to antibiotic therapy is not correlated with the in vitro susceptibility of organisms cultured from sputum at the onset of exacerbation. B: Bacterial density in sputum does not increase prior to or at the onset of exacerbation. C: Sputum bacterial community diversity is not lower during exacerbation compared to clinical baseline. A: Reproduced from Hurley and colleagues. B: Reproduced from Stressmann and colleagues. C: Reproduced from Carmody and colleagues.

Figure 5. The dysbiosis-inflammation cycle

An inflammatory trigger initiates airway inflammation, which alters environmental growth conditions of airway microbiota via positive and negative selective pressures. Disordered growth conditions result in a disordered microbiome, which provokes further airway inflammation via pathogen-associated molecular pattern (PAMP) – pattern recognition receptor (PRR) interactions, microbial metabolite signaling to leukocytes and epithelial cells, and other pathways. This results in a self-amplifying cycle of airway inflammation and respiratory dysbiosis.