Development Of Necrotizing Enterocolitis Research Articles

Silencing miR-155-5p expression improves intestinal damage through inhibiting inflammation and ferroptosis in necrotizing enterocolitis

BackgroundNecrotizing enterocolitis (NEC) is a condition characterized by acquired damage to the mucosal lining, predominantly affecting premature infants. Bioinformatics assessments uncovered a notable rise in miR-155-5p expression in the intestinal tissues of infants suffering from NEC. Nevertheless, the development of NEC's underlying mechanisms and the role of miR-155-5p are still not well understood. This research aimed to explore the role of miR-155-5p in NEC and to elucidate its underlying mechanisms. MethodsTo replicate NEC in vitro, lipopolysaccharide (LPS) was employed, whereas an in vivo rat model of NEC was established using formula feeding and exposure to hypoxia. Subsequently, levels of inflammatory cytokines, cell survival, and apoptosis rates were assessed. Various biochemical indicators such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured utilizing a purchased diagnostic kit. For the assessment of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) within FHC cells, analysis by flow cytometry was conducted. Additionally, the technique of Western blotting was utilized to analyze the levels of ferroptosis-associated proteins. Moreover, hematoxylin and eosin (H&E) staining was carried out to observe the histopathological alterations in the intestinal tissue samples from rats with necrotizing enterocolitis (NEC). ResultsReducing miR-155-5p improved the survival of FHC cells exposed to LPS, decreased cell apoptosis, inflammation, and ferroptosis, and mitigated intestinal damage in NEC rats. Furthermore, SLC7A11 was found to be a direct target of miR-155-5p. The inhibition of miR-155-5p decreased LPS-induced inflammation and ferroptosis in both FHC cells and NEC rats by promoting SLC7A11 expression. This effect was evidenced by increased levels of ferroptosis-related proteins FTH1 and GPX4, decreased COX-2 and ACSL4 levels, lower lipid peroxidation marker MDA, reduced antioxidant markers GSH, SOD, and CAT, fewer IL-6 and TNF-α, and suppression of the IκBα/NF-κB p65 signaling pathway. ConclusionsIn conclusion, reducing miR-155-5p could improve intestinal damage in NEC by inhibiting inflammation and ferroptosis. These findings may provide theoretical insights for the development of new therapies for NEC.

Transfusion-associated necrotising enterocolitis in very low birth weight babies: transfusion and feeding practices in two neonatal units in Bloemfontein, Free State

Background. Necrotising enterocolitis (NEC) is life-threatening with a rising incidence due to improved neonatal care. While researchers’ focus has shifted to causes, risk factors and preventative clinical strategies, little is known about the exact aetiology of NEC. Risk factors include the relationship between red blood cell transfusions (RBCTs) and the development of transfusion-associated NEC (TANEC) and peri-transfusion feeding, increasing the risk of TANEC. Objectives. Evaluate the relationship between RBCT and peri-transfusion feeding practices and the development of TANEC in very low birthweight (VLBW) neonates over 5 years. Methods. This was a retrospective analytical record review of all VLBW neonates admitted to two tertiary hospitals’ neonatal units in Bloemfontein, South Africa (SA), from 1 January 2012 - 31 December 2016. Results. The study population (n=1 426) had a median birthweight of 1 260 g and a median gestation age of 30 weeks. RBCTs were given to 41.9%, and NEC developed in 7.4%, of whom 47.6% had an RBCT (TANEC). Half (47.2%) were kept nil per os (NPO) around the transfusion. No association was found between NPO status and TANEC development (8.9% NPO patients, 7.9% non-NPO patients, p=0.6826). No significant differences regarding Modified Bell’s Staging were found between neonates who developed TANEC v. NEC. Conclusion. Optimising the administration of RBCTs and evidence-based feeding protocols is crucial in reducing TANEC’s impact on premature neonates.

