Prevention Of Necrotizing Enterocolitis Research Articles

Plant-Derived Substances for Prevention of Necrotising Enterocolitis: A Systematic Review of Animal Studies.

Inflammation, oxidative injury, and gut dysbiosis play an important role in the pathogenesis of necrotising enterocolitis (NEC). Plant-derived substances have historically been used as therapeutic agents due to their anti-inflammatory, antioxidant, and antimicrobial properties. We aimed to review pre-clinical evidence for plant-derived substances in the prevention and treatment of NEC. A systematic review was conducted using the following databases: PubMed, EMBASE, EMCARE, MEDLINE and Cochrane Library (PROSPERO CRD42022365477). Randomized controlled trials (RCTs) and quasi-RCTs that evaluated a plant-derived substance as an intervention for NEC in an animal model of the illness and compared pre-stated outcomes (e.g., clinical severity, severity of intestinal injury, mortality, laboratory markers of inflammation and oxidative injury) were included. Sixteen studies (n = 610) were included in the systematic review. Ten of the sixteen included RCTs (Preterm rat pups: 15, Mice: 1) reported mortality and all reported NEC-related histology. Meta-analysis showed decreased mortality [12/134 vs. 27/135; RR: 0.48 (95% CI: 0.26 to 0.87); p = 0.02, 10 RCTs] and decreased NEC in the experimental group [24/126 vs. 55/79; RR: 0.34 (95% CI: 0.22 to 0.52); p < 0.001, 6 RCTs]. Markers of inflammation (n = 11) and oxidative stress (n = 13) improved in all the studies that have reported this outcome. There was no significant publication bias for the outcome of mortality. Plant-derived substances have the potential to reduce the incidence and severity of histologically diagnosed NEC and mortality in rodent models. These findings are helpful in guiding further pre-clinical studies towards developing a food supplement for the prevention of NEC in preterm infants.

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

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

Clinical Dilemma Involving Treatments for Very Low-Birth-Weight Infants and the Potential Risk of Necrotizing Enterocolitis: A Narrative Literature Review.

Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia-reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.

A prospective evaluation of the risk factors and utility of GutCheckNEC scoring system to predict necrotizing enterocolitis in preterm newborns, in a tertiary care centre in North India

Background: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease of neonate with high fatality. GutCheckNEC scoring system can be used in predicting NEC and decrease NEC rate. Aims: To assess risk factors and use scoring system GutCheckNEC in predicting necrotising enterocolitis. Methods: A prospective observational study with preterms, birth weight &lt;1500grams was done. Risk factor assessment was done using GutCheckNEC and serial scorings were done. Descriptive analyses of the various risk factors assessed were done. Results: 51 babies included, with gestational age 24 to 35 weeks (Median (IQR) 30+2 (27+2, 31+6), birth weight 500 to 1500 grams (Median (IQR) – 1105 (893, 1300). 9 NEC cases, 6(11.5%) confirmed NEC and 2(22%) were surgical NEC. Absence of ANS, HsPDA and late onset sepsis were risk factors. The median (IQR) scoring at 72 hrs., 86 hrs., 7 days, 14days, 21days and 28 days were 34 (31, 38), 34 (30, 39), 34 (26, 43), 31 (23, 35), 35 (23, 38), 35 (30, 40). The median risk for developing NEC was high (33-36) on all days except day 14, when it was moderate (20-32). The sensitivity and specificity for a cut off &gt;32 at 86hours was 85.7% and 48.5% (PPV – 26.1%, NPV – 94%) for medical NEC and 100% and 44.7% (PPV – 8.7%, NPV – 100%) respectively for surgical NEC. Conclusion: Hence we conclude that GUTCHECK can help in early prediction of NEC and prevention of NEC.

Effect of Oral Chondroitin Sulfate Supplementation on Acute Brain Injury in a Murine Necrotizing Enterocolitis Model.

