small molecules

2026-09-24 | Safety and Effectiveness of Probiotic Preparations: A Contemporary Review.

Probiotic preparations have attracted increasing attention because of their potential to modulate the gut microbiota and improve health outcomes in a wide range of gastrointestinal and extraintestinal diseases. However, their efficacy and safety are strain-specific and remain inconsistent across many clinical indications. The aim of this review was to evaluate current evidence regarding the efficacy, safety, mechanisms of action, and clinical applications of probiotic preparations. A narrative literature review was conducted using the PubMed, Scopus, and Web of Science databases to identify publications addressing the efficacy, safety, and clinical applications of probiotic preparations. The literature search was last updated in July 2026. No publication-year restrictions were applied; the studies included in this review were published between 2000 and 2026. Priority was given to systematic reviews, meta-analyses, randomized controlled trials, international clinical practice guidelines, and mechanistic studies. The reviewed evidence indicates that probiotics may contribute to intestinal homeostasis through modulation of the gut microbiota, enhancement of intestinal barrier function, and regulation of immune responses. The strongest evidence supports the use of selected probiotic strains for the prevention of antibiotic-associated diarrhea, whereas evidence for the prevention of necrotizing enterocolitis is generally favorable but depends on the specific probiotic preparation, product quality, and clinical setting. Evidence for most other gastrointestinal and extraintestinal disorders remains heterogeneous and strain-specific. Although probiotics generally exhibit a favorable safety profile, rare infectious complications have been reported in high-risk patients. Current evidence indicates that the efficacy and safety of probiotics depend on the specific strain, clinical indication, and patient characteristics. Further high-quality, strain-specific clinical studies are needed to optimize their use in medical practice.

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2026-09-23 | Pathogenesis of necrotizing enterocolitis: mechanisms and mediators

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of preterm neonatal infants. The hallmarks of the disease include severe intestinal necrosis and systemic inflammation leading to overwhelming sepsis. There remains significant morbidity and mortality attributed to NEC, raising the urgency to investigate potential causative mechanisms in order to treat and potentially prevent the disease. This review will summarize the established and emerging mechanisms leading to NEC, including toll-like receptor 4 activation by gram-negative bacteria, microbial dysbiosis, a maladapted immune response, impairment in the enteric nervous system and mitochondrial damage. Overriding each of these factors are potential genetic and epigenetic modulators, which may drive each of the above processes. Importantly, results of experiments from a variety of laboratories have suggested that an understanding of processes may lead to the development of novel preventative or treatment modalities, including small molecules and stem cells that can interfere with the deleterious pathways. By summarizing the latest mechanistic and therapeutic advances, this review hopes to provide insights into the ultimate goal of improving outcomes for patients with this devastating disease.

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2026-09-23 | Probiotics and Risk of Death, Necrotizing Enterocolitis, and Sepsis in Very Preterm Infants.

Probiotics are reported to benefit preterm infants, but population-based clinical evidence is limited. In 2020, the Swedish Neonatal Society issued a national recommendation to supplement very preterm infants (28 weeks 0 days' to 31 weeks 6 days' gestation) with probiotics. To investigate whether probiotic supplementation was associated with risk of death, necrotizing enterocolitis (NEC), and/or culture-proven sepsis in infants born very preterm. This population-based cohort study examined data from the Swedish Neonatal Quality Register from January 1, 2017, through December 31, 2024. Live-born, very preterm infants, excluding those who died within the first 3 days of life or due to congenital or chromosomal abnormalities, were included. Daily probiotic supplementation of 1 billion colony-forming units of freeze-dried Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus initiated following birth and discontinued at postmenstrual week 34. Composites of death and/or NEC (Bell stage 2-3), death and/or surgical NEC (Bell stage 3), and death and/or culture-proven sepsis were assessed. Modified Poisson regression, propensity score-matched, and inverse probability of treatment weighting analyses were used for replication analyses. A multivariate bayesian modeling analysis accounting for the association between NEC and mortality was performed to estimate the association between probiotic exposure and mortality. Among 4695 infants (mean [SD] gestational age, 30.2 [1.1] weeks; 2550 male [54.3%]), probiotic exposure increased from 0% before the national recommendation in 2020 to 16.9% in 2020 and a mean (SD) of 64.8% (4.7%) in 2021 to 2024. Probiotic supplementation vs no supplementation was associated with lower risk of death and/or NEC (rate, 0.8% vs 3.4%; adjusted relative risk [ARR], 0.28 [95% CI, 0.14-0.56]). When assessed separately, risks of death (rate, 0.3% vs 1.4%; ARR, 0.16 [95% CI, 0.06-0.45]) and NEC (rate, 0.6% vs 2.5%; ARR, 0.25 [95% CI, 0.10-0.61]) were both lower in the probiotic group. Multivariate bayesian modeling suggested that a substantial proportion of the observed mortality reduction was mediated via reduced NEC incidence (42.3% [credible interval, 16.1%-100%]). Probiotic supplementation was not associated with death and/or culture-proven sepsis (rate, 3.4% vs 4.4%; ARR, 0.86 [95% CI, 0.58-1.26]). This cohort study of very preterm infants found that implementation of a multistrain probiotic was associated with a significant reduction in death and/or NEC, which may help inform shared decision-making between clinicians and families. These results should not be generalized to extremely preterm infants (<28 weeks' gestation).