Reduced Expression of REG4 as a Sign of Altered Goblet Cell Function in Necrotizing Enterocolitis.

Defective Goblet cells have been proposed to be involved in necrotizing enterocolitis (NEC). The aim was to study the expression of the Goblet cell marker REG4 and its potential involvement in NEC in preterm infants with and without NEC. Seventy histologically intact intestinal biopsies were studied: 43 were collected during surgery due to NEC (NEC group: 26.5 ± 3.0 weeks' gestational age [wGA]), and 27 from individuals who underwent surgery due to other conditions (Control group; 36.1 ± 4.5 wGA). The tissue samples were immunohistochemically stained for REG4. REG4 expression was quantified with a semiautomated digital image analysis and with clinical data compared between the groups. REG4 expression was lower in the NEC group than in the Control group (p = 0.035). Low REG4 expression correlated to the risk of NEC (p = 0.023). In a multivariable logistic regression analysis including GA and REG4 expression for NEC risk, only GA (p < 0.001) and not REG4 expression (p = 0.206) was associated with NEC risk. This study concludes that Goblet cell dysfunction may be involved in NEC development, as low expression of the Goblet cell marker REG4 was related to an increased NEC risk in preterm infants. Maturity could however not be excluded as a potential confounder for REG4 expression. · REG4 is a specific Goblet cell marker not yet studied in NEC.. · REG4 was quantified in intestinal biopsies from infants with and without NEC.. · REG4 expression was lower in infants with NEC, and expression seems to be maturity dependent..

Placenta and Intestinal Injury in Preterm Infants.

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal conditions affecting 6 to 10% of low-birth-weight infants and remains a leading cause of death. The risk factors associated with NEC are complex and multifactorial, including preterm birth and intrauterine exposure to inflammation and hypoxia. Chorioamnionitis has been associated with intestinal injury in animal and human clinical studies. This review presents current evidence about the clinical impact of the intrauterine environment on intestinal injury during pregnancy and postpregnancy. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus. Prospective multicenter studies, including accurate and precise clinical, maternal, and laboratory predictors (e.g., inflammatory biomarkers), will help identify the mechanisms associated with the placental pathology, the development of NEC, and the impact of in utero-triggered inflammation on the clinical outcomes. Filling the knowledge gap to link the inflammatory surge to postnatal life will aid in identifying at-risk infants for NEC in a timely manner and facilitate the development of novel immunomodulatory treatments or interventions to improve the outcomes of these vulnerable infants. KEY POINTS: · Placental inflammatory and vascular lesions are associated with NEC severity.. · Higher grade chorioamnionitis with a fetal response is associated with an increased risk of surgical NEC.. · There is a need for routine bedside utilization of placenta pathology in clinical decision-making..

RNF31-mediated IKKα ubiquitination aggravates inflammation and intestinal injury through regulating NF-κB activation in human and mouse neonates

AimsNeonatal necrotizing enterocolitis (NEC) is a leading cause of intestine inflammatory disease, and macrophage is significantly activated during NEC development. Posttranslational modifications (PTMs) of proteins, particularly ubiquitination, play critical roles in immune response. This study aimed to investigate the effects of ubiquitin-modified proteins on macrophage activation and NEC, and discover novel NEC-related inflammatory proteins. Materials and methodsProteomic and ubiquitin proteomic analyses of intestinal macrophages in NEC/healthy mouse pups were carried out. In vitro macrophage inflammation model and in vivo NEC mouse model, as well as clinical human samples were used for further verification the inhibitor of nuclear factor-κB kinase α (IKKα) ubiquitination on NEC development through Western blot, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry. Key findingsWe report here that IKKα was a new ubiquitin-modified protein during NEC through ubiquitin proteomics, and RING finger protein 31 (RNF31) acted as an E3 ligase to be involved in IKKα degradation. Inhibition of IKKα ubiquitination and degradation with siRNF31 or proteasome inhibitor decreased nuclear factor-κB (NF-κB) activation, thereby decreasing the expression of pro-inflammatory factors and M1 macrophage polarization, resulting in reliving the severity of NEC. SignificanceOur study suggests the activation of RNF31-IKKα-NF-κB axis triggering NEC development and suppressing RNF31-mediated IKKα degradation may be therapeutic strategies to be developed for NEC treatment.

