Early Gut Microbiota Changes in Preterm Infants with Bronchopulmonary Dysplasia: A Pilot Case-Control Study.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease that primarily affects premature or critically ill infants. This pilot study investigated early changes in gut microbiota composition in BPD patients and explored the potential risk factors associated with these changes. STUDY DESIGN: Preterm infants admitted to our neonatal intensive care unit with a gestational age of 26 to 32 weeks were prospectively surveyed and eligible for stool collection on days 7 and 28 of postnatal age between February 2016 and June 2017. A 16S rRNA sequencing approach was applied to compare the gut microbiota composition between the BPD group and controls. Multiple linear regression analysis was used to identify the predictor variables. RESULTS: Eight subjects in the BPD group and 10 subjects in the preterm group were analyzed during the observation period. Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes were the four dominant bacteria phyla of intestinal microflora. A significantly lower diversity of gut microbiota was observed in the BPD group compared with the preterm group on day 28 (number of observed operational taxonomic units, p = 0.034; abundance-based coverage estimator, p = 0.022; Shannon index, p = 0.028). Multiple linear regression analysis revealed that high Neonatal Therapeutic Intervention Scoring System score (≧19) at 24 hours was statistically significant in predicting the proportion of aerobic with facultative anaerobic bacteria on day 28 (p = 0.002). CONCLUSION: Infants with BPD are prone to develop gut dysbiosis in early life. A higher severity of illness and treatment intensity may indicate a higher risk of disrupting an anaerobic environment in the gut during the first month of life. KEY POINTS: · BPD patients are prone to develop gut dysbiosis.. · Lower diversity of gut microbiota.. · Higher risk of disrupting anaerobic environment..

Dissimilarity of the gut-lung axis and dysbiosis of the lower airways in ventilated preterm infants.

BACKGROUND: Chronic lung disease of prematurity (CLD), also called bronchopulmonary dysplasia, is a major consequence of preterm birth, but the role of the microbiome in its development remains unclear. Therefore, we assessed the progression of the bacterial community in ventilated preterm infants over time in the upper and lower airways, and assessed the gut-lung axis by comparing bacterial communities in the upper and lower airways with stool findings. Finally, we assessed whether the bacterial communities were associated with lung inflammation to suggest dysbiosis. METHODS: We serially sampled multiple anatomical sites including the upper airway (nasopharyngeal aspirates), lower airways (tracheal aspirate fluid and bronchoalveolar lavage fluid) and the gut (stool) of ventilated preterm-born infants. Bacterial DNA load was measured in all samples and sequenced using the V3-V4 region of the 16S rRNA gene. RESULTS: From 1102 (539 nasopharyngeal aspirates, 276 tracheal aspirate fluid, 89 bronchoalveolar lavage, 198 stool) samples from 55 preterm infants, 352 (32%) amplified suitably for 16S RNA gene sequencing. Bacterial load was low at birth and quickly increased with time, but was associated with predominant operational taxonomic units (OTUs) in all sample types. There was dissimilarity in bacterial communities between the upper and lower airways and the gut, with a separate dysbiotic inflammatory process occurring in the lower airways of infants. Individual OTUs were associated with increased inflammatory markers. CONCLUSIONS: Taken together, these findings suggest that targeted treatment of the predominant organisms, including those not routinely treated, such as Ureaplasma spp., may decrease the development of CLD in preterm-born infants.

Airway microbiome in adult survivors of extremely preterm birth: the EPICure study.

Bronchopulmonary dysplasia (BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (EP; <26 weeks gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm, with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults aged 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative PCR. 16S rRNA gene sequencing was completed on 74 samples (29 EP with BPD; 9 EP without BPD; and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes. Total Prevotella relative abundance correlated with forced expiratory volume in 1 s z-score (ρ=0.272; p<0.05). Typical respiratory pathogen loads and prevalence were similar between groups.In conclusion, extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative abundance.

Airway Microbiome and Development of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review.

