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Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality among neonates and low birth weight children in the United States. Current treatment options, such as antibiotics and intestinal resections, often result in complications related to pediatric nutrition and development. This systematic review aimed to identify alternative dietary bioactive compounds that have shown promising outcomes in ameliorating NEC in vivo studies conducted within the past six years. Following PRISMA guidelines and registering in PROSPERO (CRD42023330617), we conducted a comprehensive search of PubMed, Scopus, and Web of Science. Our analysis included 19 studies, predominantly involving in vivo models of rats (Rattus norvegicus) and mice (Mus musculus). The findings revealed that various types of compounds have demonstrated successful amelioration of NEC symptoms. Specifically, six studies employed plant phenolics, seven utilized plant metabolites/cytotoxic chemicals, three explored the efficacy of vitamins, and three investigated the potential of whole food extracts. Importantly, all administered compounds exhibited positive effects in mitigating the disease. These results highlight the potential of natural cytotoxic chemicals derived from medicinal plants in identifying and implementing powerful alternative drugs and therapies for NEC. Such approaches have the capacity to impact multiple pathways involved in the development and progression of NEC symptoms. [ABSTRACT FROM AUTHOR]

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 6 months 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, < 45 days 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 (> 24 kcal/oz), however, additional research is needed to fully establish this relationship. [ABSTRACT FROM AUTHOR]

This study investigated the correlation between quantitative echocardiographic characteristics within 3 days of birth and necrotizing enterocolitis (NEC) and its severity in preterm infants. A retrospective study was conducted on 168 preterm infants with a gestational age of < 34 weeks. Patients were categorized into NEC and non-NEC groups. Clinical and quantitative cardiac ultrasound characteristics were compared using univariate and multivariate analyses. Additionally, the NEC group was divided into two subgroups according to Bell's staging, and the quantitative echocardiographic characteristics were compared. Overall, 141 preterm infants were included. Percentage of antenatal glucocorticosteroid administrations was lower in the NEC group than those in the control group. Umbilical vein cannulation, antibiotic duration, total red blood cell infusion, duration of total parenteral and total enteral nutrition, respiratory failure, hemodynamically significant patent ductus arteriosus, anemia, neutropenia, hyperbilirubinemia were significantly higher than those in the control group. The maximum shunt velocity and differential pressure (P) on the pulmonary side of the arterial conduit were significantly lower, whereas the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly higher in the NEC group. Antenatal glucocorticoid use and umbilical vein cannulation were protective factors against NEC. Anemia, hyperbilirubinemia, and lower P were risk factors for NEC. P was significantly lower and LVFS and LVES were significantly higher in preterm infants in the NEC II B-III group than those in the NEC II A group. Preterm infants with NEC have significant abnormalities in some quantitative features on echocardiography within 3 days after birth, and a lower P may be a risk factor for the development of NEC. [ABSTRACT FROM AUTHOR]

Purpose: Necrotizing enterocolitis (NEC) majorly affects premature infants, causing not only necrosis and inflammation but also feeding intolerance and gastrointestinal dysmotility, hinting at gut hormone secretion impairment. Particularly critical is the gestation period before 26 weeks where intestinal hormonal activity is partially developed, rendering preterm neonates highly susceptible to NEC. Emerging evidence suggests a role of gut hormones, especially glucagon-like peptides (GLP) in ileum development. Herein, the aim of this study was to determine the effect of modulating GLP signaling during normal intestinal development and during intestinal injury. Methods: We employed a human intestinal organoid (HIO) model derived from ileum tissue. After ethical approval, we obtained ileal biopsies from infants with NEC in uninjured (distant from site of NEC injury) and injured intestine (site of injury). After collection, crypt isolation was performed, and HIOs were cultured for 2–3 days before glucagon peptide agonists added daily in culture media. Organoids were harvested and analyzed for morphological measures of maturation including organoid size and budding. Results: Within the same patient, injured HIOs had a decreased budding compared to uninjured HIOs. Treatment with GLP agonists improved morphology and promoted maturation compared to the untreated organoid in both uninjured and injured HIOs. Conclusion: Patient-derived organoids provide a suitable ex vivo model to study NEC pathogenesis. Increasing GLP signaling in HIOs enhanced maturation of organoids derived from uninjured and injured neonatal human intestine. Further studies are underway to assess in vivo, the efficacy of GLP agonist administration in NEC. This study opens the way to future development of precision medicine in the treatment of NEC. [ABSTRACT FROM AUTHOR]