Git2 deficiency promotes MDSCs recruitment in intestine via NF-κB-CXCL1/CXCL12 pathway and ameliorates necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.

Neonatal epithelial reparative capacity is enhanced by acellular placental extract in porcine models

Necrotizing enterocolitis (NEC) is a devastating condition with a ~30% mortality rate in pre-term, very low birth-weight infants. Premature infants lack vital in utero ingestion of amniotic fluid which accelerates intestinal maturation and reduces inflammation. Therefore, an acellular placental extract (PE) akin to amniotic fluid may be therapeutic for NEC. The objective of this study was to evaluate PE’s capacity to accelerate repair following or prevent the induction of NEC-like injury. We hypothesized that PE would enhance neonatal porcine intestinal epithelial cells’ capacity to repair in vitro and in vivo. NEC was induced in 12 piglets via pre-term cesarean delivery and hyperosmolar formula feeding. Prior to formula feeding, piglets were nil per os or enterally supplemented with PE. Tissue, collected at euthanasia, up to 72H after formula initiation, was evaluated grossly and histologically and with immunohistochemical staining for proliferation (Ki67), stem cell identity (Sox9), and apoptosis (CC3). Numerical outputs were assessed with Kolmogorov-Smirnov testing. PE’s effect on epithelial restitution was assessed with scratch assays performed on confluent monolayers derived from ~1-day old piglet ileum. Monolayers were pre-treated with either actin polymerization inhibitor, Latrunculin A, or a cell cycle inhibitor, hydroxyurea. After scratch, either media or PE in media was applied. Scratch-closure was monitored for 24H; percentage-closure was calculated and analyzed using 2-way ANOVA and Tukey multiple comparison. Scratch-wound leading-edge cells were examined for EdU and Ki67 immunofluorescent positivity which was evaluated using Kolmogorov-Smirnov analysis. Tight junction recovery was assessed using identically derived confluent monolayers grown on Transwell inserts and exposed to hypoxia (18H, 1%O2, 5%CO2). Following hypoxia, PE or media alone was added to the apical chamber. Transepithelial electrical resistance (TEER) was measured every 6-12H for 48H using a symmetrical disc electrode chamber. TEER rate of change was analyzed using a two-way ANOVA. For all analyses, significance was set at p&lt;0.05. In vivo PE administration resulted in reduced gross and histological NEC damage in treated compared to untreated piglets (p=0.02). Ki67 and Sox9 expression increased (p=0.71; p=0.93) and CC3 expression decreased with PE treatment (p=0.65). Evaluation of these markers in additional animals is pending. In vitro, PE expedited scratch wound closure (p&lt;0.05) and expanded proliferative cell number along scratch edges (EdU/DAPI, p&lt;0.05; Ki67+EdU/DAPI, p&lt;0.01). Other analyses are pending. PE application prevented gross NEC development in vivo and accelerated recovery in vitro. NIH #R44HD100243; #T32562967-39806. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Necrotizing enterocolitis: a potential protective role for intestinal alkaline phosphatase as lipopolysaccharide detoxifying enzyme.