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2026-09-21 | Melatonin ameliorates NEC-associated brain injury by suppressing pro-inflammatory (M1-like) microglia via the AMPK-IL-1β axis.

Necrotizing enterocolitis (NEC) is a severe neonatal gastrointestinal disease. Its associated brain injury involves neuroinflammation and long-term cognitive impairment, yet specific therapies are lacking. Melatonin (MEL) has shown neuroprotective effects, but its role in NEC-associated brain injury remains unclear. Neonatal C57BL/6 J mice were subjected to NEC induction and studied at short-term (acute) and long-term (chronic, up to 9 weeks). Cognitive function was assessed by Y-maze and open field tests. Microglial activation, inflammatory cytokine expression, and AMPK pathway activity were analyzed in mouse brain tissue and in LPS/IL-1β-stimulated peritoneal macrophages with pharmacological interventions. Prophylactic MEL improved survival and intestinal injury, and reversed NEC-induced long-term spatial memory deficits. NEC triggered a sustained M1 microglial polarization in the hippocampus that persisted into adulthood, which was durably attenuated by MEL. IL-1β was identified as the most prominently upregulated cytokine, and transcriptomic profiling confirmed enrichment of IL-1β-related pathways. In vitro, recombinant IL-1β directly drove M1 polarization, while IL-1β neutralization blocked this effect. Mechanistically, MEL restored AMPK phosphorylation in NEC brains, and AMPK inhibition abolished the MEL-mediated suppression of M1 polarization. Prophylactic MEL ameliorates NEC-associated brain injury by activating AMPK to suppress IL-1β production, thereby inhibiting chronic M1 microglial polarization. This AMPK-IL-1β axis represents a key therapeutic target, with MEL providing dual gut-brain protection.

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2026-09-19 | Case report of successful conservative management of neonatal gastrointestinal perforation and intestinal stenosis.

Neonatal gastrointestinal perforation (NGP) is a life-threatening condition requiring urgent intervention. While exploratory laparotomy remains the standard treatment, conservative management offers an alternative when surgery is not feasible. This case demonstrates the successful use of comprehensive conservative therapy in a high-risk infant with NGP and suspected intestinal stenosis. A 6-day-old, small-for-gestational-age male infant presented with vomiting, abdominal distension, and respiratory distress. Clinical deterioration led to the diagnosis of pneumoperitoneum, sepsis, and suspected necrotizing enterocolitis. NGP secondary to suspected necrotizing enterocolitis, with complications including septic shock, purulent meningitis, scrotal abscess, zinc deficiency, and malnutrition. Following parental refusal of laparotomy, conservative management was initiated, including peritoneal drainage, gastrointestinal decompression, broad-spectrum antibiotics, inotropic support, and parenteral nutrition. Nutritional support included zinc supplementation and gradual enteral feeding. The infant survived after 134 days of hospitalization, despite multiple complications. Long-term follow-up at 8 months revealed neurodevelopmental delays (developmental quotient 61), though physical growth was adequate with successful transition to complementary feeding. This case confirms that conservative management with peritoneal drainage and intensive multidisciplinary support can be a viable option for NGP, even in complex scenarios where surgery is not possible. It underscores the importance of vigilant monitoring, nutritional management, and awareness of potential long-term neurodevelopmental sequelae in such cases.

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cell therapies

2026-09-13 | Survival without major morbidity in very preterm infants (<32 weeks' gestation): prevalence, temporal trends, and associated factors in a single-center retrospective cohort.

To determine the proportion of very preterm infants (VPIs) surviving without major morbidity (SWMM), assess temporal trends from 2021 to 2025, and identify associated factors. This single-center retrospective cohort study included all inborn VPIs admitted to the neonatal intensive care unit (NICU) of Guangdong Women and Children Hospital between January 2021 and October 2025. Primary analyses were performed among infants receiving complete care, whereas infants discharged against medical advice (DAMA) were analyzed separately. SWMM was defined as survival without bronchopulmonary dysplasia (BPD), severe brain injury, necrotizing enterocolitis (NEC) stage II or higher, late-onset sepsis (LOS), or severe retinopathy of prematurity (ROP). Temporal trends were evaluated using logistic regression with gestational age (GA)-adjusted annual rates estimated by marginal standardization. Factors associated with SWMM were assessed using multivariable logistic regression. A total of 1,172 VPIs were included, with a median GA of 30.0 weeks (IQR, 28.6-31.1) and a median birth weight of 1,270 g (IQR, 1,050-1,500). In the complete-care cohort (n = 1,094), survival was 95.5% (1,045/1,094) and SWMM was 59.9% (655/1,094). From 2021 to 2025, survival remained high and stable. After GA adjustment, BPD, severe ROP, and LOS increased over time, whereas SWMM declined. Multivariable analysis showed that higher GA (per week: OR 2.62, 95% CI 2.30-3.01) and greater birth weight z score (per SD: OR 2.13, 95% CI 1.76-2.59) were associated with higher odds of SWMM, whereas male sex (OR 0.66, 95% CI 0.48-0.91), additional surfactant doses (per dose: OR 0.47, 95% CI 0.37-0.59), and a 5-minute Apgar score ≤7 (OR 0.27, 95% CI 0.10-0.69) were associated with lower odds. DAMA occurred in 6.7% of VPIs (78/1,172) and decreased with increasing GA, from 30.0% at ≤25 weeks to 1.9% at 31 weeks. The estimated post-DAMA survival rate was 24.4% (19/78). Survival among VPIs remained high and stable, whereas SWMM remained suboptimal and declined over time. The increasing burden of BPD and severe ROP underscores the importance of improving the quality of survival. Strategies including GA-stratified care, optimized perinatal stabilization, early respiratory management, and reduced DAMA may improve outcomes in this high-risk population.