OBJECTIVES: To summarize evidence regarding microbial dysbiosis of the airway associated with bronchopulmonary dysplasia (BPD) and to explore heterogeneity among studies. STUDY DESIGN: We included studies that evaluated the airway microbiome in preterm infants who developed BPD using culture-independent molecular techniques and reported alpha- and beta-diversity metrics and microbial profiles. RESULTS: The 6 included studies had substantial clinical and methodological heterogeneity. Most studies reported the presence of an airway microbiome early after birth and an evolution in the first weeks of life with increasing bacterial loads. The early airway microbiome was dominated by Staphylococcus and Ureaplasma spp. Two studies reported differences in alpha- and beta- diversity indices in preterm infants with BPD compared with those who did not develop BPD. Increased microbial community turnover, changes in the relative abundance of Proteobacteria and Firmicutes, and decreased Lactobacilli were reported with BPD progression. Most included infants were born by cesarean delivery, and a majority were exposed to postnatal antibiotics. No data regarding feeding human milk or correlations with the development of gut microbiota (gut-lung axis) were available. CONCLUSIONS: Microbial dysbiosis may be associated with BPD progression and severity, and further study of microbiome optimization in preterm infants at risk for BPD is warranted.

Early airway microbial metagenomic and metabolomic signatures are associated with development of severe bronchopulmonary dysplasia.

The pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. We previously identified differences in the airway microbiome at birth between preterm infants who were BPD predisposed versus those who were BPD resistant. In this study, we attempted to identify mechanisms by which the airway microbiome could modify the risk for BPD. We used a software-based method to predict the metagenome of the tracheal aspirate (TA) microbiome from 16S rRNA sequencing data in preterm infants and to identify functional ortholog genes that were differentially abundant in BPD-predisposed and BPD-resistant infants. We also identified metabolites that were differentially enriched in these samples by use of untargeted mass spectrometry and mummichog to identify the metabolic pathways involved. Microbial metagenome analysis identified specific pathways that were less abundant in the functional metagenome of the microbiota of BPD-predisposed infants compared with BPD-resistant infants. The airway metabolome of BPD-predisposed infants was enriched for metabolites involved in fatty acid activation and androgen and estrogen biosynthesis compared with BPD-resistant infants. These findings suggest that in extremely preterm infants the early airway microbiome may alter the metabolome, thereby modifying the risk of BPD. The differential enrichment of sex steroid metabolic pathways supports previous studies suggesting a role for sexual dimorphism in BPD risk. This study also suggests a role for metabolomic and metagenomic profiles to serve as early biomarkers of BPD risk.

Coexistence of Ureaplasma and chorioamnionitis is associated with prolonged mechanical ventilation.

BACKGROUND: Both histologic chorioamnionitis (HCAM) and Ureaplasma infection are considered important contributors to perinatal lung injury. We tested the hypothesis that coexistence of maternal HCAM and perinatal Ureaplasma exposure increases the risk of prolonged mechanical ventilation in extremely low-birthweight (ELBW) infants. METHODS: A retrospective cohort study was carried out of all ELBW infants born between January 2008 and December 2013 at a single academic center. Placental pathology and gastric fluid Ureaplasma data were available for all infants. Culture and polymerase chain reaction were used to detect Ureaplasma in gastric fluid. Prolonged mechanical ventilation was defined as mechanical ventilation that began within 28 days after birth and continued. RESULTS: Of 111 ELBW infants enrolled, 84 survived beyond 36 weeks of postmenstrual age (PMA) and were included in the analysis. Eighteen infants (21.4%) had both HCAM and Ureaplasma exposure. Seven infants (8.3%) required mechanical ventilation beyond 36 weeks of PMA. Coexistence of HCAM and Ureaplasma in gastric fluid was significantly associated with prolonged mechanical ventilation after adjustment for gestational age, sex, mode of delivery, and use of macrolide antibiotics (OR, 8.7; 95%CI: 1.1-67.2). CONCLUSIONS: Coexistence of maternal HCAM and perinatal Ureaplasma exposure significantly increases the risk of prolonged mechanical ventilation in ELBW infants.

The Microbiome of the Lower Respiratory Tract in Premature Infants with and without Severe Bronchopulmonary Dysplasia.