Objective Necrotizing enterocolitis (NEC) classically is diagnosed by radiographic demonstration of pneumatosis intestinalis/portal venous gas (PI/PVG). This study examines clinical characteristics of NEC confirmed by independent evaluation of abdominal radiographs, taken for clinical signs of NEC, or by pathologic findings at laparotomy or autopsy (confirmed NEC [cNEC]). Study Design The investigated cohort included 1,382 extremely low birth weight (BW) infants (BW range: 500–1,000 g) with median 27 weeks (range: 23–32) gestational age (GA) at birth. They were randomized into the placebo-controlled "Connection Trial" of the new biological drug candidate IBP-9414 with cNEC as one primary endpoint. Results Total 119 infants (8.6%) had cNEC diagnosed at median 14 days of age by confirming PI/PVG at X-ray adjudication (n = 111) and/or by surgery/autopsy (n = 21). Sixteen percent of cNEC cases died. Adverse events of NEC were reported in 8.5% of infants and 4.1% had NEC diagnosed by radiology and surgery/autopsy at the participating centers. Regression analyses showed that the risk of cNEC decreased by 11 to 30% for every 100-g increment in BW and single-week increment in GA and associated cNEC with odds ratios (ORs) > 2.0 for gastrointestinal (GI) perforation and obstruction, hypotension, hypokalemia, hypophosphatemia, and death. Comparing risks of cNEC in infants below and above 750-g BW showed higher ORs (2.7–4.3) for GI perforation, hypotension, hypokalemia, and renal complications in the smaller infants, whereas the bigger infants had higher ORs (1.9–3.2) for serious non-GI events, late-onset sepsis (LOS), and death. Predictors of cNEC (hazard ratio, HR > 1.5) included serious non-GI events (mainly infections), hyponatremia, and hyperglycemia, whereas the HR was 0.52 for intravenous antibiotics. After cNEC diagnosis, there were higher rates of GI perforation and obstruction, hypotension, hypokalemia, and LOS. Conclusion Independent adjudication of abdominal radiographs increased radiological recognition of NEC and proved to be feasible in a multicenter study setting as well as able to diagnose clinically relevant NEC. Key Points Independent adjudication of abdominal radiographs in ELBW infants increased NEC recognition. Risk of NEC decreased by 11 to 30% with every 100-g increment in BW and GA week. In infants with BW 750 to 1,000 g, the risk of death from NEC was almost twice that in infants with BW 500 to 749 g Infants with NEC received antibiotics during one-third and parenteral nutrition during half of the first 7 postnatal weeks. [ABSTRACT FROM AUTHOR]

Objective 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. Study Design 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. Results 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. Conclusion 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. Key Points 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. [ABSTRACT FROM AUTHOR]

The use of Santulli enterostomy (SE) for necrotizing enterocolitis (NEC) has been limited to a small number of studies involving a small number of patients and no control group. Our study aimed to compare the clinical safety and efficacy of Santulli enterostomy with those of single- or double-lumen enterostomy for neonatal NEC through a retrospective cohort study. One hundred ten patients who met the criteria were divided into an SE group (64 patients) and a conventional enterostomy (CE) group (46 patients). The CE group underwent single- or double-lumen enterostomy. There were no significant differences in complication rates or prognoses between the two groups after either procedure. Although the stoma was positioned higher in the SE group, the length of the unused small intestine (USI) was not significantly different. Multivariate analysis revealed that the length of the USI influenced the likelihood of malnutrition after enterostomy (OR = 1.108, P = 0.008). After stoma closure, compared with those in the CE group, the operation time, intestinal recovery time, fasting time, hospitalization time, intraoperative blood loss volume and the incidence of complications requiring surgical reintervention was significantly lower in the SE group. In conclusion, Santulli enterostomy is not only a safe treatment option for NEC but also an effective method for increasing the length of the small intestine after enterostomy, thereby improving the patient's postoperative nutritional status. In addition, the procedure is associated with good recovery and a reduced incidence of surgical reintervention after stoma closure. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to elucidate the roles of the PI3K-Akt signaling pathway and enterocyte apoptosis in necrotizing enterocolitis (NEC) pathogenesis and investigate the impact of vitamin A intervention on these factors. Methods: We employed an NEC mouse model and administered vitamin A treatment. Retinol levels in mouse blood were quantified using ELISA. Intestinal cell apoptosis in NEC mice was assessed via the TUNEL assay. We evaluated mRNA and protein expressions of Bcl-2, Bax, cytochrome C (CytoC), Caspase 3, and PI3K/Akt signaling pathway components using qPCR and western blotting. Results: In NEC models, PI3K, Akt, and Bcl-2 were downregulated, accompanied by upregulated Bax, CytoC, and Caspase 3 at both mRNA and protein levels. These molecular changes were associated with an increase in enterocyte apoptosis in the NEC models. Vitamin A supplementation increased PI3K, Akt, and Bcl-2 expression while decreasing Bax, CytoC, and Caspase 3 levels in the NEC models, resulting in reduced apoptosis. Conclusion: Vitamin A has the potential to mitigate enterocyte apoptosis in NEC by upregulating the PI3K/Akt signaling pathway and modulating apoptotic signals, providing new insights into the inhibitory effect of vitamin A on enterocyte apoptosis in NEC. [ABSTRACT FROM AUTHOR]