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2026-09-03 | Anti-inflammatory mechanisms of breast milk exosomes in neonatal immune development.

Breast milk exosomes (ΒΜΕs) are extracellular vesicles of 30-150 nm that have currently attracted research attention due to their protective role in neonatal immune development. Their bioactive cargos, including miRNAs, proteins and lipids, have been shown to facilitate cellular communication and regulate various physiological processes. In the present article, we explore known molecular mechanisms through which ΒΜΕs affect innate and adaptive immunity as well as the integrity of the intestinal epithelial barrier. BMEs can reduce symptoms of inflammatory intestinal diseases, such as necrotizing enterocolitis (NEC) by regulating key signaling pathways, including TLR4/MyD88/NF-κB, MAPK and PI3K/AKT. Their unique characteristics highlight the potential to serve as drug nanocarriers for therapeutic interventions especially in high-risk neonatal inflammatory diseases. Although the clinical application of ΒΜΕs needs to overcome several challenges such as heterogeneity, large-scale isolation and processing of ΒΜΕs, their anti-inflammatory effects are consistent and significant. Future multi-omics analyses for the comprehensive understanding of the molecular mechanisms through which exosomes exert immunomodulation are expected to reveal new opportunities to improve the health of vulnerable neonates.

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2026-06-27 | Human milk small extracellular vesicles elicit changes in inflammatory response in infant human intestinal enteroids.

Human milk (HM) is the key nutritional source for infants and the most effective preventative approach against serious gastrointestinal inflammatory diseases like necrotizing enterocolitis (NEC) in preterm infants. Numerous studies in animal models indicate HM-derived small extracellular vesicles (HMEV) reduce severity of inflammation; however, data on human-specific models are limited. Isolated HMEV were characterized from early-HM (colostrum and transitional), mature-HM, and a combined, pasteurized donor bank-like HM sample (pool-); pool-HMEV retains a profile aligned with HMEV from both early- and mature-HM samples. Exposure to pool-HMEV initiates unique gene signatures associated with reduction of inflammation including NFkB-driven TNFα signaling in human intestinal enteroids (HIEs) established from neonates with intestinal atresia or NEC. Prior exposure of HIEs to pool-HMEV lowers the magnitude of EGTA- and TNF-induced barrier disruption. This foundational research demonstrates HMEVs cause transcriptional and functional changes to the human intestinal epithelium and will support future studies on HMEV-based therapeutics.

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2026-05-25 | Early-life mucosal T cells direct intestinal stem cell fate via a coordinated developmental program.

Although early-life immunity was once considered immature, the human fetal immune system is dynamic and compartmentalized by the second trimester. By 21 weeks of gestation, T lymphocytes become a major immune population in the fetal small intestine (SI), yet their functional roles within this tissue remain largely undefined. To explore their unique contributions to intestinal development, we established an ex vivo co-culture system in which mucosal T cells isolated from fetal, neonatal, or adult SI donors were cultured with tissue-derived 3D SI organoids derived from various ages. Homeostatic early-life (fetal and neonatal) SI T cells uniquely promoted organoid generation, a metric of stem cell renewal, by upregulating cell cycle-associated gene programs. These early-life T cells also directed intestinal stem cell differentiation toward the secretory lineage in both growth and differentiation phase, highlighting that T cells poise stem cells to adopt secretory fates. T cells from infants with necrotizing enterocolitis (NEC) - an inflammatory intestinal disease affecting predominantly preterm infants - failed to activate these same programs, suggesting a pathologic role for T cells in NEC. T cells from the adult SI similarly failed to support organoid growth or differentiation, revealing developmentally specialized, nonimmune functions for early-life T cells in the intestine. Similarly, T cells derived from cord blood did not enhance organoid generation, indicating that this function is not necessarily a generalized feature of early-life T cells but rather is restricted to mucosal T cells. Organoids derived from adults or NEC, however, could re-enter regenerative states when co-cultured with fetal T cells, indicating that fetal T cells can restore stem cell self-renewal across developmentally and disease-imposed states. We further identified that T cell-derived soluble factors alone were insufficient to modulate intestinal stem cell fate, implying the need for physical interactions. Concordant with this finding, we report that T cells heavily localize to the stem cell niche during prenatal development, where they express factors involved in Notch, Wnt, and growth factor signaling to support fetal stem cell function. Collectively, these findings reveal a coordinated developmental program in which fetal SI T cells balance stem cell self-renewal and differentiation, identifying a developmental immune-epithelial axis that can be harnessed to restore intestinal regeneration.

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2026-05-02 | Staged controlled bowel expansion prior to serial transverse enteroplasty in preterm neonates with short bowel syndrome: A safe and feasible strategy to enable intestinal reconstruction.

