Early blood transcriptomic markers of necrotizing enterocolitis in preterm piglets
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE166152 | GEO | 2021/06/01
REPOSITORIES: GEO
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Project description:Most hospitalized preterm infants receive antibiotics (AB) in the first days of life to treat or prevent systemic infections. Short-term, early AB treatment may also prevent against the microbiota-dependent serious gut disorder, necrotising enterocolitis (NEC). However, it remains a challenge to predict or early detection of NEC in the first weeks of life and few diagnostic markers exist. Using preterm piglets as models for infants, we hypothesised that proteomic profiling could be used to identify new early plasma biomarkers of NEC with or without prior AB treatment. Preterm newborn pigs were treated with saline (CON) or antibiotics (ampicillin, gentamicin, and metronidazole), given enterally (ENT) or parenterally (PAR), and fed formula for four days to induce NEC. The gut was collected for scoring of NEC lesions and blood was collected for haematology and plasma proteomics
2021-09-08 | PXD015938 | Pride
Project description:Necrotizing enterocolitis (NEC) is an acute gut inflammatory disorder that mainly affects preterm neonates. A large proportion of NEC survivors develop neuronal deficits later in life, however the effect of early stages of NEC on the developing brain is unknown. Using preterm pigs as a NEC-sensitive animal model, we profiled the hippocampal gene expression in response to severe NEC lesions. The NEC-induced differentially expressed genes (DEGs) in the hippocampus segregated the piglets suffering from small intestinal NEC (Si-NEC) from those showing NEC lesions only in the colon (Co-NEC). Only when NEC lesions were observed in the small intestine, did piglets show reduced physical activity together with up-regulation of hippocampal genes related to inflammation and hypoxia, which was further verified by qPCR. Cluster analyses revealed key hippocampal NEC–related DEGs for Si-NEC (23 genes, including S100A8, PDK4, EDN1, IER3, Opalin, TXNIP) and Co-NEC (3 genes: GSTM3, TF, and S100A1). Both NEC phenotypes showed only two down-regulated DEGs (TMEM 167, HBB) and were devoid of any histological signs of microglia activation. Cerebrospinal fluid (CSF) from NEC-positive pigs contained elevated levels of several inflammatory proteins and in vitro exposure of immature hippocampal neurons to NEC-related CSF promoted neuritogenesis. Further in vitro experiments with neurite outgrowth indicated that VEGF, CINC-3, S100A9 and S100A8/S100A9 may play a role in NEC effects on hippocampal development. In conclusion, NEC lesions, especially when involving the small intestine, alter hippocampal gene expression with potential neuroinflammation and effects on neural circuit formation. Our results demonstrated that gut lesions affect the immature brain at early stages of disease progression. Thus, supportive care is important for preterm infants experienced with NEC to lessen possible later neurological dysfunctions.
2018-05-22 | GSE114705 | GEO
Project description:Intestinal microbiota colonization is important for intestinal development and health of preterm infants, especially those with extremely low birth weight. Recent studies indicated for a dynamic crosstalk between that gut microbiota and DNA methylome of host intestinal cells. Thereby, we sought to determine the epigenomic and metagenomic consequences of suppression of microbiota colonization in the intestine of preterm neonates to gain insights into biological pathways that shape the interface between the gut microbiota and the preterm intestinal cells. We examined 14 preterm piglets by comparing the conventional preterm neonates with those ones treated with oral antibiotics for genome wide DNA methylation and 16S rDNA microbiome. Our results demonstrated an extensive genome-wide DNA methylation changes in response to the suppression of intestinal microbe colonization, especially genes involved in neonatal immune response signaling and glycol-metabolism pathways were identified. Our study highlights several key genes that might predispose preterm neonates to NEC risk due to their key roles involved in the immune-metabolic networks. Our study not only provided rich omic-data to interpret molecular program in relation with microbiota-associated methylome-proteome network changes, but also confer clinical usage of key gene markers for potential early diagnostics of NEC of preterm neonates.