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease. Its onset might be triggered by Toll-Like Receptor 4 (TLR4) activation via bacterial lipopolysaccharide (LPS). We hypothesize that a deficiency of intestinal alkaline phosphatase (IAP), an enzyme secreted by enterocytes that dephosphorylates LPS, may contribute to NEC development. In this prospective pilot study, we analyzed intestinal resection specimens from surgical NEC patients, and from patients undergoing Roux-Y reconstruction for hepatobiliary disease as controls. We assessed IAP activity via enzymatic stainings and assays and explored IAP and TLR4 co-localization through immunofluorescence. The study population consisted of five NEC patients (two Bell's stage IIb and three-stage IIIb, median (IQR) gestational age 25 (24-28) weeks, postmenstrual age at diagnosis 28 (26-31) weeks) and 11 controls (unknown age). There was significantly lower IAP staining in NEC resection specimens [49 (41-50) U/g of protein] compared to controls [115 (76-144), P = 0.03]. LPS-dephosphorylating activity was also lower in NEC patients [0.06 (0-0.1)] than in controls [0.3 (0.2-0.5), P = 0.003]. Furthermore, we observed colocalization of IAP and TLR4 in NEC resection specimens. This study suggests a significantly lower IAP level in resection specimens of NEC patients compared to controls. This lower IAP activity suggests a potential role of IAP as a protective agent in the gut, which needs further confirmation in larger cohorts.

Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development.

Biomarkers and predictors of postoperative necrotizing enterocolitis in neonates with duct-dependent congenital heart defects undergoing cardiac surgery: a cohort study

The development of necrotizing enterocolitis (NEC) in neonates with duct-dependent congenital heart defects (CHD) who underwent cardiac surgery is accompanied by high mortality. Analysis of predictors is necessary for understanding the pathophysiology of NEC and development of approaches for prevention to achieve favorable outcomes of cardiac surgery. The purpose of the study was to develop a prognostic model for predicting the development of NEC after cardiac surgery in neonates with duct-dependent CHD. Methods. A prognostic cohort study was performed that included full-term neonates with duct-dependent CHD who underwent cardiac surgery at the Almazov National Medical Research Center from January 2021 to September 2023. The outcome was the development/absence of stage IB-III NEC in the postoperative period. Biomarkers of NEC (intestinal fatty acid binding protein (i-FABP, ng/ml), claudin-3 (CLDN3, ng/ml), calprotectin (CALPR, ng/ml), ischemia modified albumin (IMA, ng/ml), vascular endothelial growth factor A (VEGF A, pg/ml)) were measured by ELISA in the blood serum before cardiac surgery and 12-14 hours after surgery. We also analyzed clinical characteristics of neonates, C-reactive protein levels, complete blood count, abdominal ultrasound, ejection fraction (EF, Teicholtz) in the preoperative and postoperative periods, surgical parameters, P(v-a)CO2/C(a-v)O2 upon arrival from the operating room, vasoactive inotropic score (VIS) and arterial blood lactate levels in the first 24 hours after surgery. The association between predictors and the development of NEC after cardiac surgery was assessed using univariate and multivariate logistic regression analysis. Internal validation of the model was performed using 10-fold cross-validation. Results. During the observation period, 187 neonates underwent surgical treatment of duct-dependent CHD, of which 32 children developed stage IB-III NEC in the postoperative period (17.1%), two neonates required surgical treatment of NEC (6.3%). After meeting the non-inclusion and exclusion criteria, two groups of patients were formed: a main group (30 neonates who developed stages IB-III NEC in the postoperative period, of which stage III NEC was in one neonate) and a comparison group (40 neonates without NEC). Groups were comparable by types of CHD. Predictors associated with NEC (univariate analysis): intrauterine growth retardation (IUGR), formula feeding before surgery, high levels of IMA before on the first postoperative day (POD), procedures performed before surgery (Rashkind procedure/valvuloplasty/stenting), lower EF in in the early postoperative period, a higher maximum level of VIS in the first 24 hours after surgery, as well as a higher level of IR in the superior mesenteric artery (SMA) and thickening of the intestinal wall on the first postoperative day (POD) Independent preoperative predictors of NEC (AUC of model 0.885, specificity 0.867): IUGR (OR 32.2 (1.4-730.3), p=0.029), formula feeding (OR 12.6 (2.6-60.2), p=0.002), IMA level before surgery (OR 1.03 (1.01-1.04), p=0.004), CLDN3 level before surgery (OR 0.5 (0.3-0.9), p=0.013). Independent early postoperative predictors of NEC: IMA level on 12-14 hour after surgery (OR 1.02 (1.01-1.03), p=0.030), P(v-a)CO2/C(a-v)O2 immediately after surgery (OR 2.3 (1.2-4.4), p=0.008), IR&gt;0.93 in SMA (OR 7.2 (1.6-32.4), p=0.011) and thickness of intestinal wall by ultrasound on POD 1 (OR 4.9 (1.3-19.2), p=0.021). Adding of VEGF A level (12-14 hour after surgery, negatively associated with NEC) to the model increased the specificity, but the predictor was not significant. AUC of postoperative model 0.862, specificity 0.800. The final model included preoperative (IUGR, formula feeding) and postoperative predictors (IMA, P(v-a)CO2/C(a-v)O2, IR of SMA&gt;0.93, intestinal wall thickness), AUC=0.921, specificity 0.83. Conclusion. The identified predictors indirectly indicate the role of hypoxia in the pathophysiology of NEC in term neonates with duct-dependent CHD. Breast milk feeding/mixed feeding in the preoperative period may help reduce the risk of NEC in the postoperative period. Low levels of CLDN3 before surgery were associated with the development of NEC, but the interpretation of the result is controversial.