Preterm neonates with short bowel syndrome represent one of the most challenging populations in pediatric intestinal rehabilitation. Autologous intestinal reconstruction is frequently delayed in this group because insufficient bowel dilation precludes safe lengthening, prolonging dependence on parenteral nutrition and increasing the risk of intestinal failure-associated liver disease, sepsis, and growth failure. We conducted a retrospective single-center cohort study of preterm neonates with short bowel syndrome managed with a standardized protocol of controlled bowel expansion (CBE) followed by serial transverse enteroplasty (STEP) between 2018 and 2025. Eligible patients had pediatric intestinal failure requiring parenteral nutrition for ≥60 consecutive days. Primary outcomes were bowel length gain and achievement of enteral autonomy. Secondary outcomes included complications and resolution of intestinal failure-associated liver disease (IFALD). Nine preterm neonates were included (median gestational age 27 weeks [IQR, 25-28]; median birth weight 880 g [IQR, 820-1080]; underlying aetiology predominantly necrotizing enterocolitis [78%]). Baseline bowel length was a median of 33 cm (18% of expected for gestational age). During the CBE phase, bowel length increased by a median of 20 cm (IQR, 14.5-30), allowing progression to definitive STEP after a median expansion period of 27 weeks (IQR, 18.1-33). STEP provided an additional median gain of 20 cm (IQR, 14-40), with a cumulative median gain of 54.5 cm (IQR, 42-61) and a final bowel length of 61% of expected. Eight of nine patients (88%) achieved full enteral autonomy at a median of 29.3 weeks post-STEP (IQR, 24.1-52.5). IFALD resolved in all affected patients, and no mortality or post-STEP surgical complications occurred. In preterm neonates with short bowel syndrome, CBE was incorporated as part of a staged surgical pathway prior to STEP, during which bowel length increased. This approach was feasible and was associated with progression to STEP, with high rates of enteral autonomy observed in the cohort. These findings suggest that CBE may serve as a preconditioning strategy to enable timely reconstruction in a population traditionally considered unsuitable for early lengthening. Prospective multicentre studies are warranted to validate these outcomes and standardize patient selection.

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proteins

2026-08-27 | Current Evidence, Controversies, and the Future of Biotics in the Prevention of Necrotizing Enterocolitis: A Narrative Review.

Necrotizing enterocolitis (NEC) remains one of the most devastating gastrointestinal disorders affecting preterm infants, with substantial mortality and long-term morbidity despite advances in neonatal care. Increasing evidence implicates intestinal dysbiosis, impaired intestinal barrier function, and dysregulated immune responses as central drivers of NEC pathogenesis, making microbiome-targeted interventions a promising preventive strategy. Collectively termed "biotics," these interventions include probiotics, prebiotics, synbiotics, and postbiotics, each aimed at modulating the developing gut ecosystem. This narrative review summarizes current evidence on the efficacy, safety, and clinical applicability of biotics for NEC prevention in very preterm and very-low-birth-weight infants. Randomized controlled trials and meta-analyses involving more than 10,000 infants demonstrate that specific multi-strain probiotic formulations, particularly those combining Lactobacillus and Bifidobacterium species, reduce NEC incidence and all-cause mortality, although benefits are less consistent in extremely low-birth-weight infants. Prebiotics alone showed a limited impact on NEC prevention, while emerging evidence suggests synbiotics may offer additive or superior protection compared with probiotics alone. Postbiotics represent a novel and potentially safer alternative, especially for the most vulnerable infants, though clinical data remain limited. Despite favorable effectiveness in meta-analyses, probiotics adoption remains variable due to strain heterogeneity, variable product quality, regulatory challenges, and rare but serious safety concerns. Precision microbiome approaches, pharmaceutical-grade formulations, personalized therapies informed by multi-omics profiling, and next-generation delivery systems may drive the future in this field.

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2026-07-30 | Overexpression of CD97 in intestinal epithelial cells attenuates LPS-induced pro-inflammatory cytokine induction via stabilization of β-catenin early in life.

Acute inflammatory conditions in the intestine of preterm infants are linked to increased susceptibility due to the immature degree of the gut's epithelial barrier, microbiota, and pattern recognition receptors. Toll-like receptor 4 (TLR4) plays a pivotal role in recognizing lipopolysaccharides (LPS) from gram-negative bacteria, triggering pro-inflammatory cytokine responses (TNF-α, IL-1β, CXCL1) via nuclear factor kappa B (NF-κB) signaling. These processes are implicated in necrotizing enterocolitis (NEC), a severe gastrointestinal condition in premature infants. CD97, an adhesion G-protein coupled receptor (aGPCR), has emerged as a modulator of immune responses influencing inflammatory signaling pathways. CD97 expression is typically low in intestinal epithelial cells (IECs); however, protective effects of increased CD97 levels have been described in experimentally induced colitis. In this study, we examined the role of CD97 in modulating the inflammatory response in the immature gut, utilizing wild-type (WT) and transgenic CD97-overexpressing mice (TgCD97) with epithelial-specific expression in the intestinal epithelium. LPS was administered to IECs and organ segments isolated from the small intestine of mice of specific ages, modeling certain stages of human perinatal/postnatal gut development. CD97 overexpression attenuated LPS-induced TNF-α expression in IECs during early intestinal development while IECs from adult mice remained unaffected. This effect was attributed specifically to ileal tissue. Attenuation was mediated by β-catenin stabilization, leading to suppressed LPS/NF-κB signaling. Inhibition of β-catenin in TgCD97 IECs reversed the anti-inflammatory phenotype restoring pro-inflammatory gene expression. These findings suggest that CD97 overexpression modulates the inflammatory response in the developing gut by stabilizing β-catenin and interacting with the LPS/NF-κB axis. This effect was restricted to early developmental stages and ileal tissue, highlighting a previously unrecognized role of CD97 in age-dependent endotoxin tolerance. These findings identify a novel CD97-β-catenin-NF-κB regulatory axis in the immature small intestine and highlight its potential as a therapeutic target to protect the immature neonatal gut from inflammatory damage.