Necrotizing enterocolitis (NEC) is a devastating condition where inflammatory changes and necrosis in the gut results in activation of brain microglia and subsequent neurodevelopmental impairment. Chondroitin sulfate (CS) is a glycosaminoglycan in human breast milk that is absent in conventional formulas. We hypothesized that oral formula supplementation with CS during a murine model of experimental NEC would not only attenuate intestinal injury, but also brain injury. NEC was induced in mouse pups on postnatal days (PNDs) 5 to 8. Three conditions were studied: (1) breastfed controls, (2) NEC, and (3) NEC+enteral CS (formula+200 mg/kg/d of CS). Pups were euthanized on PND 9 or reunited with dams by the evening of PND 8. Intestinal segments were H&E stained, and immunohistochemistry was performed on brain tissue for Iba-1 to assess for microglial morphology and cortical changes. Neurodevelopmental assays were performed on mice reunited with foster dams on PND 9. Single-cell RNA-sequencing analysis was performed on human intestinal epithelial cells exposed to (1) nothing, (2) hydrogen peroxide (H 2 O 2 ) alone, or (3) H 2 O 2 + CS to look at the differential gene expression between groups. Groups were compared with ANOVA or Kruskal-Wallis tests as appropriate with p < 0.05 considered significant. Compared with NEC, mice treated with oral CS showed improved clinical outcomes, decreased intestinal injury, and attenuated microglial activation and deleterious cortical change. Mice with CS performed better on early neurodevelopmental assays when compared with NEC alone. Single-cell analysis of HIEC-6 cells demonstrated that CS treatment down regulated several inflammatory pathways including nuclear factor κB-suggesting an explanation for the improved Th17 intestinal cytokine profile. Oral CS supplementation improved both physiological, clinical, and developmental outcomes. These data suggest that CS is a safe compound for formula supplementation for the prevention of NEC.

Superior performance of biofilm versus planktonic Limosilactobacillus reuteri in protection of the intestines and brain in a piglet model of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal-related death in premature infants. Its etiology is multifactorial, with intestinal dysbiosis playing a major role. Probiotics are a logical preventative therapy for NEC, however their benefits have been inconsistent. We previously developed a novel probiotic delivery system in which planktonic (free-living) Limosilactobacillus reuteri (Lr) is incubated with biocompatible dextranomer microspheres (DM) loaded with maltose (Lr-DM-maltose) to induce biofilm formation. Here we have investigated the effects of Lr-DM-maltose in an enteral feed-only piglet model of NEC. We found a significant decrease in the incidence of Definitive NEC (D-NEC), death associated with D-NEC, and activated microglia in the brains of piglets treated with Lr-DM-maltose compared to non-treated piglets. Microbiome analyses using 16S rRNA sequencing of colonic contents revealed a significantly different microbial community composition between piglets treated with Lr-DM-maltose compared to non-treated piglets, with an increase in Lactobacillaceae and a decrease in Clostridiaceae in Lr-DM-maltose-treated piglets. Furthermore, there was a significant decrease in the incidence of D-NEC between piglets treated with Lr-DM-maltose compared to planktonic Lr. These findings validate our previous results in rodents, and support future clinical trials of Lr in its biofilm state for the prevention of NEC in premature neonates.

Factors Influencing Neonatal Gut Microbiome and Health with a Focus on Necrotizing Enterocolitis.

