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Altered Cellular Metabolism Links the Respiratory Microbiome to Mortality in Critically Ill Patients
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A2773 - Altered Cellular Metabolism Links the Respiratory Microbiome to Mortality in Critically Ill Patients
Author Block: D. Jones1, C. Molnar2, Z. Ma3, K. Nakahira1, I. I. Siempos1, L. Schultz4, J. Broach4, A. M. Choi1, J. A. Howrylak5; 1Weill Cornell Medical College, New York, NY, United States, 2Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States, 3Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States, 4Penn State Milton S. Hershey Medical Center, New York, NY, United States, 5Penn State Milton S. Hershey Medical Center, Hershey, PA, United States.
Rationale: Recent advances have identified associations between changes in host microbial communities and a variety of disease states. However, the role of the respiratory microbiome in critical illness remains unclear. To assess whether changes in the respiratory microbiome were associated with disease outcomes in critically ill patients and to identify microbe-associated metabolites with potential physiologic relevance.
Methods: We performed concurrent 16 rRNA sequencing and metabolomics profiling on tracheal aspirates from a cohort (n=54) of mechanically ventilated patients in our Intensive Care Unit (ICU).
Main Results: Phyla level differences in the 16S profiles of survivors versus non-survivors were not observed. However, pair-wise correlation network analysis identified several metabolic pathways that were linked to both the respiratory microbiome and mortality. Among these, alterations in fatty acid oxidation (acylcarnitines) and tricarboxylic acid cycle metabolites (aconitate and itaconate) were among the most strongly associated with mortality. Of note, the levels of the TCA cycle intermediate itaconate were >4-fold lower in the tracheal aspirates of non-survivors versus survivors. We also show that expression of immunoresponsive gene 1 (IRG1), the gene encoding the enzyme that catalyzes the production of itaconate from aconitate, is similarly decreased in the blood of non-survivors.
Conclusion: Our findings suggest that the respiratory microbiome may influence disease outcomes via modulation of the regional metabolome including fatty acid metabolites and the production of itaconate.
Author Block: D. Jones1, C. Molnar2, Z. Ma3, K. Nakahira1, I. I. Siempos1, L. Schultz4, J. Broach4, A. M. Choi1, J. A. Howrylak5; 1Weill Cornell Medical College, New York, NY, United States, 2Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States, 3Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States, 4Penn State Milton S. Hershey Medical Center, New York, NY, United States, 5Penn State Milton S. Hershey Medical Center, Hershey, PA, United States.
Rationale: Recent advances have identified associations between changes in host microbial communities and a variety of disease states. However, the role of the respiratory microbiome in critical illness remains unclear. To assess whether changes in the respiratory microbiome were associated with disease outcomes in critically ill patients and to identify microbe-associated metabolites with potential physiologic relevance.
Methods: We performed concurrent 16 rRNA sequencing and metabolomics profiling on tracheal aspirates from a cohort (n=54) of mechanically ventilated patients in our Intensive Care Unit (ICU).
Main Results: Phyla level differences in the 16S profiles of survivors versus non-survivors were not observed. However, pair-wise correlation network analysis identified several metabolic pathways that were linked to both the respiratory microbiome and mortality. Among these, alterations in fatty acid oxidation (acylcarnitines) and tricarboxylic acid cycle metabolites (aconitate and itaconate) were among the most strongly associated with mortality. Of note, the levels of the TCA cycle intermediate itaconate were >4-fold lower in the tracheal aspirates of non-survivors versus survivors. We also show that expression of immunoresponsive gene 1 (IRG1), the gene encoding the enzyme that catalyzes the production of itaconate from aconitate, is similarly decreased in the blood of non-survivors.
Conclusion: Our findings suggest that the respiratory microbiome may influence disease outcomes via modulation of the regional metabolome including fatty acid metabolites and the production of itaconate.
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