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2026-06-27 | Enteral nutrition to optimize health and neurodevelopmental outcomes in very preterm infants.

Very preterm infants are born before a critical window of nutrient accrual that occurs during the third trimester, resulting in a nutritional deficit that is vital to restore to support further growth and development. Although the gut is underdeveloped, optimizing administration of nutrition via the enteral route has been linked to improved long term outcomes, particularly when mother's own milk is prioritized as the initial source of nutrition. The goal of this review was to synthesize current evidence on best enteral nutrition practices for very preterm infants focusing on strategies that optimize long term neurodevelopment and infant health outcomes. This review examines the physiological importance of early enteral nutrition to support growth and neurodevelopment of very preterm infants. Clinical outcomes data related to different types of enteral nutrition sources are reviewed, as well as evidence-based practices regarding initiation of enteral nutrition, advancement, supplementation and fortification. Additionally, limitations in the existing literature are identified to inform future research directions. The collective evidence reviewed in this manuscript supports early, consistent, and human milk-based enteral nutrition as a central modifiable factor to improve growth, brain development, and long-term neurodevelopmental outcomes. While there are remaining uncertainties regarding the ideal timing for initiation, specific advancement strategies, and fortification methods, the available data supports the following: minimizing enteral fasting, prioritizing mother's own milk, and using protocolized feeding guidelines.

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2026-06-15 | Preterm infant formulas with glucose polymers and reduced lactose content increase the risk of necrotizing enterocolitis.

After more than 70 years of research, necrotizing enterocolitis (NEC) remains the most serious gastrointestinal disease among preterm infants and a leading cause of mortality, morbidity, and disability. Although causes of NEC are multifactorial, this contribution reviews the causal relationship between commercial preterm formulas (PTF) and NEC. The responses of the immature preterm intestine to PTF and the relationship to NEC have been extensively investigated using animal models and in human studies, but the mechanisms by which PTF increases the risk of NEC have not been fully elucidated. Two categories of risk factors may contribute to the higher rates of NEC with PTF compared to breast milk: (1) protective elements in breast milk are missing from PTF and (2) specific ingredients of PTF increase NEC risk. Our comprehensive review of animal studies and clinical trials highlights at least one substance in each category. The principle carbohydrate in breast milk is non-nocive lactose; in PTF, 50%-60% of the lactose is replaced by glucose polymers, which are not present in breast milk, and represent a pathogenic agent. We advocate a complementary research agenda to identify additional protective elements of breast milk (besides lactose) that could be added to PTF and additional nocive elements of PTF (besides glucose polymers) that could be removed to reduce the risk of NEC.

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2026-06-08 | Current operative approaches for necrotizing enterocolitis.

Necrotizing enterocolitis is an overwhelming, catastrophic gastrointestinal disease largely affecting premature infants. The disease is manifested by exaggerated intestinal inflammation, which can progress to necrosis of the bowel and systemic sepsis. Prognosis is poor, with unacceptably high mortality. There is currently no known cure, with management focused on supportive measures, including bowel rest, gastric decompression, and antibiotic administration. Surgical intervention is required for cases unresponsive to medical management. In this review, we describe the determination of the need for surgical intervention, the surgical procedures commonly employed, and novel perioperative adjuncts being developed to improve outcomes.

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antibodies

2026-09-03 | Prenatal Exposures to High Ambient Temperatures and Heatwaves Increase the Risk of Necrotizing Enterocolitis: Evidence from Twin Pairs across China.

The association between necrotizing enterocolitis (NEC) and prenatal heat exposure has not been adequately studied. We estimated the association of prenatal high ambient temperature (TM) and heatwave exposure with NEC and to identified susceptible exposure windows. Generalized linear models were applied to examine the associations between high TM and heatwaves exposures with NEC. Mediation analysis was used to investigate the role of preterm birth (PTB) in the relationship between high TM and NEC during pregnancy. We included 8,334 twin pairs and their mothers: 227 (2.72%) twin pairs were NEC cases. Compared to the reference temperature (19.8 °C), prenatal exposure to the 90th percentile TM (24.8 °C) was associated with NEC risk [odds ratio ( OR), 2.68; 95% confidence interval ( CI): 1.93-3.72]. Trimester-specific ORs were 2.41 (95% CI: 1.63-3.55), 3.30 (95% CI: 2.18-4.99), and 2.06 (95% CI: 1.43-2.98) for the first, second, and third trimesters, respectively. Exposure to heatwaves during the entire pregnancy, first, and second trimesters showed ORs of 1.98 (95% CI: 1.14-3.43), 1.81 (95% CI: 1.26-2.59), and 1.81 (95% CI: 1.19-2.75), respectively. PTB mediated the association between the 90th and 95th percentile TM exposure during the entire pregnancy and NEC, with the mediation proportions of 30.10% (95% CI: 8.57-45.28) and 36.20% (95% CI: 16.18-50.28), respectively. Prenatal exposure to high TM levels and heat waves, especially in the first and second trimesters, was positively associated with the risk of NEC. PTB may partially mediate the relationshipbetween high TM exposure and NEC.