Aim We determined whether the bacteria in the lower respiratory tract (LRT) in extremely premature infants with severe bronchopulmonary dysplasia (BPD) are different from those with nonsevere BPD. Study Design We conducted a retrospective study of extremely premature infants who were admitted to the neonatal intensive care unit of Fukushima Medical University Hospital, Japan between April 2005 and March 2014. We screened for the bacterial colonization of the LRT using tracheobronchial aspirate fluid. Results A total of 169 extremely premature infants were included. Overall, 102 did not experience severe BPD, whereas the remaining 67 experienced severe BPD. Corynebacterium species (Cs) were more frequently detected in the severe BPD than nonsevere BPD infants (p = 0.03). There were significant differences between infants with and without severe BPD in the duration of endotracheal ventilation (p = 0.00, odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06), the duration of supplemental oxygen (p = 0.00, OR, 1.02; 95% CI, 1.01-1.03) before 36 weeks of postmenstrual age, and the frequency of sepsis after 7 postnatal days (p = 0.01, OR, 1.73; 95% CI, 1.18-2.54). Conclusion Cs are more likely to be present in the severe BPD infants with longer duration of endotracheal ventilation.

Macrolides do not affect the incidence of moderate and severe bronchopulmonary dysplasia in symptomatic ureaplasma-positive infants.

AIM: The aim of this study was to compare the incidence of bronchopulmonary dysplasia (BPD) in symptomatic ureaplasma-positive treated preterm infants and asymptomatic preterm infants not tested or treated for ureaplasma. METHODS: A retrospective matched cohort study was conducted in a tertiary, neonatal unit between January 2007 and December 2012. Infants ≤29 completed weeks with signs and symptoms suggesting ureaplasma pneumonia who received macrolides comprised the study group. Infants ≤29 weeks without signs and symptoms not tested or treated with macrolides were the controls. Infants were mandatorily matched for gestational age ± one week or birthweight ± 100 grams. RESULTS: There were 31 infants in the study group and 62 in the control group. The baseline demographic data of both groups were similar on the whole. The incidence of moderate and severe BPD, defined by oxygen dependency or the need for continuous positive airway pressure at 36 weeks of postconceptual age, was 45.2% in the study group and 40.3% in the controls (p = 0.65). There was no significant difference in morbidities or mortality between the groups. CONCLUSION: A selective approach of treating symptomatic ureaplasma-positive preterm infants with macrolides did not affect the incidence of moderate and severe BPD.

The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with perinatal inflammatory triggers. Methods targeting bacterial rRNA may improve detection of microbial colonization in premature infants. We hypothesize that respiratory microbiota differs between preterm infants who develop BPD and those unaffected and correlates with inflammatory mediator concentrations. METHODS: Twenty-five infants, born at ≤32 wk of gestation and intubated in the first 24 h, were enrolled. Tracheal aspirates were obtained at intubation and on days 3, 7, and 28. Bacterial DNA was extracted, and 16S rRNA genes were amplified and sequenced. Concentrations of interleukins (IL-1ß, IL-6, IL-8, IL-10, and IL-12), tumor necrosis factor-α, interferon-γ, lipopolysaccharide (LPS), and lipoteichoic acid (LTA) were measured. Chorioamnionitis was diagnosed by histology. BPD was defined as an oxygen requirement at 36 wk postmenstrual age. RESULTS: Acinetobacter was the predominant genus in the airways of all infants at birth. Ten infants developed BPD and showed reduced bacterial diversity at birth. No differences were detected in bacterial diversity, cytokines, LPS, and LTA from infants with and without exposure to chorioamnionitis. CONCLUSION: The airways of premature infants are not sterile at birth. Reduced diversity of the microbiome may be an important factor in the development of BPD and is not associated with differences in inflammatory mediators.

Association of Ureaplasma urealyticum colonization with development of bronchopulmonary dysplasia: a systemic review and meta-analysis.