Maturational changes in the gut start in utero and rapidly progress after birth, with some functions becoming fully developed several months or years post birth including the acquisition of a full gut microbiome, which is made up of trillions of bacteria of thousands of species. Many factors influence the normal development of the neonatal and infantile microbiome, resulting in dysbiosis, which is associated with various interventions used for neonatal morbidities and survival. Extremely low gestational age neonates (<28 weeks' gestation) frequently experience recurring arterial oxygen desaturations, or apneas, during the first few weeks of life. Apnea, or the cessation of breathing lasting 15-20 s or more, occurs due to immature respiratory control and is commonly associated with intermittent hypoxia (IH). Chronic IH induces oxygen radical diseases of the neonate, including necrotizing enterocolitis (NEC), the most common and devastating gastrointestinal disease in preterm infants. NEC is associated with an immature intestinal structure and function and involves dysbiosis of the gut microbiome, inflammation, and necrosis of the intestinal mucosal layer. This review describes the factors that influence the neonatal gut microbiome and dysbiosis, which predispose preterm infants to NEC. Current and future management and therapies, including the avoidance of dysbiosis, the use of a human milk diet, probiotics, prebiotics, synbiotics, restricted antibiotics, and fecal transplantation, for the prevention of NEC and the promotion of a healthy gut microbiome are also reviewed. Interventions directed at boosting endogenous and/or exogenous antioxidant supplementation may not only help with prevention, but may also lessen the severity or shorten the course of the disease.

Utilization of a High Potency Probiotic Product for Prevention of Necrotizing Enterocolitis in Preterm Infants at a Level IV NICU.

Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease that can be seen in premature infants with high risk for morbidity and mortality. There is currently no US Food and Drug Administration (FDA) medication approved for the prevention of NEC. Despite great heterogeneity among available studies, large meta-analyses of clinical trials have demonstrated the efficacy of multiple-strain probiotics in reducing NEC and all-cause mortality. In 2020, Medical City Dallas's Level IV neonatal intensive care unit (NICU) implemented a probiotic protocol for NEC prevention. As a result, a reduction in NEC was observed, with no occurrence of probiotic-related sepsis.

Interfering with Rac1-activation during neonatal monocyte-macrophage differentiation influences the inflammatory responses of M1 macrophages

Necrotizing enterocolitis (NEC) is a life-threatening, inflammatory disease affecting premature infants with intestinal necrosis, but the mechanism remains unclear. Neonatal macrophages are thought to play an important role in the pathogenesis of NEC through the production of proinflammatory cytokines. Restriction of cytokine expression in macrophages of NEC tissues may be beneficial. In adult macrophages, interfering with Rac1 has been shown to influence the expression of cytokines. Here, we investigated whether interfering with Rac1 in neonatal macrophages affects their inflammatory responses. First, we found that Rac1-activation was upregulated in the macrophages of rats with NEC model induction compared to controls. The M1 macrophages derived from human neonatal monocytes showed greater Rac1-activation than the M2 macrophages derived from the same monocytes. Inhibition of Rac1-activation by NSC23766 potently reduced the production of proinflammatory cytokines in these M1 macrophages. While neonatal monocytes differentiated into M1 macrophages in vitro, NSC23766 significantly altered cell function during the first six days of incubation with GM-CSF rather than during the subsequent stimulation phase. However, the same effect of NSC23766 was not observed in adult macrophages. Using mass spectrometry, Y-box binding protein 1 (YB1) was identified as being downregulated upon inhibition of Rac1-activation in the neonatal macrophages. Moreover, we found that inhibition of Rac1-activation shortens the poly A tail of PABPC1 mRNA, thereby reducing the translation of PABPC1 mRNA. Consequently, the downregulation of PABPC1 resulted in a reduced translation of YB1 mRNA. Furthermore, we found that TLR4 expression was downregulated in neonatal macrophages, while YB1 expression was reduced. Adding resatorvid (TLR4 signaling inhibitor) to the macrophages treated with NSC23766 did not further reduce the cytokine expression. These findings reveal a novel Rac1-mediated pathway to inhibit cytokine expression in neonatal M1 macrophages and suggest potential targets for the prevention or treatment of NEC.