Excessive autophagy has been implicated in the pathogenesis of necrotizing enterocolitis (NEC), yet the molecular underpinnings of the autophagy-lysosomal pathway (ALP) in NEC are not well characterized. This study aimed to elucidate alterations within the ALP in NEC by employing RNA sequencing on intestinal tissues obtained from affected infants. Concurrently, we established animal and cellular models of NEC to assess the therapeutic efficacy of itaconic acid (ITA). Our results indicate that the ALP is significantly disrupted in NEC. Notably, ITA was found to modulate the ALP, enhancing autophagic flux and lysosomal function, which consequently alleviated NEC symptoms. Further analysis revealed that ITA's beneficial effects are mediated through the promotion of TFEB nuclear translocation, thereby augmenting the ALP. These findings suggest that targeting the ALP with ITA to modulate TFEB activity may represent a viable therapeutic approach for NEC. [Display omitted] • Autophagy is active and lysosomal activity is compromised in NEC. • The autophagy-lysosomal pathway is impaired in NEC, which correlated with reduced TFEB expression levels. • Itaconic acid can prevent intestinal epithelial barriers and inflammation to ameliorate NEC. • Itaconic acid increases TFEB nuclear translocation, enhancing the autophagy-lysosomal pathway and correcting dysregulated autophagy. [ABSTRACT FROM AUTHOR]

Background: The oropharyngeal administration of colostrum (OAC) in neonates has several benefits. Purpose: To investigate the short-term outcomes of OAC in preterm neonates. Methods: We performed this 2-arm, double-blind, placebo-controlled randomized trial at a tertiary neonatal center in Iran in 2021-2023. The intervention and control arms received 0.2 mL of their mother's colostrum or distilled water via oropharyngeal administration every 6 hours for 3 days starting from birth until 72 hours of age. The main study outcomes were neonatal death, the incidence of necrotizing enterocolitis, sepsis, retinopathy of prematurity (ROP), length of hospital stay, and period to full enteral feeding. A regression analysis was used to adjust for possible confounders. Results: A total of 126 neonates (mean gestational age, 30.05 weeks) were randomized to the intervention and placebo groups (n=63 each) and had a mean±standard deviation weight of 1,247±193 g versus 1,156±215 g (P=0.013) and 1- and 5-min Apgar scores of 6.35 versus 5.38 (P=0.003) and 7.84 versus 7.13 (P=0.001), respectively. The mortality rate was 12.7% in the intervention group versus 14.3% in the placebo group (P=0.794). The necrotizing enterocolitis rate was significantly lower in the intervention versus placebo arm (11.1% vs. 28.6%, respectively, P=0.010), as was the clinically suspected sepsis rate (15.9% vs. 39.7%, respectively, P=0.004). The ROP and bronchopulmonary dysplasia rates did not differ significantly between groups after the adjustment for confounders. The mean length of hospital stay was shorter in the intervention group (26.1 days vs. 37.32 days, P=0.023). Moreover, the mean duration of antibiotic therapy and period to full feeding were significantly shorter in the intervention group. Conclusion: OAC could effectively decrease the incidence of complications in preterm infants and facilitate earlier patient discharge. [ABSTRACT FROM AUTHOR]

L-citrulline (L-CIT), a precursor to L-arginine (L-ARG), is a key contributor to the nitric oxide (NO) signaling pathway. Endothelial dysfunction, characterized by deficient nitric oxide synthesis, is implicated in the pathogenesis of various neonatal conditions such as necrotizing enterocolitis (NEC) and bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH). This review summarizes the current evidence around the possible role of L-CIT supplementation in the treatment of these conditions. Detoxification of endogenously produced superoxide radicals is inadequate in preterm infants due to immature antioxidants that leads to the production of peroxynitrite, a reactive oxygen-free radical that is cytotoxic and causes damage to organelles and cellular membranes, further disrupting the coupling of endothelial NO synthase enzyme and the generation of high levels of reactive nitrogen and oxygen species. Animal studies in lipopolysaccharide-induced models of chorioamnionitis and hyperoxia- and inflammation-induced BPD-PH in rodent lung models revealed that L-CIT supplementation significantly mitigated structural changes in the pulmonary vasculature, preserved alveolar growth, and increased vascular endothelial growth factor gene expression, highlighting the anti-inflammatory and antioxidant effects of L-CIT supplementation. Similar benefits were noted in newborn piglet models of chronic hypoxia-induced PH and NEC. Pharmacokinetic studies in neonates have shown doses of 100–300 mg/kg/day to be safe and well tolerated. A few studies have shown the beneficial effects of L-CIT supplementation in pulmonary hypertension secondary to congenital heart disease, but evidence of efficacy in the neonatal population is lacking. While L-CIT shows promise in the treatment of various neonatal conditions, adequately powered studies to evaluate the safety and efficacy of L-CIT supplementation post-surgical NEC and BPD ± PH in the extremely preterm population are needed to translate this novel therapy to clinical practice. [ABSTRACT FROM AUTHOR]