There is controversy regarding the roles of Ureaplasma urealyticum (U. urealyticum) colonization in the development of bronchopulmonary dysplasia (BPD). This study explored the association between U. urealyticum and bronchopulmonary dysplasia at 36 weeks post-menstrual age (BPD36). Studies published before December 31, 2013 were searched from Medline, Embase, Ovid, Web of Science, and Cochrane databases, with the terms "Ureaplasma urealyticum", "chronic lung disease", or "BPD36" used, and English language as a limit. The association between U. urealyticum colonization and BPD36 was analyzed with RevMan 4.2.10 software, using the odds ratio (OR) and relative risk (RR) for dichotomous variables. Out of the enrolled 81 studies, 11 investigated the BPD36 in total 1193 infants. Pooled studies showed no association between U. urealyticum colonization and subsequent development of BPD36, with the OR and RR being 1.03 (95% CI=0.78-1.37; P=0.84) and 1.01 (95% CI= 0.88-1.16, P=0.84), respectively. These findings indicated no association between U. urealyticum colonization and the development of BPD36.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 µg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

A quantitative analysis of Ureaplasma urealyticum and Ureaplasma parvum compared with host immune response in preterm neonates at risk of developing bronchopulmonary dysplasia.

Multiplex, real-time PCR for the identification of Ureaplasma urealyticum and Ureaplasma parvum was performed on nucleic acids extracted from sequential endotracheal aspirates obtained from preterm neonates born at <29 weeks of gestation and ventilated for more than 48 h admitted to two level 3 neonatal intensive care units. Specimens were obtained shortly after birth and sequentially up until extubation. One hundred fifty-two specimens (93.8%) contained material suitable for analysis. Ureaplasma spp. were identified in 5 of 13 neonates studied. In most cases, the DNA load of the detected Ureaplasma species was low and decreased over time. In addition, changes in detectable Ureaplasma species DNA did not relate to changes in the inflammatory marker C-reactive protein (CRP) or respiratory status. All but two blood samples obtained at times of suspected sepsis were culture positive for other microorganisms; the species cultured were typically coagulase-negative staphylococci and were associated with increased levels of CRP (>10 mg/liter). This study was limited by the small number of patients examined and does not have the power to support or contradict the hypothesis that postnatal lung infection with Ureaplasma parvum is causally related to bronchopulmonary dysplasia (BPD) or adverse respiratory outcomes after preterm birth. However, in this study, increases in CRP levels were not associated with patients in whom Ureaplasma parvum was detected, in contrast to the detection of other bacterial species.

In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants.

AIMS: We determined the association between short-term neonatal morbidities, such as bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH), and Ureaplasma spp. in amniotic fluid, placental and amniotic membrane of preterm infants. METHODS: This study enrolled 257 patients who were born by cesarean section at <34 weeks' gestation. Patients were divided into two groups according to detection of Ureaplasma spp. by culture-based and/or polymerase chain reaction (PCR) techniques. RESULTS: Significant differences were observed between both groups for all IVH (P=0.032) and IVH grades III or IV (P=0.013), as wells as for BPD [odds ratio (OR) 5.46, 95% confidence interval (CI) 2.02-14.77], oxygen requirement at 28 days postnatal age (OR 1.93, 95% CI 1.00-3.70), and for death between 28 days and 36 postmenstrual weeks or BPD (OR 4.20, 95% CI 1.77-9.96). Ureaplasma spp. was a significant predictor (P<0.001) of BPD after correcting for birth weight (P=0.003) and positive pressure ventilation (P=0.001). CONCLUSIONS: In our study population Ureaplasma spp. was associated with BPD and IVH in preterm infants even after adjustment for multiple risk factors.