Human milk-derived MANF, as an immuno‐nutritional factor, maintains the intestinal epithelial barrier and protects against necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a leading cause of death in preterm infants. Compared to formula milk, breastfeeding protects against NEC. However, the composition of breast milk is quite complicated, and many immunological compositions remain unknown. In this study, we aimed to investigate the concentration of a secreted protein, Mesencephalic astrocyte-derived neurotrophic factor (MANF), in breastmilk and evaluate its immune-regulatory function in protecting the intestinal epithelial barrier. Our data indicated that MANF was secreted in human milk but could not be detected in infant formulas. More importantly, the amount of MANF in colostrum was higher than that in mature milk. We also clarified that MANF was mainly expressed in intestinal macrophages and was capable of inducing apoptosis and decreasing the inflammation of pro-inflammatory macrophages in both NEC intestinal tissues and BMDMs. Mechanismly, MANF protein significantly inhibited the apoptosis of intestinal epithelial cells and protected epithelial tight junctions through downregulation of the NF-κB pathway in pro-inflammatory macrophages. These results reveal the crucial function of human milk-derived MANF in intestinal macrophages, which contributes to downregulating the intestinal inflammatory response and protecting the homeostasis of intestinal epithelial cells. Our study not only demonstrates a potential mechanism underlying breastfeeding protective effects in NEC but also, more importantly, enables clinical translation, facilitating new strategies for the development of nutritional interventions in the prevention of NEC.

Probiotics and novel probiotic delivery systems

Necrotizing enterocolitis (NEC) is an infectious and inflammatory intestinal disease that is the most common surgical emergency in the premature patient population. Although the etiology of the disease is multifactorial, intestinal dysbiosis is a hallmark of this disease. Based on this, probiotics may play a therapeutic role in NEC by introducing beneficial bacteria with immunomodulating, antimicrobial, and anti-inflammatory functions into the gastrointestinal tract. Currently, there is no Food and Drug Administration (FDA)-approved probiotic for the prevention and treatment of NEC. All probiotic clinical studies to date have administered the bacteria in their planktonic (free-living) state. This review will discuss established probiotic delivery systems including planktonic probiotics, prebiotics, and synbiotics, as well as novel probiotic delivery systems such as biofilm-based and designer probiotics. We will also shed light on whether or not probiotic efficacy is influenced by administration with breast milk. Finally, we will consider the challenges associated with developing an FDA-approved probiotic for NEC.

Probiotics to prevent necrotizing enterocolitis in very low birth weight infants: A network meta-analysis.

This study aims to review the evidence for the optimal regimen of probiotics for the prevention of necrotizing enterocolitis (NEC) in very low birth weight infants. Through searching PubMed, EMBASE, Cochrane Library, and Web of Science till September 30, 2022, only randomized controlled trials were included to evaluate the optimal regimen of probiotics for the prevention of NEC in very low birth weight infants. The methodological quality of the included studies was assessed by the Cochrane risk of bias assessment tool (RoB 2), and the collected data were analyzed accordingly using Stata software. Twenty-seven RCTs were included, and the total sample size used in the study was 529. The results of the network meta-analysis showed that Bovine lactoferrin + Lactobacillus rhamnosus GG (RR 0.03; 95% CI 0.00-0.35), Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis (RR 0.06; 95% CI 0.00-0.70), Bifidobacterium lactis + inulin (RR 0.16; 95% CI 0.03-0.91) were superior to the control group (Bifidobacterium lactis + Bifidobacterium longum) in reducing the incidence of NEC. The reduction in the incidence of NEC were as follows: Bovine lactoferrin + Lactobacillus rhamnosus GG (SUCRA 95.7%) > Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis (SUCRA 89.4%) > Bifidobacterium lactis + inulin (SUCRA 77.8%). This network meta-analysis suggests that Lactobacillus rhamnosus GG combined with bovine lactoferrin maybe the most recommended regimen for the prevention of NEC in very low birth weight infants.

Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites.