Objective: The analysis of abdominal radiography is essential for the diagnosis and management of necrotizing enterocolitis (NEC) in newborns (NB). Studies, however, show a lack of agreement among physicians in the interpretation of images. This study aims to evaluate the agreement in the radiological interpretation of the NEC between examiners from different specialties (interexaminer analysis) and between the same examiner at different times (intraexaminer analysis). Methods: Cross-sectional study for concordance analysis using plain radiographs of the abdomen of NB with suspected or confirmed NEC. The study included two neonatologists (Neo), two surgeons (SU), and two radiologists (RD). The participants filled out a form with questions about the radiographic findings; regarding the presence of intestinal loop distension, the specialists answered subjectively (yes or no) and objectively (calculation of the ratio between loop diameter and lumbar vertebrae measurements). Kappa coefficients were calculated for agreement analysis. Results: A total of 90 radiological images were analyzed. For the interexaminer evaluation, the agreement was low (kappa<0.4) in 30 % of the answers (Neo versus SU), 38 % (Neo versus RD), and 46 % (SU versus RD). In the intraexaminer evaluation, the neonatologist and the surgeon presented substantial or almost perfect agreement in 92 % of the answers, and the radiologist in 77 %. In the evaluation of intestinal loop distention, the greatest agreement between the specialties occurred when done objectively. Conclusion: The results confirmed the low intra- and interexaminer agreement in the radiological analysis of the NEC, reinforcing the importance of standardizing the methods of radiological interpretation of the disease. [ABSTRACT FROM AUTHOR]

Introduction: This study investigates risk factors and surgical outcomes in pediatric patients with congenital heart defects (CHD) who develop ischemic colitis (IC). Previous research indicates a higher IC risk in very low birth weight neonates with CHD. Methods: A retrospective analysis compared an IC-CHD group to a CHD-only group. Key variables included gestational age, birth weight, multiple pregnancies, prematurity, APGAR scores, cardiac and surgical characteristics, Aristotle-Score, and mortality rates. Surgical outcomes such as bowel resection and stoma procedures were also evaluated. Results: IC-CHD exhibited significantly lower gestational ages and birth weights, with higher rates of multiple pregnancies and prematurity. APGAR scores were notably lower. Cardiac and surgical data showed more frequent ECMO use and shorter cardiopulmonary bypass durations in the IC-CHD group. High rates of bowel resection highlighted severe gastrointestinal involvement. Mortality was significantly higher in IC-CHD with elevated Aristotle scores correlating with poorer outcomes. Conclusion: Gestational age, birth weight, and initial health status are critical in predicting IC risk and surgical outcomes in pediatric patients with CHD. The significantly higher mortality and complex surgical needs in the IC-CHD group underscore the necessity for vigilant monitoring and tailored interventions. Development of targeted therapeutic strategies adjustment for confounding factors in future studies is needed. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a severe inflammatory and necrotizing disease of the intestine that primarily affects the neonates, particularly premature infants. It has a high incidence of approximately 8.9% in extremely preterm infants, with a mortality rate ranging from 20 to 30%. In recent years, exosomes, particularly those derived from breast milk, have emerged as potential candidates for NEC therapy. Human breast milk-derived exosomes (BME) have been shown to enhance intestinal barrier function, protect intestinal epithelial cells from oxidative stress, promote the proliferation and migration of intestinal epithelial cells, and reduce the severity of experimental NEC models. As a subset of extracellular vesicles, BME possess the membrane structure, low immunogenicity, and high permeability, making them ideal vehicles for the treatment of NEC. Additionally, exosomes derived from various sources, including stem cells, intestinal epithelial cells, plants, and bacteria, have been implicated in the development and protection of intestinal diseases. This article summarizes the mechanisms through which exosomes, particularly BME, exert their effects on NEC and discusses the feasibility and obstacles associated with this novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionsTo assess the efficacy of the DIGIROP-Birth algorithm in identifying infants at risk for developing retinopathy of prematurity (ROP).In a retrospective study, we included preterm infants over 11 years, 2010–2020, meeting the inclusion criteria for the DIGIROP-Birth calculator (24 + 0/7 to 30 + 6/7 weeks of gestational age). We assessed the validity of DIGIROP-Birth using receiver-operating characteristic (ROC) curves and calculated area-under-curve (AUC), sensitivity, specificity, and positive and negative predictive values.897 infants were included in the analysis. The median age of the first ophthalmological examination was 40 days (IQR 32–50), the median gestational age was 198 days (IQR 185–209; corresponding to 28 + 2/7 gestational weeks), median birth weight was 1000 g (IQR 790–1300). Of 897 screened children, 458 (51.1%) were diagnosed with ROP, and 34 of 897 (3.8%) required treatment.Analysis of ROP requiring treatment predicted by DIGIROP showed an AUC of 0.860 [95%-CI 0.795–0.925]. An equilibrium of sensitivity and specificity existed at a probability of 4.12%. The positive predictive value was 10.95%, and the negative predictive value was 99.36%. Independent significant peri- and postnatal risk factors were emergency cesarean section and mass blood transfusions.The DIGIROP-Birth calculator showed good predictive power in our studied population, with an incidence of 3.79% for therapy-requiring ROP. Peri- and postnatal risk factors should be included in ROP screening. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a devastating disease observed in premature infants, characterized by intestinal ischemia and inflammation. Hypoxia‐inducible factor‐1 alpha (HIF‐1α), a master regulator of the cellular response to hypoxia and ischemia, plays a critical role in NEC pathogenesis. However, the precise mechanisms by which HIF‐1α influences the intestines in NEC remain poorly understood. Herein, we aimed to explore the role of HIF‐1α in NEC using a transgenic mouse model. We induced NEC in neonatal mice from postnatal day 5 to 9, and various parameters, including intestinal injury, oxidative stress, inflammatory responses, intestinal epithelial cell (IEC) proliferation, and apoptosis, were assessed. The results confirmed that the absence of intestinal epithelial HIF‐1α increased the susceptibility of mice to NEC‐induced intestinal injury, as evidenced by increased oxidative stress, inflammatory responses, apoptosis, and inhibition of proliferation. Additionally, we observed an upregulation of the Toll‐like receptor 4 (TLR4)/nuclear factor kappa B (NF‐κB) signaling pathway specifically in the intestines of mice lacking HIF‐1α in IECs (HIF‐1αΔIEC) with NEC. These findings provide crucial insights into the role of HIF‐1α in regulating intestinal oxidative stress and inflammation to maintain intestinal homeostasis, highlighting its association with the TLR4–NF‐κB signaling pathway. Furthermore, these insights might lead to the identification of novel therapeutic targets for the treatment of NEC. [ABSTRACT FROM AUTHOR]