Association between probiotics and bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary dysplasia is a chronic pulmonary disease with a high incidence in premature infants, and there is still no effective treatment. The purpose of our study was to analyze the association between the use of probiotics and BPD in premature infants. We retrospectively collected clinical data of infants with gestational age < 32 weeks admitted to the NICU of The First Hospital of Jilin University from January 1, 2019 to March 31, 2020. Demographic and clinicopathological data of the inclusion population were collected. The outcome was the incidence of BPD or death. The χ2 tests was used to compare the categorical variables. The t test and non-parametric Wilcoxon rank-sum test were used to compare the continuous data. Univariate and multivariate logistic regression were used to analyze the association between probiotics and BPD. A total of 318 newborns met the inclusion criteria, of which 94 received probiotics and 224 received no probiotics. There were 16 deaths and 115 newborns with BPD in the included population. The results of univariate analysis showed differences in the maternal diabetes, the proportion of systemic antibiotics given to mother within 24 h before birth, the receiving rate of invasive mechanical ventilation, the prevalence of BPD/death, PDA, RDS and Ivh between newborns with and without probiotics (p < 0.05); The results of unadjusted univariate logistic regression model showed that probiotic (OR 0.034, 95% CI 0.012-0.096) was the factor affecting BPD in preterm infants (p < 0.05). Multivariate logistic regression result (OR 0.037, 95% CI 0.013-0.105) was consistent with univariate analysis (P < 0.001). Probiotics are associated with a reduced risk of BPD in preterm infants < 32 weeks of age. More prospective studies with large samples are still needed.

Relationship of proteinases and proteinase inhibitors with microbial presence in chronic lung disease of prematurity.

BACKGROUND: A proteolytic imbalance has been implicated in the development of "classical" chronic lung disease of prematurity (CLD). However, in "new" CLD this pattern has changed. This study examines the longitudinal relationship between neutrophil proteinases and their inhibitors in ventilated preterm infants and their relationship to microbial colonisation. METHODS: Serial bronchoalveolar lavage fluid was obtained from ventilated newborn preterm infants. Neutrophil elastase (NE) activity, cell counts, metalloproteinase (MMP)-9, MMP-9/TIMP-1 complex, SerpinB1 concentration and percentage of SerpinB1 and alpha(1)-antitrypsin (AAT) in complex with elastase were measured. The presence of microbial genes was examined using PCR for 16S rRNA genes. RESULTS: Statistically more infants who developed CLD had NE activity in at least one sample (10/20) compared with infants with resolved respiratory distress syndrome (RDS) (2/17). However, NE activity was present in a minority of samples, occurring as episodic peaks. Peak levels of MMP-9, MMP-9/TIMP-1 complex, percentage of AAT and SerpinB1 in complex and cell counts were all statistically greater in infants developing CLD than in infants with resolved RDS. Peak values frequently occurred as episodic spikes and strong temporal relationships were noted between all markers. The peak values for all variables were significantly correlated to each other. The presence of bacterial 16S rRNA genes was associated with the development of CLD and with elevated elastase and MMP-9. CONCLUSION: NE activity and MMP-9 appear to be important in the development of "new" CLD with both proteinase and inhibitor concentrations increasing episodically, possibly in response to postnatal infection.

Molecular microbiological characterization of preterm neonates at risk of bronchopulmonary dysplasia.

The role of infection in bronchopulmonary dysplasia (BPD) is unknown. We present an observational study of 55 premature infants born weighing less than 1.3 kg within two level III neonatal intensive care units. Endotracheal aspirates (ETA) and nasogastric aspirates (NGA) were studied with denaturing gradient gel electrophoresis (DGGE) profiling to elucidate the total bacterial community, and species-specific PCR was used to detect the presence of Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum. DGGE identified bacterial species in 59% of NGA and ETA samples combined. A diverse range of species were identified including several implicated in preterm labor. Species-specific PCR identified M. hominis in 25% of NGA and 11% of ETA samples. Among the 48 infants surviving up to 36 wk-postconceptual age, ordinal logistic regression showed the odds ratio for BPD or death where Ureaplasma was present/absent as 4.80 (95% CI 1.15-20.13). After adjusting for number of days ventilated, this was reduced to 2.04 (0.41-10.25). These data demonstrate how the combined use of DGGE and species-specific PCR identifies a high exposure in utero and around the time of birth to bacteria that might be causally related to preterm delivery and subsequent lung injury.

The use of culture-independent tools to characterize bacteria in endo-tracheal aspirates from pre-term infants at risk of bronchopulmonary dysplasia.