Values of serum intestinal fatty acid-binding protein, fecal calprotectin, and fecal human β-defensin 2 for predicting necrotizing enterocolitis

BackgroundThis study aimed to assess the diagnostic potential of serum intestinal fatty acid-binding protein (I-FABP), fecal calprotectin (FC), and fecal human β-defensin 2 (hBD2) in predicting necrotizing enterocolitis (NEC) in preterm infants.MethodsA prospective cohort of neonates with a gestational age < 32 weeks, suspected of NEC, was enrolled between June 2021 and December 2022. Serum I-FABP, FC, and fecal hBD2 levels were measured upon NEC suspicion, and diagnosis was confirmed through radiological examination or surgical intervention. Diagnostic precision of serum I-FABP, FC, and fecal hBD2 was assessed using a logistic regression model with multiple variables.ResultsThe study included 70 neonates (45 males, 25 females), with 30 developing NEC (40% Stage III, n = 12; 60% Stage II, n = 18) and 40 in the control group. NEC patients exhibited significantly higher serum I-FABP and FC levels (4.76 ng/mL and 521.56 µg/g feces, respectively) than those with other diagnoses (1.38 ng/mL and 213.34 µg/g feces, respectively; p ˂ 0.05 for both biomarkers). Stage II NEC neonates showed elevated fecal hBD2 levels (376.44 ng/g feces) than Stage III NEC neonates and controls (336.87 ng/g and 339.86 ng/g feces, respectively; p ˂ 0.05). No such increase was observed in infants progressing to Stage III NEC. Using a serum I-FABP threshold of > 2.54 ng/mL yielded 76.7% sensitivity, 87.5% specificity, 82.1% positive predictive value (PPV), and 83.3% negative predictive value (NPV). For FC (cutoff > 428.99 µg/g feces), corresponding values were 76.7% sensitivity, 67.5% specificity, 63.9% PPV, and 79.4% NPV.ConclusionSerum I-FABP and FC levels are valuable for early NEC detection and provide insights into disease severity. Low fecal hBD2 levels suggest an inadequate response to luminal bacteria, potentially rendering these infants more susceptible to NEC development or exacerbation.