Bovine colostrum (BC), the first milk secreted by mammals after birth, is a trending alternative source for supplementing infants and children, offering benefits for gut and immune health. Its rich components, such as proteins, immunoglobulins, lactoferrin, and glycans, are used to fortify diets and support development. Preterm development is crucial, especially in the maturation of essential systems, and from 2010 to 2020, approximately 15% of all premature births occurred at less than 32 weeks of gestation worldwide. This review explores the composition, benefits, and effects of BC on general infants and children, along with preterm infants who require special care, and highlights its role in growth and development. BC is also associated with specific pediatric diseases, including necrotizing enterocolitis (NEC), infectious diarrhea, inflammatory bowel disease (IBD), short-bowel syndrome (SBS), neonatal sepsis, gastrointestinal and respiratory infections, and some minor conditions. This review also discusses the clinical trials regarding these specific conditions which are occasionally encountered in preterm infants. The anti-inflammatory, antimicrobial, immunomodulatory, and antiviral properties of BC are discussed, emphasizing its mechanisms of action. Clinical trials, particularly in humans, provide evidence supporting the inclusion of BC in formulas and diets, although precise standards for age, feeding time, and amounts are needed to ensure safety and efficacy. However, potential adverse effects, such as allergic reactions to caseins and immunoglobulin E, must be considered. More comprehensive clinical trials are necessary to expand the evidence on BC in infant feeding, and glycans, important components of BC, should be further studied for their synergistic effects on pediatric diseases. Ultimately, BC shows promise for pediatric health and should be incorporated into nutritional supplements with caution. [ABSTRACT FROM AUTHOR]

Chorioamnionitis (CAM) refers to an inflammatory condition resulting from pathogen infection of the chorion, amnion, and decidua of the placenta. CAM is associated with preterm birth and an increased risk of adverse outcomes in neonates, including respiratory distress syndrome, bronchopulmonary dysplasia, and elevated perinatal mortality rates. Therefore, early identification, diagnosis, and treatment of CAM are crucial for optimizing therapeutic success in pregnant women and newborns while enhancing the quality of life and disease prognosis for neonates. This review aims to elucidate the correlation between CAM and neonatal diseases as well as provide insights into current prevention strategies and treatment approaches to offer novel clinical perspectives for improved management of CAM⁃related newborns. [ABSTRACT FROM AUTHOR]

Background: Over the past two decades, gut microbiota has demonstrated unprecedented potential in human diseases and health. The gut microbiota in early life is crucial for later health outcomes. This study aims to reveal the knowledge collaboration network, research hotspots, and explore the emerging trends in the fields of infant and gut microbiome using bibliometric analysis. Method: We searched the literature on infant and gut microbiome in the Web of Science Core Collection (WOSCC) database from 2004 to 2024. CiteSpace V (version: 6.3.R1) and VOSview (version: 1.6.20) were used to display the top authors, journals, institutions, countries, authors, keywords, co-cited articles, and potential trends. Results: A total of 9,899 documents were retrieved from the Web of Science Core Collection. The United States, China, and Italy were the three most productive countries with 3,163, 1,510, and 660 publications. The University of California System was the most prolific institution (524 publications). Van Sinderen, Douwe from University College Cork of Ireland was the most impactful author. Many studies have focused on atopic dermatitis (AD), necrotizing enterocolitis (NEC), as well as the immune mechanisms and microbial treatments for these diseases, such as probiotic strains mixtures and human milk oligosaccharides (HMOs). The mother-to-infant microbiome transmission, chain fatty acids, and butyrate maybe the emerging trends. Conclusion: This study provided an overview of the knowledge structure of infant and gut microbiome, as well as a reference for future research. [ABSTRACT FROM AUTHOR]

