Dataset Information

Metabolome and microbiome multi-omics integration from a murine lung inflammation model of bronchopulmonary dysplasia.

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.

SUBMITTER: El Saie A

PROVIDER: S-EPMC9509498 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Metabolome and microbiome multi-omics integration from a murine lung inflammation model of bronchopulmonary dysplasia.

El Saie Ahmed A Fu Chenlian C Grimm Sandra L SL Robertson Matthew J MJ Hoffman Kristi K Putluri Vasanta V Ambati Chandra Shekar R CSR Putluri Nagireddy N Shivanna Binoy B Coarfa Cristian C Pammi Mohan M

Pediatric research 20220325 6

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 35338351

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Project description:ObjectivesWe investigated the genomic and metabolic characteristics of the airway microbiome in mild, moderate, severe, and non-bronchopulmonary dysplasia (BPD) preterm infants and explored possible mechanisms underlying BPD.MethodsTwenty-eight preterm infants with gestational age ≤34 weeks and intubated within 24 h after birth were enrolled. According to the severity of BPD, the patients were divided into mild, moderate and severe BPD groups, and the non-BPD group was the control group. Tracheal aspirates (TA) were obtained at intubation and on day 7 after birth. The bacterium in the aspirates were sequenced by 16S rRNA, and the metabolomics of the aspirates were identified by high performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC-Q-TOF/MS). The correlation between the differential metabolite and differential bacteria was investigated using Pearson's correlation coefficient corrected for gestational age and birth weight and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases.ResultsThere were significant differences in the diversity and composition of airway microbiome and metabolome between severe, moderate and mild BPD and non-BPD premature infants. At birth (day 1), the difference was more pronounced than at day 7. The diversity of airway microbial community decreased, the abundance of Stenotrophomonas increased, and the increased level of sn-glycerol 3-phosphoethanolamine was positively correlated with the severity of BPD. There was a significant positive correlation between the abundance of Stenotrophomonas and the level of sn-glycerol 3-phosphoethanolamine.ConclusionDecreased diversity of the airway microbiome, increased abundance of Stenotrophomonas, and increased level of sn-glycerol 3-phosphoethanolamine may have potential as biomarkers for BPD. The occurrence and severity of BPD are closely related to Stenotrophomonas, which may influence the composition of the lower airway microbiome through its metabolite sn-glycerol 3-phosphoethanolamine, and may be the triggering factor of the disease. The causal relationship needs further study.

Project description:The histopathology of bronchopulmonary dysplasia (BPD) includes hypoalveolarization and interstitial thickening due to abnormal myofibroblast accumulation. Chorioamnionitis and sepsis are major risk factors for BPD development. The cellular mechanisms leading to these lung structural abnormalities are poorly understood. We used an animal model with repeated lipopolysaccharide (LPS) administration into the airways of immature mice to simulate prolonged airway exposure to gram-negative bacteria, focusing on the role of C-C chemokine receptor type 2-positive (CCR2+) exudative macrophages (ExMf). Repetitive LPS exposure of immature mice induced persistent hypoalveolarization observed at 4 and 18 days after the last LPS administration. LPS upregulated the expression of lung pro-inflammatory cytokines (TNF-α, IL-17a, IL-6, IL-1β) and chemokines (CCL2, CCL7, CXCL1, and CXCL2), while the expression of genes involved in lung alveolar and mesenchymal cell development (PDGFR-α, FGF7, FGF10, and SPRY1) was decreased. LPS induced recruitment of ExMf, including CCR2+ ExMf, as well as other myeloid cells like DCs and neutrophils. Lungs of LPS-exposed CCR2-/- mice showed preserved alveolar structure and normal patterns of α-actin and PDGFRα expression at the tips of the secondary alveolar crests. Compared to wild type mice, a significantly lower number of ExMf, including TNF-α+ ExMf were recruited to the lungs of CCR2-/- mice following repetitive LPS exposure. Further, pharmacological inhibition of TLR4 with TAK-242 also blocked the effect of LPS on alveolarization, α-SMA and PDGFRα expression. TNF-α and IL-17a induced α-smooth muscle actin expression in the distal airspaces of E16 fetal mouse lung explants. In human preterm lung mesenchymal stromal cells, TNF-α reduced mRNA and protein expression of PDGFR-α and decreased mRNA expression of WNT2, FOXF2, and SPRY1. Collectively, our findings demonstrate that in immature mice repetitive LPS exposure, through TLR4 signaling increases lung inflammation and impairs lung alveolar growth in a CCR2-dependent manner.

Project description:BackgroundMicrobiome-gut-brain axis may be involved in the progression of age-related cognitive impairment and relevant brain structure changes, but evidence from large human cohorts is lacking. This study was aimed to investigate the associations of gut microbiome with cognitive impairment and brain structure based on multi-omics from three independent populations.MethodsWe included 1430 participants from the Guangzhou Nutrition and Health Study (GNHS) with both gut microbiome and cognitive assessment data available as a discovery cohort, of whom 272 individuals provided fecal samples twice before cognitive assessment. We selected 208 individuals with baseline microbiome data for brain magnetic resonance imaging during the follow-up visit. Fecal 16S rRNA and shotgun metagenomic sequencing, targeted serum metabolomics, and cytokine measurements were performed in the GNHS. The validation analyses were conducted in an Alzheimer's disease case-control study (replication study 1, n = 90) and another community-based cohort (replication study 2, n = 1300) with cross-sectional dataset.ResultsWe found protective associations of specific gut microbial genera (Odoribacter, Butyricimonas, and Bacteroides) with cognitive impairment in both the discovery cohort and the replication study 1. Result of Bacteroides was further validated in the replication study 2. Odoribacter was positively associated with hippocampal volume (β, 0.16; 95% CI 0.06-0.26, P = 0.002), which might be mediated by acetic acids. Increased intra-individual alterations in gut microbial composition were found in participants with cognitive impairment. We also identified several serum metabolites and inflammation-associated metagenomic species and pathways linked to impaired cognition.ConclusionsOur findings reveal that specific gut microbial features are closely associated with cognitive impairment and decreased hippocampal volume, which may play an important role in dementia development.

Dataset Information

Metabolome and microbiome multi-omics integration from a murine lung inflammation model of bronchopulmonary dysplasia.

Background

Methods

Results

Conclusions

Impact

Publications

Metabolome and microbiome multi-omics integration from a murine lung inflammation model of bronchopulmonary dysplasia.

Similar Datasets

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