Although premature infants are increasingly surviving the neonatal period, up to one-third develop bronchopulmonary dysplasia (BPD). Despite evidence that bacterial colonization of the neonatal respiratory tract by certain bacteria may be a risk factor in BPD development, little is known about the role these bacteria play. The aim of this study was to investigate the use of culture-independent molecular profiling methodologies to identify potential etiological agents in neonatal airway secretions. This study used terminal restriction fragment length polymorphism (T-RFLP) and clone sequence analyses to characterize bacterial species in endo-tracheal (ET) aspirates from eight intubated pre-term infants. A wide range of different bacteria was identified in the samples. Forty-seven T-RF band lengths were resolved in the sample set, with a range of 0-15 separate species in each patient. Clone sequence analyses confirmed the identity of individual species detected by T-RFLP. We speculate that the identification of known opportunistic pathogens including S. aureus, Enterobacter sp., Moraxella catarrhalis, Pseudomonas aeruginosa and Streptococcus sp., within the airways of pre-term infants, might be causally related to the subsequent development of BPD. Further, we suggest that culture-independent techniques, such as T-RFLP, hold important potential for the characterization of neonatal conditions, such as BPD.

Metabolomics of bronchopulmonary dysplasia.

The pathogenesis of Bronchopulmonary dysplasia (BPD) remains poorly understood. It is a multifactorial disease having a genetic-environmental basis. Although attempts have been made to identify a biomarker, none have been validated for clinical use to date. Metabolomics is a promising field of the "omics technologies" that could allow for better understanding of the pathogenesis and underlying mechanisms of BPD as well as facilitate detection of biomarkers. Identification of these biomarkers would improve diagnosis, identify patients in early disease stages and potentially target intervention. This review focuses on the evidence arising from metabolomics and its interaction with microbiomics and pharmacology with respect to pathogenesis and treatment options for this multifactorial complex disease.

The association between the microbes in the tracheobronchial aspirate fluid and bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: The study aimed to evaluate the association between microbes in the lower respiratory tract (LRT) and the srisk for severe bronchopulmonary dysplasia (sBPD) in premature infants. METHODS: We conducted a retrospective, single-center study of preterm infants who were admitted to the neonatal intensive care unit (NICU) of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, China, between January 2015 and December 2017. The microbes in the LRT were screened by using tracheobronchial aspirate fluid (TAF) culture. RESULTS: One hundred and fifty-five infants were included in the analysis. Among 155 infants, 41 were diagnosed with sBPD, and 114 were diagnosed without sBPD. There were significant differences between infants with and without sBPD in regard to birth weight (BW), gestational age (GA), the duration of endotracheal ventilation and supplemental oxygen. The incidence of retinopathy (ROP) and sepsis was higher in the sBPD infants than in the infants without sBPD. There was a difference in the detection rate of Gram-negative bacteria (GNB) between the two groups. Stenotrophomonas maltophilia and Klebsiella pneumoniae were mainly detected in TAF. CONCLUSIONS: The LRT microbes were different between infants with and without sBPD, and GNB is more frequently detected in sBPD infants.

A novel mouse model of Ureaplasma-induced perinatal inflammation: effects on lung and brain injury.

Chorioamnionitis is associated with increased lung and brain injury in premature infants. Ureaplasma is the microorganisms most frequently associated with preterm birth. Whether Ureaplasma-induced antenatal inflammation worsens lung and brain injury is unknown. We developed a mouse model combining antenatal Ureaplasma infection and postnatal oxygen exposure. Intraamniotic Ureaplasma Parvum (UP) increased proinflammatory cytokines in placenta and fetal lungs. Antenatal exposure to UP or broth caused mild postnatal inflammation and worsened oxygen-induced lung injury. Antenatal UP exposure induced central microgliosis and disrupted brain development as detected by decreased number of calbindin-positive and calretinin-positive neurons in the neocortex. Postnatal oxygen decreased calretinin-positive neurons in the neocortex but combined with antenatal UP exposure did not worsen brain injury. Antenatal inflammation exacerbates the deleterious effects of oxygen on lung development, but the broth effects prohibit concluding that UP by itself is a compounding risk factor for bronchopulmonary dysplasia. In contrast, antenatal UP-induced inflammation alone is sufficient to disturb brain development. This model may be helpful in exploring the pathophysiology of perinatal lung and brain injury to develop new protective strategies.