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2026-08-29 | Stage-specific neutrophil states in neonatal injury: from antimicrobial deficiency to pro-resolution repair.

Neonatal neutrophils are often described as immature effector cells with limited marrow reserves and reduced antimicrobial capacity. This account is clinically useful but incomplete: individual functions mature at different rates, neutrophil populations are heterogeneous, and observed phenotypes vary with gestational age, maternal health, tissue context, and time after injury. This Mini Review first places neonatal findings against canonical mature-neutrophil functions, then examines context-dependent programs in neonatal sepsis, hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, and necrotizing enterocolitis. We use state as an operational, cross-sectional description supported by phenotypic, functional, or molecular evidence, without assuming a stable lineage or a proven conversion from inflammatory to reparative cells. Temporal change may instead reflect emergency granulopoiesis, selective recruitment, survival, clearance, or population replacement. Human neonatal studies show that chemotaxis and extracellular-trap formation are often developmentally constrained, whereas phagocytosis, oxidative burst, granule content, and degranulation can be relatively preserved under specific assay conditions. Disease models further reveal competing roles for neutrophils in pathogen control, thromboinflammation, angiogenic support, and resolution. Conflicting findings on extracellular traps in necrotizing enterocolitis illustrate why model, microbial burden, intervention timing, and whether an experiment prevents trap formation or removes established traps must be distinguished. No clinically validated neonatal neutrophil-state classifier exists. Routine laboratory values provide clinical context and trajectories, whereas proposed interventions targeting extracellular traps, myeloperoxidase, trained immunity, lipid mediators, or efferocytosis remain experimental. Taken together, the evidence favors a context-dependent approach that preserves antimicrobial defense while testing ways to limit tissue injury.

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2026-08-08 | Necrotizing Enterocolitis in Infants with Hybrid Stage 1 Palliation is Common and Difficult to Predict.

Hybrid stage 1 palliation (HS1P) is performed at many centers for patients with single ventricle heart disease or complex biventricular heart disease and high-risk features. Necrotizing enterocolitis (NEC) is common in these infants, although specific risk factors have not been identified to predict those who will develop NEC. A single-center retrospective chart review of 105 infants who underwent HS1P at < 30 days of age was performed. Clinical, procedural, and echocardiographic features at HS1P and prior to NEC episodes were collected. Hypoplastic left heart syndrome accounted for 54.3% of patients. HS1P was performed at a median of 5 days of life, with 78.1% having a ductal stent placed and 35.2% having an atrial septal intervention. Overall, 56 infants (53.3%) developed NEC prior to their next surgery. Stage 1 NEC occurred in 42 infants (75.0%), with stage 2/3 NEC occurring in 14 infants (25.0%). Having three or more risk factors leading to the decision to undergo HS1P was associated with development of NEC (p = 0.01). Infants with stage 2/3 NEC were more likely to receive a general surgery consult (100% vs. 33.3%), had longer NPO times (median 7 vs. 3 days), longer antibiotic course (median 7 vs. 4 days), longer hospital length of stay (median 73.5 vs. 43 days), and were less likely to be discharged home prior to next surgical intervention (28.6% vs. 47.6%) than those with stage 1 NEC (all p < 0.05). Infants undergoing HS1P are at high risk for NEC with a significant impact on patients' clinical courses.

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2026-07-27 | Necrotizing Enterocolitis in Term Neonates with Critical Congenital Heart Disease: Associated Risk Factors and Clinical Outcomes.

Background: Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication that may develop in term neonates with critical congenital heart disease (CHD), despite the absence of prematurity. We aimed to evaluate the incidence of NEC and identify clinical factors associated with NEC development in term neonates with critical CHD. Methods: This retrospective cohort study included term neonates (≥37 weeks' gestation) with critical CHD admitted to a tertiary pediatric cardiac intensive care unit between 1 January 2022, and 1 January 2026. NEC was defined as stage IIA or higher according to modified Bell's criteria. Demographic, clinical, perioperative, and nutritional variables were analyzed. Multivariable logistic regression analysis was performed to identify factors independently associated with NEC development. Results: A total of 780 term neonates with critical CHD were included. NEC developed in 18 infants (2.3%). The median age at NEC diagnosis was 7 days (IQR 5-10), and four patients (22%) required surgical intervention. Seven NEC cases occurred preoperatively, whereas 11 developed after cardiac surgery; among postoperative cases, 64% occurred within the first 72 h after surgery. Birth weight < 2.5 kg (aOR 4.1, 95% CI 1.2-13.4; p = 0.021), gestational age < 38 weeks (aOR 3.9, 95% CI 1.3-12.0; p = 0.018), functional single-ventricle physiology (aOR 5.8, 95% CI 1.6-20.7; p = 0.007), and mechanical ventilation dependency (aOR 5.1, 95% CI 1.7-15.2; p = 0.004) were independently associated with NEC development. Mortality was significantly higher among infants with NEC compared with those without NEC (50% vs. 7.7%, p < 0.001). Conclusions: NEC remains an important complication associated with substantial mortality in term neonates with critical CHD, despite its relatively low incidence. Early-term birth, low birth weight, functional single-ventricle physiology, and dependence on mechanical ventilation were independently associated with increased NEC risk in this vulnerable population.