Objective: Necrotizing enterocolitis (NEC) is the leading cause of death among premature infants, and there is a lack of specific early diagnostic markers. Blood sampling is expected to better reflect pathophysiological and metabolic changes in systematic illness, but there is a risk of iatrogenic anemia, especially in premature infants. Dried blood spots technique seems to have important advantages compared to whole blood sampling as it requires only 12–15 μL as sample volume. This study aimed to investigate the special metabolomics of preterm neonates at high risk of NEC using dried blood spots. Methods: Cases and controls were strictly matched 1:1. Dried blood spots (n = 32, 16 cases–16 controls) from newborn screening were subjected to LC–MS/MS. Metabolomic data were analyzed by orthogonal partial least squares-discriminant analysis (OPLS-DA) and univariate/multivariate statistical analysis. Results: Compared to the control group, the NEC group had a significant reduction in seven amino acids (glycine, alanine, threonine, proline, ornithine, lysine, and asparagine). Conclusions: The metabolic profile of neonates with NEC differs significantly from that of controls, making possible their separation with the use of targeted (LC–MS/MS) dried blood spots-based metabolomic analysis. Seven specific markers were identified for early detection and intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bowel ultrasound (US) is one of the methods used to enhance diagnostic accuracy of necrotizing enterocolitis (NEC) and its associated complications in premature newborns. AIM: To explore the diagnostic accuracy of bowel US in extremely low birth weight (ELBW) infants with NEC. METHODS: A single-center retrospective case-control study included 84 extremely low birth weight (ELBW) infants. The infants were divided into three groups: Group 1 –infants with NEC (n = 26); Group 2 –infants with feeding problems (n = 28); Group 3 –control group (n = 30). RESULTS: The specific bowel US findings in premature newborns with NEC (stage 3) included bowel wall thinning, complex (echogenic) ascites, and pneumoperitoneum, p < 0.05. The diagnostic effectiveness of these sonographic signs was 96.8% (sensitivity 75.0% and specificity 97.6%), p < 0.05. These findings with high specificity were associated with the need for surgical intervention, poor outcomes, or increased mortality. Stage 2 NEC which did not require surgery showed impaired differentiation of the bowel wall layers, absent or decreased bowel peristalsis, pneumatosis intestinalis, portal venous gas, or simple ascites, with a diagnostic accuracy of 82.9% (sensitivity 55.6%, specificity 91.4%, p < 0.05). CONCLUSIONS: Bowel US can be used as an adjunct to abdominal radiography to aid in the diagnosis of infants with suspected NEC by providing more detailed evaluation of the intestine. [ABSTRACT FROM AUTHOR]

Objectives: Necrotizing enterocolitis (NEC) is a common and sometimes fatal disease affecting premature infants. Elevated formate has been found in the stool of patients with NEC. Sodium formate (NaF) is used to explore the role of formate in the intestinal epithelial injury. Methods: In this study, 150 mM NaF solution was intraluminally injected in 14-day-old and 28-day-old mice. Mice were sacrificed after 24 h of feces collection, and the blood and small intestinal tissues were collected to detect the pathological damage of intestinal tissue, intestinal permeability, oxidative stress indicators including SOD, HO-1, MDA, and 4-HNE, inflammatory cytokines including IL-1β, TNF-α and IL-6, mitochondrial function such as ATP and PGC-1α in mice intestinal tissue, indicators of the cell death modes including necroptosis-related protein RIPK1 and p-MLKL, and apoptosis- related protein cleaved-caspase-3 and p-AKT (S473). Results: NaF treatment significantly damaged intestinal epithelial tissue and barrier function, caused mitochondrial dysfunction, manifesting as decreased ATP and PGC-1α levels, increased lipid peroxidation products MDA and 4-HNE, depleted antioxidant enzyme SOD, and upregulated the expression of HO-1. Furthermore, NaF treatment induced inflammatory responses by promoting the release of IL-1β, IL-6 and TNF-α in a development-dependent manner, eventually inducing necroptosis and apoptosis. Conclusions: Formate may be a source of metabolic intestinal injury contributing to the pathogenesis of NEC in human newborns. [ABSTRACT FROM AUTHOR]