Necrotizing enterocolitis (NEC) is a life-threatening disease that predominantly affects very low birth weight preterm infants. Development of NEC in preterm infants is accompanied by high mortality. Surgical treatment of NEC can be complicated by short bowel syndrome, intestinal failure, parenteral nutrition-associated liver disease, and neurodevelopmental delay. Issues surrounding pathogenesis, prevention, and treatment of NEC remain unclear. This review summarizes data on prenatal risk factors for NEC, the role of pre-eclampsia, and intrauterine growth retardation in the pathogenesis of NEC. The role of hypoxia in NEC is discussed. Recent data on the role of the intestinal microbiome in the development of NEC, and features of the metabolome that can serve as potential biomarkers, are presented. The Pseudomonadota phylum is known to be associated with NEC in preterm neonates, and the role of other bacteria and their metabolites in NEC pathogenesis is also discussed. The most promising approaches for preventing and treating NEC are summarized.

Efficacy of Probiotics in Preterm Neonates in the Prevention of Necrotising Enterocolitis: A Randomised Controlled Tria

Introduction: The most frequent and dangerous gastrointestinal emergency in newborns is Necrotising Enterocolitis (NEC). A novel and promising strategy for preventing NEC is enterally given probiotics. Aim: To evaluate the efficacy of probiotics in preterm neonates in the prevention of NEC and to assess the time of achievement of full feeds and duration of Intensive Care Unit (ICU) stay. Materials and Methods: The present study was a parallel design single-centre randomised controlled trial, conducted in Neonatal Intensive Care Unit (NICU), Department of Paediatrics, Kempegowda Institute of Medical Sciences, Bangalore, Karnataka, India, from November 2018 to April 2020. Total of 130 newborns were included after inclusion and exclusion criteria and were randomised into two groups: that is probiotic (group I, n=61) and non probiotic (group II, n=69) groups. The probiotic group was given probiotics with breastmilk and non probiotic group were given only breastmilk. Probiotic (Bifidobacterium breve M16V) 0.5 g was mixed with breastmilk and given twice daily till full feeds were reached. All neonates were followed-up on daily basis for the appearance of features of NEC. Other parameters like time of achievement of full feeds and duration of ICU stay were compared between the two groups. Descriptive and inferential statistical analysis was carried out in the present study. Results: Out of total sample, majority of babies belonged to the gestational age group of 30-33 weeks i.e., 30 (49.2%) in group I and 30 (43.5%) in group II. There were 29 (47.5%) females and 32 (52.5%) males in group I and, 32 (46.4%) females and 37 (53.6%) males in group II. There was a significant reduction of incidence of NEC (p-value=0.024) and earlier achievement of full feeds in the probiotic group (p-value=0.003) when compared to non probiotic group. The mean duration of ICU stay compared between the two groups was not statistically significant (p-value=0.366). Conclusion: Supplementation of probiotics to the preterm Low Birth Weight (LBW) babies helps in the reduction of incidence of NEC and also helps in earlier achievement of full feeds.

Butyrate induces development-dependent necrotizing enterocolitis-like intestinal epithelial injury via necroptosis.

The accumulation of short-chain fatty acids (SCFAs) from bacterial fermentation may adversely affect the under-developed gut as observed in premature newborns at risk for necrotizing enterocolitis (NEC). This study explores the mechanism by which specific SCFA fermentation products may injure the premature newborn intestine mucosa leading to NEC-like intestinal cell injury. Intraluminal injections of sodium butyrate were administered to 14- and 28-day-old mice, whose small intestine and stool were harvested for analysis. Human intestinal epithelial stem cells (hIESCs) and differentiated enterocytes from preterm and term infants were treated with sodium butyrate at varying concentrations. Necrosulfonamide (NSA) and necrostatin-1 (Nec-1) were used to determine the protective effects of necroptosis inhibitors on butyrate-induced cell injury. The more severe intestinal epithelial injury was observed in younger mice upon exposure to butyrate (p = 0.02). Enterocytes from preterm newborns demonstrated a significant increase in sensitivity to butyrate-induced cell injury compared to term newborn enterocytes (p = 0.068, hIESCs; p = 0.038, differentiated cells). NSA and Nec-1 significantly inhibited the cell death induced by butyrate. Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury in NEC is necroptosis. Necroptosis inhibition may represent a potential preventive or therapeutic strategy for NEC. Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury caused by butyrate in NEC is necroptosis. Necroptosis inhibitors proved effective at significantly ameliorating the enteral toxicity of butyrate and thereby suggest a novel mechanism and approach to the prevention and treatment of NEC in premature newborns.