MiR-375-3p targets YWHAB to attenuate intestine injury in neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a significant contributor to neonatal mortality. This study aimed to investigate the role of high levels of miR-375-3p in breast milk in the development of NEC and elucidate its mechanism. Differential expression of miR-375-3p in the intestines of breast-fed and formula-fed mice was confirmed using real-time polymerase chain reaction (RT-PCR). NEC mice models were established, and intestinal injury was assessed using HE staining. RT-PCR and Western blot were conducted to examine the expression of miR-375-3p, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB), as well as the inflammatory in IEC-6 cells, and intestinal tissues obtained from NEC mice and patients. Flow cytometry and cell counting kit-8 (CCK-8) were employed to elucidate the impact of miR-375-3p and YWHAB on cell apoptosis and proliferation. Breastfeeding increases miR-375-3p expression in the intestines. The expression of miR-375-3p in NEC intestinal tissues exhibited a significant decrease compared to the healthy group. Additionally, the expression of interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) was higher in the NEC group compared to the control group. Down-regulation of miR-375-3p inhibited IEC-6 cell proliferation, increased apoptosis, and elevated secretion of inflammatory factors. Bioinformatics revealed that YWHAB may be a target of miR-375-3p. RT-PCR and Western blot indicated a down-regulation of YWHAB expression in intestines of NEC patients and mice. Furthermore, YWHAB was found to be positively connected with miR-375-3p. Knockdown miR-375-3p down-regulated YWHAB expression in cells. Inhibition of YWHAB exhibited similar effects to miR-375-3p in IEC-6 cells. YWHAB plasmid partially reverse cellular functional impairment induced by miR-375-3p knockdown. Breastfeeding elevated miR-375-3p expression in intestines in neonatal mice. MiR-375-3p leads to a decrease in apoptosis of intestinal epithelial cells, an increase in cell proliferation, and a concomitant reduction in the expression of inflammatory factors partly through targeting YWHAB.

Feeding Practices in Infants with Hematochezia and Necrotizing Enterocolitis on Acute Care Cardiology Units.

Infants with congenital heart disease (CHD) are at risk for developing both benign hematochezia and necrotizing enterocolitis (NEC). Despite these risks there are very few studies that investigate modifiable risk factors such as feeding practices. It remains unclear what feeding practices should be avoided due to higher incidence of CHD-NEC. We aim to assess the feeding practices across three high volume tertiary centers to establish a relationship between various feeding practices and development of NEC. A multicenter retrospective review of feeding practices at the time of documented hematochezia event that occurred between 1/2019 and 1/2021 in infants with CHD who were less than 6months of age. NEC was defined as Bells Stage 2 or greater. Age, weight, ventricular morphology, primary diagnoses, feeding route, feed change, and formula type were evaluated. 176 hematochezia events occurred in 121 patients, 72% of these events were considered benign hematochezia with the remaining 28% being true NEC. Single ventricle (SV) physiology (p < 0.05), younger age, < 45days of life, (p < 0.001), and feeding route were statistically associated with true NEC (p < 0.01). Formula type and recent change in feed administration were not associated with NEC. The caloric density of feeds at the time of hematochezia was nearing significance. The majority of hematochezia events are benign in nature, however, there should be heightened awareness in patients who are SV, younger in age, and those who are post-pylorically fed. There may be some risk in using higher caloric density feeds (> 24kcal/oz), however, additional research is needed to fully establish this relationship.

Gestational age-specific hematological features in preterm infants with necrotizing enterocolitis.