Human milk (HM) is rich in bioactive factors promoting postnatal small intestinal development and maturation of the microbiome. HM is also protective against necrotizing enterocolitis (NEC), a devastating inflammatory condition predominantly affecting preterm infants. The HM glycosaminoglycan, hyaluronan (HA), is present at high levels in colostrum and early milk. Our group has demonstrated that HA with a molecular weight of 35 kDa (HA35) promotes maturation of the murine neonatal intestine and protects against two distinct models of NEC. However, the molecular mechanisms underpinning HA35-induced changes in the developing ileum are unclear. CD-1 mouse pups were treated with HA35 or vehicle control daily, from P7 to P14, and we used network and functional analyses of bulk RNA-seq ileal transcriptomes to further characterize molecular mechanisms through which HA35 likely influences intestinal maturation. HA35-treated pups separated well by principal component analysis, and cell deconvolution revealed increases in stromal, Paneth, and mature enterocyte and progenitor cells in HA35-treated pups. Gene set enrichment and pathway analyses demonstrated upregulation in key processes related to antioxidant and growth pathways, such as nuclear factor erythroid 2-related factor-mediated oxidative stress response, hypoxia inducible factor-1 alpha, mechanistic target of rapamycin, and downregulation of apoptotic signaling. Collectively, pro-growth and differentiation signals induced by HA35 may present novel mechanisms by which this HM bioactive factor may protect against NEC. [ABSTRACT FROM AUTHOR]

Aim Necrotizing enterocolitis (NEC) is an important disease which particularly affects premature babies. Although its pathogenesis is not fully explained, it is thought that the mucosal barrier of the intestine is disrupted. Sucralfate is a cytoprotective drug which supports the mucosal barrier. This study aimed to investigate the effects and mechanisms of sucralfate on enterocytes in an in vitro NEC model. Materials and Methods Intestinal epithelial cells were cultured. NEC was created with lipopolysaccharide (LPS). Sucralfate dose and concentration (106 µL/cm2 2:1 diluted) were determined according to the results of the cell viability test. Control group: This was the cell culture without treatment. Sham group: Only sucralfate was applied to the cell culture. NEC group (NG): Only LPS was applied to the cell culture. Treatment group (TG): the cell culture was first treated with LPS and then sucralfate. Prophylaxis group (PG): First sucralfate and then LPS were applied to the cell culture. Terminal deoxynucleotidyl transferase dUTP end-labeling (TUNEL), caspase 3-8-9, RIPK 1-3, MLKL, occludin, claudin, ICAM and MadCAM were investigated immunohistochemically. Differences between the groups were compared via the one-way ANOVA test. Results TNF-α and IL-8 levels were higher in the NG (p<0.05). TUNEL positive cells were 65.6±8.2% in the NG and 15.4±3.2% in the TG (p<0.05). Caspase-8,9 and RIPK1 were higher in the NG (p<0.05). The RIPK3 level was low in the NG (p<0.05). MLKL was high in the NG, low in the TG and PG (p<0.05). ICAM-1 was not significantly different between groups. MadCAM-1 was higher in the NG than in the TG and PG (p<0.05). Occludin expression was high and claudin expression was low in the TG (p<0.05). Conclusion In the vitro NEC model, apoptosis and necroptosis and the expression of cell adhesion molecules change. Sucralfate helps regulate apoptotic - necroptotic activity and cell adhesion molecules. The prophylactic administration of sucralfate does not appear to be as effective as therapeutic administration. Keywords:Necrotizing enterocolitis, sucralfate, cell culture, apoptosis, necroptosis, cell adhesion molecules: [ABSTRACT FROM AUTHOR]

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Background/Objectives: Research on the roles of stem cells in necrotizing enterocolitis (NEC) has primarily focused on the effects of bone marrow- and amniotic fluid-derived stem cells in mitigating the clinical manifestations of the disease. However, the potential of adipose tissue-derived stem cells (ADSCs) remains unexplored in this context. The aim of this study was to evaluate the therapeutic potential of ADSC administration during the active inflammatory phase of NEC, with a specific focus on reducing the levels of the inflammatory cytokines IL-1 and IL-6. Methods: A self-modified hypoxia–hypothermia–formula feeding rat NEC model was employed. A total of 117 rat pups were divided into two groups: a treatment group (NEC-ADSC, n = 55) and a control group (NEC-PLCB (placebo), n = 62). In the NEC-ADSC group, ADSCs were administered intraperitoneally 24 h into the NEC protocol. After 72 h, bowel and fluid samples were collected for analysis. Results: The analysis revealed no significant effect on NEC histopathology (p = 0.347) or on the levels of IL-1 and IL-6 (p = 0.119 and p = 0.414, respectively). Conclusions: The administration of adipose tissue-derived stem cells after the onset of necrotizing enterocolitis does not reduce the levels of inflammatory cytokines IL-1 and IL-6, nor does it influence the histopathological outcomes of the disease in the rat model. Further research is needed to explore the potential therapeutic role of adipose tissue-derived stem cells in the treatment of necrotizing enterocolitis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Necrotizing enterocolitis (NEC), a devastating neonatal gastrointestinal disease mostly seen in preterm infants, lacks accurate prediction despite known risk factors. This hinders the possibility of applying targeted preventive therapies. This study explores the use of vital signs, including cerebral and splanchnic oxygenation, measured with near-infrared spectroscopy in early NEC prediction. Methods: Several machine learning algorithms were trained on data from very preterm patients (<30 weeks gestational age). Time Series FeatuRe Extraction on the basis of scalable hypothesis tests (TSFRESH) extracted significant features from the vital signs of the first 5 postnatal days. We present the F1-scores and area under the precision-recall curve (AUC-PR) of the models. The contribution of separate vital signs to the selected TSFRESH features was also determined. Results: Among 267 patients, 32 developed NEC Bell's stage > 1. Using a 1:4 NEC:control ratio, support vector machine and logistic regression predicted NEC better than extreme gradient boosting regarding the F1-score (0.82, 0.82, 0.76, resp., p = 0.001) and AUC-PR (0.82, 0.83, 0.77, resp., p < 0.001). Splanchnic and cerebral oxygenation contributed most to the prediction (40.1% and 24.8%, resp.). Conclusions: Using vital signs, we predicted NEC in the first 5 postnatal days with an F1-score up to 0.82. Splanchnic and cerebral oxygenation were the most contributing vital predictors. This pioneering effort in early NEC prediction using vital signs underscores the potential for targeted preventive measures and also emphasizes the need for additional data in future studies. [ABSTRACT FROM AUTHOR]