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2026-07-24 | Morbidity and Mortality of Very-Low-Birth-Weight Preterm Neonates in a Tertiary Neonatal Intensive Care Unit in Northeastern Mexico: A Five-Year Retrospective Cohort Study.

Prematurity remains a major global health challenge and is a leading cause of neonatal morbidity and mortality worldwide. The risk of adverse outcomes is inversely associated with gestational age and birth weight. Although advances in neonatal intensive care have improved survival rates over recent decades, very-low-birth-weight (VLBW) preterm neonates continue to experience substantial morbidity and remain vulnerable to long-term complications. This study aimed to evaluate the morbidity and mortality of very-low-birth-weight preterm neonates (<1500 g) admitted to the Neonatal Intensive Care Unit (NICU) of the Hospital Regional de Alta Especialidad de Ciudad Victoria (HRAEV), Mexico. A retrospective observational cohort study was conducted through a review of medical records of VLBW preterm neonates admitted to the NICU between January 2019 and December 2023. Demographic, perinatal, clinical, and outcome-related data were collected and analyzed. A total of 58 VLBW preterm neonates were included. Mean gestational age was 29.8 ± 2.7 weeks, and mean birth weight was 1109 ± 238 g. The most common morbidities were respiratory distress syndrome (81.0%), apnea of prematurity (72.4%), hyperbilirubinemia (68.9%), pneumonia (34.5%), sepsis (32.7%), patent ductus arteriosus (25.8%), bronchopulmonary dysplasia (26.9% among infants who survived to 36 weeks' PMA), necrotizing enterocolitis (15.5%), and intraventricular hemorrhage (12.0%) and retinopathy of prematurity (8.6%). Overall mortality was 10.3%. VLBW preterm neonates remain at high risk for significant morbidity despite relatively favorable survival rates. Respiratory distress syndrome, apnea of prematurity, hyperbilirubinemia, and sepsis were the most frequent complications, whereas deaths occurred mainly in the context of severe respiratory and systemic complications, including neonatal asphyxia, pulmonary hypertension, sepsis, shock, and multiple organ failure. Survival outcomes should be interpreted cautiously because of differences in study populations, referral patterns, local viability practices, and study design across neonatal settings.

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2026-07-30 | Human milk exosomal-miR-144-5p alleviates neonatal necrotizing enterocolitis by regulating the TLR4/NF-κB pathway.

Human breast milk-derived exosomes have been shown to prevent necrotizing enterocolitis (NEC). However, the mechanism remains unclear. This study aims to examine the role of miR-144-5p in repairing the damage of the tight junction barrier caused by NEC and its underlying mechanism. Differentially expressed exosome-derived miRNAs from term and preterm breast milk were identified through miRNA sequencing. Subsequently, the biological role and mechanism of the miRNA were studied both in vitro and in vivo. We found that exosomal miR-144-5p enhances the viability of intestinal epithelial cells in vitro and increases claudin-1 protein levels in vivo; Overexpressed miR-144-5p decreases interleukin-1beta (IL-1β) protein levels both in vitro and in vivo. Mechanistically, miR-144-5p alleviates intestinal inflammation and improves epithelial barrier function by downregulating toll-like receptor 4 (TLR4) expression and inhibiting the NF-κB signaling pathway. Exosomal miR-144-5p protects against experimental NEC by inhibiting the TLR4/NF-κB signaling pathway. This study reveals a previously unknown regulatory mechanism in the progression of NEC. Overexpression of miR-144-5p significantly decreases TLR4 expression, thereby inhibiting the TLR4 signaling pathway. MiR-144-5p reduces the production of inflammatory cytokines and prevents disruption of the tight junction protein claudin-1. This study is the first to confirm that human milk exosome miRNAs protect tight junctions from LPS-induced damage by modulating the TLR4/NF-κB signaling pathway. It offers a new perspective on understanding the pathogenesis of NEC. It expands the therapeutic options for necrotizing enterocolitis.

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2026-07-26 | Evolving role of mitochondrial dysfunction and mitophagy in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a severe, multifactorial disease of prematurity characterized by a heterogeneous pathophysiology. A dysregulated cytokine-driven inflammatory response is central to its progression, underscoring the need to identify key molecular triggers and pathways. Emerging evidence suggests that mitochondrial dysfunction represents a central nidus linking microbial signals to immune responses, and ultimately to epithelial injury. Future studies defining the timing and mechanisms of mitochondrial dysfunction and the role of mitophagy to better understand the interplay of the microbiome, immune responses, and mitochondria in the pathogenesis of NEC are greatly needed. IMPACT: Mitochondrial dysfunction is central to NEC pathogenesis, linking dysbiosis, immune dysregulation, and epithelial injury, and redefining NEC as an immunometabolic disease. ACSL1 emerges as a promising biomarker and therapeutic target, with potential to guide early diagnosis and modulate inflammation and oxidative stress. Future focus on timing and mitophagy may enable early detection and targeted interventions before irreversible intestinal injury develops, improving outcomes in NEC.