This study aimed to investigate gestational age-specific hematological features in preterm infants with necrotizing enterocolitis (NEC) and identify predictive hematological biomarkers for surgical NEC. We conducted a retrospective study comparing gestational age (GA)-specific clinical data between medical NEC (m-NEC) and surgical NEC (s-NEC) subgroups, stratified by GA as <28 weeks, 28 ≤ GA < 32 weeks, and 32 ≤ GA < 37 weeks. Multivariate logistic analysis and receiver operating characteristic curve were used to identify the independent predictors of s-NEC. In comparison to m-NEC at NEC onset, s-NEC infants exhibited the following findings: In GA < 28 weeks, s-NEC infants had lower platelet counts. In 28 ≤ GA < 32 weeks, lower absolute lymphocyte counts, and significant percent drop in platelets, lymphocytes, and monocytes were observed. In 32 ≤ GA < 37 weeks, lower absolute lymphocyte counts and significant percent drop in lymphocytes were found. Independent predictors were able to distinguish s-NEC from m-NEC. The area under the curve (AUC) for platelet counts in GA < 28 weeks was 0.880, while C-reactive protein in 28 ≤ GA < 32 weeks had an AUC of 0.889. The AUC for lymphocyte counts in 32 ≤ GA < 37 weeks was 0.892. This study identified hematological abnormalities in the development of NEC based on gestational age. Independent predictors may help clinicians distinguish surgical NEC from medical NEC. Necrotizing enterocolitis (NEC) patients with different gestational ages (GA) exhibit different hematological features and independent predictors of surgical NEC differ among different GAs. Our research made the current studies about peripheral hematological features with NEC more complete by analyzing peripheral data collected within 24 h of birth, at day 5-7, day 3-4, day 1-2 before NEC onset, at the time of NEC onset, day 1, day 2, day 3, day 4-5, day 6-7 after NEC onset. Our study is helpful to clinicians in developing a more detailed diagnostic strategy based on GA for the early identification of surgical NEC.

Analysis of Risk Factors for Necrotizing Enterocolitis (NEC) in Newborns: A Systematic Literature Review

Necrotizing enterocolitis (NEC) is a serious condition in newborns involving inflammation and intestinal necrosis. A number of risk factors have been identified, which complexly interact and contribute to the development of this condition. An in-depth understanding of these risk factors has major implications for the prevention, diagnosis and management of NEC in newborns. Babies born prematurely, especially before 32 weeks' gestation, have a higher risk of developing NEC. Low birth weight, regardless of prematurity status, remains a significant independent risk factor. Imbalances in blood circulation, especially in the intestines, can increase the risk of NEC. Hypotension and other medical conditions that affect blood flow to the intestines can be potential triggers. Infection and inflammation, both systemic and local, play a central role in the development of NEC. Bacterial contamination in the digestive tract can trigger an inflammatory response that contributes to the pathophysiological process of NEC. Formula feeding, especially in premature infants, is associated with an increased risk of NEC. The importance of providing exclusive breastfeeding and introducing foods slowly to protect the newborn's intestinal health. Excessive use of antibiotics or without clear indications can change the balance of intestinal microflora and increase the risk of NEC. The importance of judicious selection and use of antibiotics to minimize negative impacts on gut health.

Active polypeptide MDANP protect against necrotizing enterocolitis (NEC) by regulating the PERK-eIF2ɑ-QRICH1 axis

The effect of MDANP effects on ER stress signalling not well known or elucidated. Endoplasmic reticulum (ER) stress plays a critical role in necrotizing enterocolitis (NEC) pathogenesis through the PERK-eIF2ɑ-QRICH1 axis. The present study aimed to explore the protective effects of MDANP in NEC development. Firstly, a function screening was designed to identify the candidate peptides in human milk, and then the identified peptides were validated in NEC patients. In vivo, NEC was induced in mice pups and divided into four groups: (1) control group, (2) NEC group, (3) MDANP + NEC group, and (4) NS + NEC group. In vitro, lentivirus-mediated QRICH1 silencing, was used to transfect NCM460 cell lines, then stimulated with LPS. After LPS stimulation, cells were treated with chemically synthesized MDANP, and the essential proteins in the QRICH1 signalling pathway in cells were tested and compared. After the small-scale screening, a peptide (SKSKKFRRPDIQYPDATDED) named MDANP was determined as the principal peptide. Its protective effect against NEC through inhibiting the expression of ERS key proteins and impeding the intestinal cells’ apoptosis was observed in the animal models. Furthermore, the inhibitive effect of MDANP on apoptosis of intestinal epithelial cells through modulating the PERK-eIF2ɑ-QRICH1 ERS pathway was also confirmed in vitro. Taken together, our data suggest that MDANP effectively ameliorates apoptosis in NEC through attenuating PERK-eIF2ɑ-QRICH1.