2017-10-12 | GSE88697 | GEO
Project description:Caesarean-delivered preterm pigs were fed 3 d of parenteral nutrition followed by 2 d of enteral formula feeding. Antibiotics (n=11) or control saline (n=13) were given twice daily from birth to tissue collection at d 5. NEC-lesions and intestinal structure, function, microbiology and immunity markers were recorded. We used Affymetrix microarrays to investigate gene expression in intestinal tissues of preterm piglets treated with antibiotics or control saline. Twenty-four preterm piglets were delivered by caesarean section on day 105 of gestation from two healthy sows. All piglets were initially provided with parenteral nutrition via a vascular catheter, combined with small amounts of minimal enteral nutrition. On day three, all parenteral nutrition was stopped and total enteral nutrition was given through an oro-gastric feeding tube. Piglets were allocated into controls ( n=13) and an intervention group receiving oral and systemic broad-spectrum antibiotics ( n=11). To assure high systemic and intra luminal MIC values antibiotics were given both orally and intramuscularly. All antibiotics were given directly after feeding with an oral bolus and control pigs were given corresponding amounts of saline. On day five, all piglets were euthanized, and small intestinal tissue collected.
2013-08-21 | E-GEOD-48125 | biostudies-arrayexpress
Project description:Necrotizing enterocolitis (NEC) is an acute and life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventative therapy, but potential bacterial infection raise concern. Removal of bacteria from donor feces may reduce this risk while maintaining the NEC-preventive effects. We aimed to assess preclinical efficacy and safety of bacteria-free fecal filtrate transfer (FFT). Using fecal material from healthy suckling piglets, we administered FMT rectally, or cognate FFT either rectally or oro-gastrically to formula-fed preterm, cesarean-delivered piglets as a model for preterm infants, We compared gut pathology and related safety parameters with saline controls, and analyzed ileal mucosal transcriptome to gauge the host e response to FMT and FFT treatments relative to control. Results showed that oro-gastric FFT prevented NEC, whereas FMT did not perform better than control. Moreover, FFT but not FMT reduced intestinal permeability, whereas FMT animals had reduced body weight increase and intestinal growth. Global gene expression of host mucosa responded to FMT but not FFT with increased and decreased bacterial and viral defense mechanisms, respectively. In conclusion, as preterm infants are extremely vulnerable to enteric bacterial infections, rational NEC-preventive strategies need incontestable safety profiles. Here we show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects. If translatable to preterm infants, this could lead to a change of practice and in turn a reduction in NEC burden.
2021-10-01 | GSE158878 | GEO
Project description:Caesarean-delivered preterm pigs were fed 3 d of parenteral nutrition followed by 2 d of enteral formula feeding. Antibiotics (n=11) or control saline (n=13) were given twice daily from birth to tissue collection at d 5. NEC-lesions and intestinal structure, function, microbiology and immunity markers were recorded. We used Affymetrix microarrays to investigate gene expression in intestinal tissues of preterm piglets treated with antibiotics or control saline.
2013-08-21 | GSE48125 | GEO
Project description:Necrotizing enterocolitis (NEC) is the most common and lethal gastrointestinal disease affecting preterm infants. NEC develops suddenly and is characterized by gut barrier destruction, an inflammatory response, intestinal necrosis and multi-system organ failure. There is currently no method for early NEC detection, and the pathogenesis of NEC remains unclear.