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2026-06-15 | Autoinflammation with infantile enterocolitis induced by a heterozygous variant (c.1357C > T) in the NLRC4 gene: a case report.

Necrotizing enterocolitis (NEC) is s a life-threatening inflammatory intestinal disorder primarily affecting preterm infants, though rare in full-term neonates. NLR-family CARD domain-containing protein 4 (NLRC4), a cytosolic inflammasome component driving IL-1β-mediated inflammation, is linked to autoinflammatory syndromes via germline gain-of-function mutations, though its role in term infant NEC remains underexplored. A full-term male infant developed NEC shortly after birth, requiring emergency surgical interventions including ileostomy and intestinal resection. Intraoperative findings revealed multifocal necrosis in the small intestine (80 cm total length) and colon. Genetic testing identified a heterozygous NLRC4 variant (c.1357C > T, p. Arg 453*), inherited from an asymptomatic father. Sanger sequencing confirmed the mutation's de novo origin. Pathological analysis demonstrated transmural inflammation without evidence of Hirschsprung disease. This report identifies a novel truncating variant in the NLRC4 gene associated with severe autoinflammatory enterocolitis presenting as NEC in a term neonate. Early NLRC4 screening may guide targeted therapies and improve outcomes in severe intestinal inflammation.

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2026-01-20 | Identification of key mitochondria-related genes in necrotizing enterocolitis using single-cell hdWGCNA and experimental verification.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disorder in preterm infants. The interplay between mitochondrial metabolism and immune inflammation in its development is not fully understood. Single-cell data were analyzed using dimensionality reduction, clustering, and the high-dimensional weighted gene co-expression network analysis (hdWGCNA) algorithm to identify key gene modules in monocytes. GSE46619 was integrated with the MitoCarta3.0 to identify mitochondria-associated differentially expressed genes (MitoDEGs). Acyl-CoA synthetase long-chain family member 1 (ACSL1) was selected as a candidate. Immune infiltration was evaluated via the CIBERSORT algorithm, and a competing endogenous RNA (ceRNA) regulatory network was constructed using Cytoscape. The expression and function of ACSL1 were validated both in vivo and in vitro, using immunohistochemistry (IHC), qRT-PCR, western blot, and siRNA knockdown. A key monocyte subset was identified in NEC. Integrated analysis revealed three MitoDEGs (ACSL1, SOD2, SLC25A37) were linked to NEC, with ACSL1 showing the most significant upregulation. ACSL1 expression correlated strongly with immune cell infiltration and was confirmed to be elevated in vivo and in vitro models. Knocking down ACSL1 suppressed lipopolysaccharide (LPS)-induced inflammatory factor expression and ROS production. ACSL1 plays a critical role in the pathogenesis of NEC, suggesting its potential as a novel biomarker. Our study reveals massive monocyte infiltration and identifies the mitochondria-related gene ACSL1 as highly expressed and functionally significant in NEC. This is the first integrated analysis (single-cell, hdWGCNA, MitoCarta3.0) pinpointing ACSL1 as a novel immunometabolic hub specific to NEC pathophysiology. ACSL1 provides a crucial mechanistic link between mitochondrial function and NEC development. It significantly correlates with key immune cells (neutrophils/mast cells/macrophages/T cells), highlighting its role in NEC immune dysregulation. These findings reveal a critical role of ACSL1 in NEC pathogenesis, highlighting its potential as a novel biomarker.

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2026-01-09 | ALAS2 Prevents Neonatal Necrotizing Enterocolitis by Improving Ferroptosis in Intestinal Epithelial Cells Through Inhibition of Oxidative Stress.

Neonatal necrotizing enterocolitis (NEC) is an intestinal disease that occurs in the neonatal period. The purpose of this study was to investigate the role of 5'-aminolevulinate synthase 2 (ALAS2) in NEC-induced intestinal injury. In a neonatal mouse, NEC model was induced by high-osmolarity formula and hypoxia-cold stress, and ALAS2 expression was significantly downregulated in ileal tissues (p  < 0.01), coinciding with elevated oxidative stress (increased Fe2+/malondialdehyde [MDA] and decreased superoxide dismutase [SOD]), inflammation (increased TNF-α/interferon-gamma [IFN-γ]), and ferroptosis activation (increased acyl-CoA synthetase long-chain family member 4 [ACSL4] and decreased ferritin heavy chain 1 [FTH1] with mitochondrial shrinkage). In vitro, tumor necrosis factor-alpha (TNF-α)/IFN-γ-treated intestinal epithelial cell (IEC) exhibited progressive ALAS2 suppression and increased necrosis. Crucially, lentivirus-mediated ALAS2 overexpression reversed these effects, reducing cell necrosis by 22% while suppressing ferroptosis markers (Fe2+ accumulation, lipid reactive oxygen species [ROS], and mitochondrial depolarization) and oxidative damage (decreased MDA and restored glutathione [GSH]/catalase [CAT]/SOD). Untargeted metabolomics further revealed ALAS2-mediated modulation of nutrient metabolism and redox pathways. Collectively, ALAS2 ameliorates NEC by blocking oxidative stress-driven ferroptosis in IECs, proposing a novel therapeutic target.

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