Clostridium butyricum and Clostridium tyrobutyricum: angel or devil for necrotizing enterocolitis?

This study sheds light on that treatment with Clostridium tyrobutyricum but not Clostridium butyricum is entitled to protect against necrotizing enterocolitis (NEC) development potentially. The mechanisms behind the opposite effect on NEC may result in different modulation on the level of Akkermansia muciniphila, which is deeply associated with intestinal homoeostasis. Briefly, through improving the abundance of A. muciniphila to alleviate intestinal inflammation and enhance intestinal barrier integrity, C. tyrobutyricum supplement may become a promising therapy for NEC.

Incidence of Necrotizing Enterocolitis and an Assessment of Related Risk Factors and Outcomes

Necrotizing Enterocolitis (NEC), defined as inflammation of the intestines most commonly due to a bacterial cause, is a relatively rare condition widely encountered in premature infants. Established risk factors for developing NEC include low gestational age, extremely low birth weight, sepsis, and hypotension. However, studies have investigated other causes that may alter the gut microbiome, such as blood transfusions, antibiotic use, and co-morbid conditions. The study design is a retrospective cohort study, and patient data were collected from King Hamad University Hospital (KHUH) after receiving the necessary approvals. Patients included in this study were from 2012 to 2020. The variables assessed included gestational age, birth weight, hemoglobin and hematocrit levels, prenatal and postnatal antibiotic use, blood transfusions, other transfusion products the patients received, and blood culture results. A total of 16 patients were identified as having NEC after thoroughly reviewing their files, and the data were analyzed at the KHUH Research Department. Although a small sample size was involved in this study, antibiotic use was a significant factor in the development of NEC as antibiotics such as ampicillin, gentamicin, and cefotaxime have been shown to alter the gut microbiome, which can predispose a patient to the development of NEC, as was reflected in our study. We also observed a 10.4-time relative risk for developing NEC in patients who had received blood transfusions. The use of antibiotics in patients with NEC has been shown to increase the likelihood of developing the condition, especially with the predominance of Enterobacteriaceae. Although controversial, blood transfusions have also been associated with the development of NEC. Due to the fragile vascular system in patients with NEC, constant phlebotomies and the introduction of packed red blood cells can alter the levels of nitric oxide present, predisposing premature infants to hypoxic conditions and, therefore, the development of NEC.

The Impact of Stress, Microbial Dysbiosis, and Inflammation on Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on maternal factors. Utilizing human tissue plays a crucial role in enhancing our comprehension of the underlying mechanisms accountable for this devastating disease. In this review, we will discuss how maternal stress affects the pathogenesis of NEC and how changes in the intestinal microbiome can influence the development of NEC. We will also discuss the results of transcriptomics-based studies and analyze the gene expression changes in NEC tissues and other molecular targets associated with the pathogenesis of NEC.

Phototherapy: a new risk factor for necrotizing enterocolitis in very low birth weight preterm infants? aretrospective case-control study.

To investigate the association between phototherapy (PT) and the development of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. A retrospective case-control study was conducted on VLBW infants with or without NEC (stage IIA or greater) born at ≤35 weeks' gestation in a tertiary hospital over 7 years. Sample size calculation, trend test, as well as univariate and multiple logistic regression analyses were employed. A total of 824 VLBW infants were reviewed, with 74 cases and 122 controls finally enrolled. The odds of NEC increased with the duration and number of PT sessions. Exposure to >120 h and >4 instances of PT were significantly associated with NEC in multivariate analysis. This is the first study suggesting a potential association between PT and development of NEC in VLBW infants. This association needs further exploration.