137 Standing in the gap of Neonatal Microbe-Host Barrier Function

Abstract The provision of mammary secretions in the form of colostrum and mature milk for newborns is an essential survival function that has evolved over millennia in mammalian species. Colostrum serves a vital function for neonates by providing nutrients for energy and growth as they transition from placental nutrition to oral ingestion of more complex macromolecules, including lactose, proteins, and triglycerides. Colostrum also provides critical immune protection from colonizing commensal and pathogenic microbes that supports neonatal immunity until maturation of the immune system. This concept of homologous passive immunity conferred by colostrum is well known in farm animal species and has been largely attributed to immunoglobulins transferred from mother to offspring. Heterologous passive immunity is also an approach whereby bovine colostrum obtained from normal or hyperimmunized cows is used therapeutically to prevent specific GI diseases in swine and human infants. The critical importance of colostrum to survival of newborn farm animals also holds true in the prevention of intestinal diseases, such as necrotizing enterocolitis (NEC), in hospitalized premature infants. In preterm infants, mother’s own milk may not always be available and infants are instead fed donor human milk, which provides effective protection against NEC. Whether the benefits of human milk in the prevention of NEC are due to immunoglobulins is not well established. These scenarios whereby colostrum from different species or different mothers within a species protect the neonatal gut point to common elements of host protection. New experimental approaches and tools are being applied to understanding the molecular mechanism of how components of maternal milk impact gut microbial colonization and interaction with the host immune system.

Antimicrobial Peptides in Early-Life Host Defense, Perinatal Infections, and Necrotizing Enterocolitis-An Update.

Host defense against early-life infections such as chorioamnionitis, neonatal sepsis, or necrotizing enterocolitis (NEC) relies primarily on innate immunity, in which antimicrobial peptides (AMPs) play a major role. AMPs that are important for the fetus and neonate include α and β defensins, cathelicidin LL-37, antiproteases (elafin, SLPI), and hepcidin. They can be produced by the fetus or neonate, the placenta, chorioamniotic membranes, recruited neutrophils, and milk-protein ingestion or proteolysis. They possess antimicrobial, immunomodulating, inflammation-regulating, and tissue-repairing properties. AMPs are expressed as early as the 13th week and increase progressively through gestation. Limited studies are available on AMP expression and levels in the fetus and neonate. Nevertheless, existing evidence supports the role of AMPs in pathogenesis of chorioamnionitis, neonatal sepsis, and NEC, and their association with disease severity. This suggests a potential role of AMPs in diagnosis, prevention, prognosis, and treatment of sepsis and NEC. Herein, we present an overview of the antimicrobial and immunomodulating properties of human AMPs, their sources in the intrauterine environment, fetus, and neonate, and their changes during pre- and post-natal infections and NEC. We also discuss emerging data regarding the potential utility of AMPs in early-life infections, as diagnostic or predictive biomarkers and as therapeutic alternatives or adjuncts to antibiotic therapy considering the increase of antibiotic resistance in neonatal intensive care units.

Adenosine Alleviates Necrotizing Enterocolitis by Enhancing the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Newborns.

