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Background: Preterm birth is a major determinant of neonatal survival and morbidity, but the gut microbiome and associated enteric inflammation are also key factors in neonatal development and the risk of associated morbidities. We prospectively and longitudinally followed two cohorts of preterm infants, one of which was fed activated Bifidobacterium longum subsp. infantis (B. infantis) EVC001 8 × 109 CFU daily, and the other was not fed a probiotic. Hospital feeding protocol assigned all infants born at <1500 g and/or < 32 weeks corrected gestational age to the probiotic feeding protocol, whereas infants born at >1500 g and/or >32 weeks corrected gestational age were not fed a probiotic. Fecal samples were opportunistically collected from 77 infants throughout the hospital stay, and subjected to shotgun metagenomic sequencing and quantification of enteric inflammation. De-identified metadata was collected from patient medical records. Results: The gut microbiome of preterm infants was typified by a high abundance of Enterobacteriaceae and/or Staphylococcaceae, and multivariate modeling identified the probiotic intervention, rather than degree of prematurity, day of life, or other clinical interventions, as the primary source of change in the gut microbiome. Among infants fed B. infantis EVC001, a high abundance of total Bifidobacteriaceae developed rapidly, the majority of which was B. infantis confirmed via subspecies-specific qPCR. Associated with this higher abundance of Bifidobacteriaceae, we found increased functional capacity for utilization of human milk oligosaccharides (HMOs), as well as reduced abundance of antibiotic resistance genes (ARGs) and the taxa that harbored them. Importantly, we found that infants fed B. infantis EVC001 exhibited diminished enteric inflammation, even when other clinical variables were accounted for using multivariate modeling. Conclusion: These results provide an important observational background for probiotic use in a NICU setting, and describe the clinical, physiological, and microbiome-associated improvements in preterm infants associated with B. infantis EVC001 feeding.
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Antenatal steroids suppress growth in the fetus and newborn. Although weight deficits are regained by weaning, studies show that intrauterine growth restriction with postnatal "catch-up" growth is a risk factor for hypertension, insulin resistance, and ischemic heart disease in adult life, with multigenerational consequences. We tested the hypothesis that fetal exposure to betamethasone suppresses fetal growth in the F1 pups and their untreated F2 offspring. Timed pregnant rats received a single two-dose course of intramuscular betamethasone (0.25 mg/kg/day) on days 17 and 18 of gestation. Matched controls received equivalent volumes sterile normal saline. The first-generation (F1) offspring were studied at term, P21, and P70, or mated at P60 to produce the following subgroups: (1) saline male/saline female (SM/SF), (2) betamethasone (B) male/BFemale (BM/BF), (3) BM/SF, and (4) SM/BF. The unexposed second-generation (F2) offspring were examined at birth and P70. Growth, neurological outcomes, and growth factors were determined. At birth, the F1 pups exposed to B were significantly growth suppressed compared with the controls, with correspondingly lower blood glucose, insulin, IGF-I, corticosterone, and leptin levels and delayed neurological outcomes. Catchup growth occurred at P21, surpassing that of the control group. By P70, growth was comparable, but glucose was higher, insulin was lower, and memory was retarded in the B group, and transmitted to the unexposed F2 offspring of B-exposed rats. Antenatal betamethasone has sustained metabolic and neurological effects that may impact the unexposed offspring. Whether these intergenerational effects reverse in future generations remain to be determined.
