The role of the microbiome in critical illness

The microbiome - of the gut and lungs - represents a tremendous source of biologic variation across patients, yet has largely been overlooked in our efforts to understand the heterogeneity of respiratory failure, shock, and multiorgan failure. We study how the microbiome contributes to the pathogenesis of organ failure in critically ill patients, and how our everyday ICU interventions (antibiotics, oxygen) alter gut and lung microbiota. Our long-term goal is to treat the microbiome as a therapeutic target for the prevention and treatment of critical illness.

We have demonstrated that: 1) lung and gut microbiota are profoundly disordered in critically ill patients, 2) the lung microbiome is correlated with alveolar and systemic inflammation in this population, 3) the lung microbiome is predictive of 28-day outcomes in mechanically ventilated patients, 4) the lung microbiome is enriched with gut bacteria in sepsis and ARDS, representing hematogenous and lymphatic translocation of gut bacteria, 5) hyperoxia alters lung and gut microbiota, and the microbiome contributes to the pathogenesis of oxygen-induced lung injury, 6) the gut microbiome plays a major role in calibration of temperature response in sepsis, and 7) depletion of gut microbiota (via anti-anaerobic antibiotics) increases ICU patients’ risk of mortality.

The microbial ecology of the respiratory tract

Though long considered sterile, lungs are now known to harbor diverse and dynamic communities of bacteria. The “lung microbiome” is detectable in health, altered in disease, modified by exposures (antibiotics, oxygen, environment), and correlated with alveolar and airway immunity. We study the ecological determinants of the respiratory microbiome, how respiratory microbiota calibrate lung immunity, and how lung disease alters the microbial ecology of the alveolar microenvironment.

The lung microbiome and chronic lung disease

The ecosystem of the human respiratory tract changes during chronic lung disease, resulting in profoundly altered growth conditions and microbial population dynamics. We study the effects of chronic, noninfectious lung disease on respiratory microbiota, and how an altered respiratory microbiome contributes to respiratory disease.

We have demonstrated that 1) the lung microbiome is altered in chronic lung diseases (pulmonary fibrosis, lung transplantation), 2) disruption of lung microbiota is correlated with alveolar inflammation in these diseases, 3) the lung microbiome is predictive of disease progression in idiopathic pulmonary fibrosis and lung transplantation, and 4) the microbiome plays a causal role in the pathogenesis of murine models of pulmonary fibrosis.

Bringing molecular microbiology to the bedside

While the revolution in culture-independent microbiology has revolutionized our understanding of the host-microbe interface, it not yet significantly changed our diagnosis and management of respiratory infections and their sequelae. We work to bring the techniques and analyses of contemporary molecular microbiology to our bedside diagnosis of respiratory infections. Our group 1) published the first systematic comparison of quantitative culture, qPCR and 16S-amplified microbiome analysis in the interpretation of bronchoalveolar lavage specimens in pneumonia, 2) identified the key ecologic features of lung microbial communities in bacterial pneumonia (low community diversity, high microbial biomass, and community domination by a single taxonomic group), and 3) published the first demonstration that respiratory pathogens can be identified using real-time metagenomics within hours of specimen acquisition.

Methods in low-biomass microbiome studies

Study of the respiratory microbiome is challenging due to 1) low bacterial biomass and high host:microbe ratio of DNA, 2) vulnerability to procedural and sequencing contamination, and 3) logistical challenges of sampling the lower respiratory tract. We have published numerous studies related to the experimental, analytical, and bioinformatic study of respiratory (and gastrointestinal) bacterial communities.