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Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.

ABSTRACT: Sepsis and the acute respiratory distress syndrome (ARDS) are major causes of mortality without targeted therapies. Although many experimental and clinical observations have implicated gut microbiota in the pathogenesis of these diseases, culture-based studies have failed to demonstrate translocation of bacteria to the lungs in critically ill patients. Here, we report culture-independent evidence that the lung microbiome is enriched with gut bacteria both in a murine model of sepsis and in humans with established ARDS. Following experimental sepsis, lung communities were dominated by viable gut-associated bacteria. Ecological analysis identified the lower gastrointestinal tract, rather than the upper respiratory tract, as the likely source community of post-sepsis lung bacteria. In bronchoalveolar lavage fluid from humans with ARDS, gut-specific bacteria (Bacteroides spp.) were common and abundant, undetected by culture and correlated with the intensity of systemic inflammation. Alveolar TNF-α, a key mediator of alveolar inflammation in ARDS, was significantly correlated with altered lung microbiota. Our results demonstrate that the lung microbiome is enriched with gut-associated bacteria in sepsis and ARDS, potentially representing a shared mechanism of pathogenesis in these common and lethal diseases.

SUBMITTER: Dickson RP

PROVIDER: S-EPMC5076472 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.

Dickson Robert P RP Singer Benjamin H BH Newstead Michael W MW Falkowski Nicole R NR Erb-Downward John R JR Standiford Theodore J TJ Huffnagle Gary B GB

Nature microbiology 20160718 10

Sepsis and the acute respiratory distress syndrome (ARDS) are major causes of mortality without targeted therapies. Although many experimental and clinical observations have implicated gut microbiota in the pathogenesis of these diseases, culture-based studies have failed to demonstrate translocation of bacteria to the lungs in critically ill patients. Here, we report culture-independent evidence that the lung microbiome is enriched with gut bacteria both in a murine model of sepsis and in human ...[more]

PMID: 27670109

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Project description:BackgroundIn the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS.MethodsWe conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14.ResultsThe study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range.ConclusionsRosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Project description:Background: Acute respiratory distress syndrome (ARDS) is an unresolved challenge in the field of respiratory and critical care, and the changes in the lung microbiome during the development of ARDS and their clinical diagnostic value remain unclear. This study aimed to explore the role of the lung microbiome in disease progression in patients with sepsis-induced ARDS and potential therapeutic targets. Methods: Patients with ARDS were divided into two groups according to the initial site of infection, intrapulmonary infection (ARDSp, 111 cases) and extrapulmonary infection (ARDSexp, 45 cases), and a total of 28 patients with mild pulmonary infections were enrolled as the control group. In this study, we sequenced the DNA in the bronchoalveolar lavage fluid collected from patients using metagenomic next-generation sequencing (mNGS) to analyze the changes in the lung microbiome in patients with different infectious site and prognosis and before and after antibiotic treatment. Results: The Shannon-Wiener index indicated a statistically significant reduction in microbial diversity in the ARDSp group compared with the ARDSexp and control groups. The ARDSp group was characterized by a reduction in microbiome diversity, mainly in the normal microbes of the lung, whereas the ARDSexp group was characterized by an increase in microbiome diversity, mainly in conditionally pathogenic bacteria and intestinal microbes. Further analysis showed that an increase in Bilophila is a potential risk factor for death in ARDSexp. An increase in Escherichia coli, Staphylococcus aureus, Candida albicans, enteric microbes, or conditional pathogens may be risk factors for death in ARDSp. In contrast, Hydrobacter may be a protective factor in ARDSp. Conclusion: Different initial sites of infection and prognoses are likely to affect the composition and diversity of the pulmonary microbiome in patients with septic ARDS. This study provides insights into disease development and exploration of potential therapeutic targets.

Project description:ObjectivesAcute respiratory distress syndrome occurring in the setting of direct versus indirect lung injury may reflect different pathobiologies amenable to different treatment strategies. We sought to test whether a panel of plasma biomarkers differed between children with sepsis-associated direct versus indirect acute respiratory distress syndrome. We hypothesized that a biomarker profile indicative of endothelial activation would be associated with indirect acute respiratory distress syndrome.DesignObservational cohort.SettingAcademic PICU.SubjectsPatients less than 18 years old with sepsis-associated direct (pneumonia, n = 52) or indirect (extrapulmonary sepsis, n = 46) acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsOf 58 biomarkers examined, 33 differed by acute respiratory distress syndrome subtype. We used classification and regression tree methodology to examine associations between clinical and biochemical markers and acute respiratory distress syndrome subtype. The classification and regression tree model using only clinical variables (age, sex, race, oncologic comorbidity, and Pediatric Risk of Mortality-III score) performed worse than the classification and regression tree model using five clinical variables and 58 biomarkers. The best classification and regression tree model used only four endothelial biomarkers, including elevated angiopoietin-2/angiopoietin-1 ratio, vascular cell-adhesion molecule, and von Willebrand factor, to identify indirect acute respiratory distress syndrome. Test characteristics were 89% (80-97%) sensitivity, 80% (69-92%) specificity, positive predictive value 84% (74-93%), and negative predictive value 86% (76-96%).ConclusionsIndirect lung injury in children with acute respiratory distress syndrome is characterized by a biomarker profile indicative of endothelial activation, excess inflammation, and worse outcomes. A model using four biomarkers has the potential to be useful for more precisely identifying patients with acute respiratory distress syndrome whose pathobiology may respond to endothelial-targeted therapies in future trials.

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Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.

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Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.

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