Advances in pediatric surgery, intensive care, and anesthesiology have significantly improved the outcomes of surgical treatment of full-term and premature infants with intestinal malformations and necrotizing enterocolitis (NEC). The main challenges in treating children of this complex group today lie in improving diagnostics, choosing treatment tactics, and ensuring the postoperative period. Monoamine oxidase (MAO) is a mitochondrial enzyme that catalyzes oxidative deamination of biogenic and xenobiotic monoamines, including those in intestinal wall cells and tissues. It can be a prognostic and diagnostic marker of the effectiveness and rate of intestinal recovery in the postoperative period, and also serve as a point of application for pharmacological correction. The aim of the study is to determine the activity of intestinal MAO in children of the first year of life with surgical pathology. Material and methods. The study included 24 patients with colon and small intestine pathologies, aged from 1 day to 3 months, who were treated at the Chelyabinsk Regional Children’s Clinical Hospital from October 2022 to May 2024. MAO-A and MAO-B activity was studied by spectrophotometry in intestinal homogenates obtained at the proximal resection margin. Results and discussion. Intestinal samples obtained from patients with diseases accompanied by pronounced inflammatory changes (NEC stage IIIA–IIIB, enterostomy closure after NEC III, intestinal neuronal dysplasia (IND), Hirschsprung’s disease) showed a significant decrease in the activity of the MAO-A isoform. A decrease in MAO-B activity was demonstrated in intestinal wall samples obtained from children with confirmed diagnoses of Hirschsprung’s disease and intestinal neuronal dysplasia, as well as in premature infants with surgical stages of NEC. The highest activity of both enzyme isoforms was found in sigmoid colon samples without pathological changes in patients with anal and rectum atresia.

Abstract Objective The identification of risk factors is crucial for the clinical prevention and diagnosis of necrotizing enterocolitis (NEC). Monochorionic twins (MCT), due to the high genetic homogeneity, provided a valuable model for investigating the risk factors of various diseases. This study aimed to explore the risk factors for NEC using MCT. Methods A retrospective review was conducted on the medical records of monochorionic twins (MCT) treated at Guangzhou Women and Children’s Medical Center from January 2012 to March 2023. We compared perinatal condition, feeding and preceding condition between MCT pairs with NEC (NEC MCT) and without NEC(No NEC MCT).Logistic regression analysis was utilized to identify independent risk factors. Result In 85 pairs of monochorionic twins (MCT), NEC occurred in one twin in 78.8% of cases, whereas both twins were affected in 21.2% of cases. In the final cohort of 60 pairs of MCT, several parameters were found to differ significantly between NEC MCT group and No NEC MCT group. Compared to No NEC MCT group, the incidence of umbilical cord abnormalities was significantly higher in the NEC MCT group (25% vs. 8.3%, P = 0.014). Meanwhile, NEC MCT group showed higher prevalence of SGA infants (48.3% vs. 21.7%, P = 0.002) and sFGR (38.3% vs. 6.7%, P = 0.000). Furthermore, TTTs (13.3% vs. 3.3%, P = 0.027) and septicemia (25% vs. 5%, P = 0.002) were more common in NEC MCT group. In a multivariable logistic regression model, sFGR (OR 6.81,95%CI 2.1–21.9, p = 0.001) was eventually output as an independent risk factor. Conclusion Non-genetic factors play a predominant role in the pathogenesis of NEC. Umbilical cord abnormalities, SGA, sFGR, TTTs and septicemia significantly increase the risk of NEC. sFGR is an independent risk factor of NEC.