2022-09-13 | GSE212913 | GEO
Project description:Chorioamnionitis (CA), resulting from intra-amniotic inflammation, is a frequent cause of preterm birth and exposes the immature intestine to bacterial toxins and/or inflammatory mediators before birth via fetal swallowing. This may affect intestinal immune development, interacting with the effects of enteral feeding and gut microbiota colonization just after birth. Using preterm pigs as model for preterm infants, we hypothesized that prenatal exposure to gram-negative endotoxin influences postnatal bacterial colonization and gut immune development. Pig fetuses were given intra-amniotic lipopolysaccharide (LPS) 3 d before preterm delivery by cesarean section, and were compared with litter-mate controls (CON) at birth and after 5 d of formula feeding and spontaneous bacterial colonization. Amniotic fluid was collected for analysis of leukocyte counts and cytokines, and the distal small intestine was analyzed for endotoxin level, morphology and immune cell counts. Intestinal gene expression and microbiota were analyzed by transcriptomics and metagenomics, respectively. At birth, LPS-exposed pigs showed higher intestinal endotoxin, neutrophil/macrophage density and shorter villi. About 1.0% of intestinal genes were affected at birth and DMBT1, a regulator of mucosal immune defense, was identified as the hub gene in the co-expression network. Genes related to innate immune response (TLR2, LBP, CD14, C3, SFTPD), neutrophil chemotaxis (C5AR1, CSF3R, CCL5) and antigen processing (MHC II, CD4) were also affected and expression levels correlated with intestinal neutrophil/macrophage density and amniotic fluid cytokine levels. On day 5, LPS and CON pigs showed similar necrotizing enterocolitis (NEC) lesions, endotoxin levels, morphology, immune cell counts, gene expressions and microbiota (except for difference in some low-abundant species). Our results show that CA markedly affects intestinal genes at preterm birth, including genes related to immune cell infiltration. However, a few days later, following the physiological adaptations to preterm birth, CA had limited effects on intestinal structure, function, gene expression, bacterial colonization and NEC sensitivity. We conclude that short-term, prenatal intra-amniotic inflammation is unlikely to exert marked effects on intestinal immune development in preterm neonates beyond the immediate neonatal period.
2019-10-25 | GSE139366 | GEO
Project description:Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infant occuring in neonatal intensive care units. NEC is associated with severe intestinal inflammation, intestinal perforation leading to mortality. The challenge for neonatologists is to detect early clinical manifestations of NEC. Therefore, one of the strategies to prevent or treat NEC would be to develop an early diagnostic tool allowing identification of preterm infants either at risk of developing NEC or at the onset of the disease. Illumina’s deep sequencing technology (RNA-seq) was used to establish the gene expression profile between resected ileal healthy preterm (control, n=5) and NEC diagnosed preterm infant (NEC, n=9) and analyzed by IPA Core analysis system. IPA analysis indicated that the most significant functional pathways overrepresented in NEC neonates were associated with innate immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors in recognition of bacteria and viruses. Among genes that were strongly modulated in NEC neonates, we observed a high degree of similarity with those linked to the development of IBD. By comparing gene expression patterns between NEC and Crohn’s disease, we identified several new potential protein targets for helping to predict and/or diagnose NEC in preterm infant. Gene expression profile revealed an uncontrolled innate immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn’s disease evidenced high degree of similarity between these two inflammatory diseases and allowed us to identify several new potential NEC biomarkers.
2016-01-25 | GSE64801 | GEO
Project description:Background: Neonatal infection and sepsis are common for preterm infants due to their immature immune system. Early diagnosis is important for effective treatment but few early markers of systemic and neuro-inflammatory responses in neonates are known. We hypothesized that systemic infection with Gram-positive Staphylococcus epidermidis (SE) induces acute changes to proteins in plasma and cerebrospinal fluid (CSF), potentially affecting the immature brain of preterm neonates. Methods: Using preterm pigs as model for preterm infants, plasma and CSF samples were collected up to 24 h after SE infection and investigated by untargeted mass spectrometry (MS)-based proteomics. Selected differential proteins were further studied in vitro assays. Results: The clinical signs of sepsis and neuroinflammation in SE-infected piglets were associated with changes in multiple CSF and plasma proteins. Eight plasma proteins, including APOA4, haptoglobin, MBL1, vWF, LBP and sCD14, were affected already 6 h after infection. Likewise, acute phase reactants, including complement components, showed a time-dependent activation pattern after infection. Feeding bovine colostrum reduced the sepsis-related change in clinical parameters as well as plasma proteins. Neuroinflammation-related neuropeptide Y (NPY), IL-18 and MMP-14 showed distinct changes in the CSF and several brain regions (prefrontal cortex, PVWM, hippocampus) 24 h after infection. These changes were verified in TLR2 agonist-challenged primary microglia cells, where exogenous NPY suppressed the inflammatory response. Conclusion: Systemic infection with Gram-positive SE induces inflammation with rapid proteome changes in plasma and CSF in preterm newborn pigs. The observed early markers of sepsis and neuroinflammation in preterm pigs may serve as novel biomarkers for sepsis in preterm infants.
2020-05-26 | PXD016013 | Pride