Ahmed El Saie1,2, Chenlian Fu3,4, Sandra L Grimm4,5,6, Matthew J Robertson5, Kristi Hoffman7, Vasanta Putluri8, Chandra Shekar R Ambati8, Nagireddy Putluri4,8, Binoy Shivanna1, Cristian Coarfa9,10,11, Mohan Pammi1. 1. Section of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA. 2. Department of Pediatrics, Cairo University, Cairo, Egypt. 3. Department of Biology, Harvey Mudd College, Claremont, CA, USA. 4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 5. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. 6. Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA. 7. Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA. 8. Advanced Technology Core, Baylor College of Medicine, Houston, TX, 77030, USA. 9. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. coarfa@bcm.edu. 10. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. coarfa@bcm.edu. 11. Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA. coarfa@bcm.edu.
Abstract
BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence. METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group). RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included hyperoxia 31 up/18 down, LPS 7 up/4 down, exposure interaction 8. Hyperoxia increased Intestinimonas abundance, whereas LPS decreased Clostridiales, Dorea, and Intestinimonas; exposure interaction affected Blautia. Differential co-expression analysis on multi-omics data identified exposure-altered modules. Hyperoxia metabolomics response was integrated with a published matching transcriptome, identifying four induced genes (ALDOA, GAA, NEU1, RENBP), which positively correlated with BPD severity in a published human newborn cohort. CONCLUSIONS: We report hyperoxia and LPS lung microbiome and metabolome signatures in a clinically relevant BPD model. We identified four genes correlating with BPD status in preterm infants that are promising targets for therapy and prevention. IMPACT: Using multi-omics, we identified and correlated key biomarkers of hyperoxia and LPS on murine lung micro-landscape and examined their potential clinical implication, which shows strong clinical relevance for future research. Using a double-hit model of clinical relevance to bronchopulmonary dysplasia, we are the first to report integrated metabolomic/microbiome landscape changes and identify novel disease biomarker candidates.
BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence. METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group). RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included hyperoxia 31 up/18 down, LPS 7 up/4 down, exposure interaction 8. Hyperoxia increased Intestinimonas abundance, whereas LPS decreased Clostridiales, Dorea, and Intestinimonas; exposure interaction affected Blautia. Differential co-expression analysis on multi-omics data identified exposure-altered modules. Hyperoxia metabolomics response was integrated with a published matching transcriptome, identifying four induced genes (ALDOA, GAA, NEU1, RENBP), which positively correlated with BPD severity in a published human newborn cohort. CONCLUSIONS: We report hyperoxia and LPS lung microbiome and metabolome signatures in a clinically relevant BPD model. We identified four genes correlating with BPD status in preterm infants that are promising targets for therapy and prevention. IMPACT: Using multi-omics, we identified and correlated key biomarkers of hyperoxia and LPS on murine lung micro-landscape and examined their potential clinical implication, which shows strong clinical relevance for future research. Using a double-hit model of clinical relevance to bronchopulmonary dysplasia, we are the first to report integrated metabolomic/microbiome landscape changes and identify novel disease biomarker candidates.
Authors: Michele C Walsh; Stanley Szefler; Jonathan Davis; Marilee Allen; Linda Van Marter; Steve Abman; Lillian Blackmon; Alan Jobe Journal: Pediatrics Date: 2006-03 Impact factor: 7.124
Authors: Robert P Dickson; John R Erb-Downward; Nicole R Falkowski; Ellen M Hunter; Shanna L Ashley; Gary B Huffnagle Journal: Am J Respir Crit Care Med Date: 2018-08-15 Impact factor: 21.405