Asunto(s)
Betametasona/farmacología , Desarrollo Fetal/efectos de los fármacos , Hígado/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/sangre , Reflejo/efectos de los fármacos , Animales , Glucemia/metabolismo , Corticosterona/sangre , Femenino , Hormona del Crecimiento/sangre , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Hígado/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Embarazo , Ratas , Reflejo/fisiologíaRESUMEN
Preterm infants are often exposed to both antenatal and postnatal glucocorticoids (GCs). We tested the hypothesis that combined antenatal and postnatal GCs have long-lasting adverse effects on fetal and neonatal growth, growth factors, and neurological outcomes. Pregnant rats were administered a single IM dose of betamethasone (0.2 mg/Kg, AB), dexamethasone (0.2 mg/Kg, AD), or equivalent volumes of saline (AS) at 17 & 18 days gestation. Following delivery, pups from each treatment group were sacrificed at P0, and the remainder was treated with a single IM dose of either betamethasone (0.25 mg/Kg, PB), dexamethasone (0.25 mg/Kg, PD), or equivalent volumes of saline (PS) on P5, P6, and P7. Somatic growth, neurological status, and growth factors were determined at P14, P21, and P45. At birth, AD resulted in decreased somatic growth. AB advanced the hopping reflex associated with spinal rhythmic mechanisms. At P21, all GC groups were growth suppressed, but only the AS/PD group had deficits in brain weight and delayed plantar reflex associated with brainstem function. By P45, sustained reductions in body and brain weight occurred all combined antenatal and postnatal GC groups, as well as elevated ACTH and corticosterone. Retardation in plantar reflex occurred in all AD groups. IGF-I, GH and insulin levels were elevated at all ages with dexamethasone. Combined antenatal and postnatal GCs has persistent detrimental lasting effects on growth, growth factors, neurological outcomes, and HPA axis activity. Whether these effects persist in adult life and are risk factors for insulin resistance, remains to be elucidated.
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The lungs of extremely low gestational age neonates (ELGANs) are deficient in pulmonary surfactant and are incapable of efficient gas exchange necessary for successful transition from a hypoxic intrauterine environment to ambient air. To improve gas exchange and survival, ELGANs often receive supplemental oxygen with mechanical ventilation which disrupts normal lung developmental processes, including microvascular maturation and alveolarization. Factors that regulate these developmental processes include vascular endothelial growth factor and matrix metalloproteinases, both of which are influenced by generation of oxygen byproducts, or reactive oxygen species (ROS). ELGANs are also deficient in antioxidants necessary to scavenge excessive ROS. Thus, the accumulation of ROS in the preterm lungs exposed to prolonged hyperoxia, results in inflammation and development of bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). Despite advances in neonatal care, BPD/CLD remains a major cause of neonatal morbidity and mortality. The underlying mechanisms are not completely understood, and the benefits of current therapeutic interventions are limited. The association between ROS and biomarkers of microvascular maturation and alveolarization, as well as antioxidant therapies in the setting of hyperoxia-induced neonatal lung injury are reviewed in this article.
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BACKGROUND AND PURPOSE: Hydrocortisone (HC), at different dosages, is used in critically ill newborns for lung stability, blood pressure support, and prevention of chronic lung disease (CLD). Its long-term effects on postnatal growth are not well studied. We hypothesized that early exposure to high doses of HC adversely affects growth, growth factors, metabolic hormones, and neurological outcomes, persisting in adulthood. EXPERIMENTAL DESIGN: Rat pups received a single daily intramuscular dose of HC (1â¯mg/kg/day, 5â¯mg/kg/day, or 10â¯mg/kg/day on days 3, 4 & 5 postnatal age (P3, P4, P5). Age-matched controls received equivalent volume saline. Body weight, linear growth, and neurological outcomes were monitored. Animals were sacrificed at P21, P45, and P70 for blood glucose, insulin, IGF-I, GH, leptin, and corticosterone levels. Liver mRNA expression of IGFs and IGFBPs were determined at P21 and P70. Memory and learning abilities were tested using the Morris water maze test at P70. RESULTS: HC suppressed body weight and length at P12, P21 and P45, but by P70 there was catchup overgrowth in the 5 and 10â¯mg/kg/day groups. At P70 blood insulin, IGF-I, GH, and leptin levels were low, whereas blood glucose, and liver IGFs and IGFBPs were high in the high dose groups. High HC also caused delayed memory and learning abilities at P70. CONCLUSIONS: These data demonstrate that while higher doses of HC may be required for hemodynamic stability and prevention of CLD, these doses may result in growth deficits, as well as neurological and metabolic sequelae in adulthood.