Necrotizing enterocolitis (NEC) is a common disorder in premature infants that is characterized by hyperinflammation and severe necrosis in the intestine. The pathogenesis of NEC remains to be elucidated. In this study, we demonstrate that adenosine, a metabolite more abundant in infants than in adults, plays an important role in the prevention of NEC. Administration of adenosine or its analog, adenosine-5'-N-ethyluronamide (NECA), dramatically relieved the severity of NEC in neonatal mice. Meanwhile, adenosine treatment significantly enhanced the immunosuppressive function, antibacterial activity, and migration of myeloid-derived suppressor cells (MDSCs). However, depletion of MDSCs or inhibition of their migration using the CXCR2 inhibitor SB225002 almost completely abrogated the protective effect of adenosine on NEC. Mechanistic studies showed that MDSCs in newborns expressed abundant adenosine receptor A2B (A2BR) that elicits intracellular cAMP signaling and its downstream target NF-κB. Importantly, intestinal tissues from patients with NEC showed significantly lower infiltration of A2BR-positive MDSCs than those from healthy donors. These observations revealed that adenosine-induced MDSCs represent an essential immune axis for intestinal homeostasis in newborns.

Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury

Necrotizing enterocolitis (NEC), an acute intestinal inflammatory disease of premature infants, is one of the leading causes of death in neonates. Effective measures for clinical treatment are limited and there is a pressing need in searching for new therapeutic strategies. Jumonji domain-containing protein D3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase plays a proinflammatory role in sepsis and neuroinflammation. However, whether JMJD3 is involved in the pathogenesis of NEC has not been elucidated. Here we report that overexpressed JMJD3 was revealed in the intestine of NEC patients by bioinformatic analysis. Moreover, upregulated JMJD3 and suppressed H3K27me3 were detected in both NEC patients and neonatal mice subjected to experimental NEC. Importantly, administration of GSK-J4, a specific JMJD3 inhibitor, rescued neonatal mice from NEC-associated lethality by suppressing proinflammatory response with attenuated IL-6, TNF-α, and MCP-1 levels and ameliorating intestinal injury with reversed claudin-1, occludin, and E-cadherin expression. Remarkably, administration of GSK-J4 attenuated intestinal injury by inhibiting activation of intestinal necroptosis in NEC mice. Administration of GSK-J4 regulated intestinal inflammation via NF-κB and JAK2/STAT3 pathway. These results indicate that JMJD3 is involved in the development of NEC and inhibition of JMJD3 overexpression by mean of GSK-J4 could be a potential therapeutic approach in the prevention and treatment of NEC.

Donor-dependent fecal microbiota transplantation efficacy against necrotizing enterocolitis in preterm pigs

The development of necrotizing enterocolitis (NEC), a life-threatening inflammatory bowel disease affecting preterm infants, is connected with gut microbiota dysbiosis. Using preterm piglets as a model for preterm infants we recently showed that fecal microbiota transplantation (FMT) from healthy suckling piglet donors to newborn preterm piglets decreased the NEC risk. However, in a follow-up study using donor stool from piglets recruited from another farm, this finding could not be replicated. This allowed us to study donor-recipient microbiota dynamics in a controlled model system with a clear difference in NEC phenotype. Preterm piglets (n = 38) were randomly allocated to receive control saline (CON), or rectal FMT using either the ineffective (FMT1) or the effective donor stool (FMT2). All animals were followed for four days before necropsy and gut pathological evaluation. Donor and recipient colonic gut microbiota (GM) were analyzed by 16 S rRNA gene amplicon sequencing and shotgun metagenomics. As expected, only FMT2 recipients were protected against NEC. Both FMT groups had shifted GM composition relative to CON, but FMT2 recipients had a higher lactobacilli relative abundance compared to FMT1. Limosilactobacillus reuteri and Lactobacillus crispatus strains of FMT recipients showed high phylogenetic similarity with their respective donors, indicating engraftment. Moreover, the FMT2 group had a higher lactobacilli replication rate and harbored specific glycosaminoglycan-degrading Bacteroides. In conclusion, subtle species-level donor differences translate to major changes in engraftment dynamics and the ability to prevent NEC. This could have implications for proper donor selection in future FMT trials for NEC prevention.