Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou Q
PROVIDER: S-EPMC8762998 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The nature and role of the intestinal leukocytes in necrotizing enterocolitis (NEC), a severe disease affecting premature infants, remain unknown. We now show that the intestine in mouse and human NEC is rich in lymphocytes that are required for NEC development, as recombination activating gene 1–deficient (Rag1–/–) mice were protected from NEC and transfer of intestinal lymphocytes from NEC mice into naive mice induced intestinal inflammation. The intestinal expression of the lipopolysaccharide receptor TLR4, which is higher in the premature compared with full-term human and mouse intestine, is required for lymphocyte influx through TLR4-mediated upregulation of CCR9/CCL25 signaling. TLR4 also mediates a STAT3-dependent polarization toward increased proinflammatory CD3+CD4+IL-17+ and reduced tolerogenic Foxp3+ Treg lymphocytes (Tregs). Th17 lymphocytes were required for NEC development, as inhibition of STAT3 or IL-17 receptor signaling attenuated NEC in mice, while IL-17 release impaired enterocyte tight junctions, increased enterocyte apoptosis, and reduced enterocyte proliferation, leading to NEC. Importantly, TLR4-dependent Th17 polarization could be reversed by the enteral administration of retinoic acid, which induced Tregs and decreased NEC severity. These findings identify an important role for proinflammatory lymphocytes in NEC development via intestinal epithelial TLR4 that could be reversed through dietary modification.
| S-EPMC4731173 | biostudies-literature
Project description:BackgroundNecrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC.MethodsBrains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC.ResultsNEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively.ConclusionsNEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage.
| S-EPMC6511222 | biostudies-literature
Project description:Background: Neonatal necrotizing enterocolitis (NEC) is a complex and lethal inflammatory bowel necrosis that primarily affects premature infants. Gut dysbiosis has been implicated in the pathogenesis of NEC. We aim to assess the association between NEC and two other diseases in children, including allergic diseases and constipation, considered to be associated with the alterations in gut microbiota composition. Methods: This retrospective population-based cohort study was conducted using the Taiwan Birth Registration Database, Birth Certificate Application, and National Health Insurance Research Database to inter-link the medical claims of neonates and their mothers. A total of 2,650,634 delivery events were retrieved from 2005 to 2015. We identified a NEC cohort and selected a comparison cohort according to propensity score matching (1:1). Cox proportional hazard regression models were used to determine possible associations of predictors and to obtain adjusted hazard ratios (aHRs). Results: A total of 1,145 subjects in the NEC cohort and 1,145 subjects in the matched cohort were analyzed during the observation period. No significant difference was observed in the incidence of allergic diseases between the two groups. NEC patients had a significant 30.7% increased risk of developing constipation (aHR = 1.307; 95% CI 1.089-1.568). The cumulative incidence of constipation was significantly higher in the NEC cohort than in the matched cohort by the end of follow-up (log-rank test P = 0.003). Conclusion: Infants with NEC have a significantly higher incidence rate of developing constipation and FTT but no increased risk of allergic diseases.
| S-EPMC7147349 | biostudies-literature
Project description:BackgroundThe objective of this study was to determine the risk factors and outcomes of white matter brain injury (WMBI) on magnetic resonance imaging (MRI) at term-equivalent age in infants with surgical necrotizing enterocolitis (NEC).MethodsThis retrospective study compared clinical/pathological information between infants with and those without WMBI.ResultsOut of 69 infants with surgical NEC, 17 (24.6%) had mild WMBI, 13 (18.8%) had moderate WMBI, and six (8.7%) had severe WMBI on the brain MRI. Several clinical factors (gestational age, more red blood cell (RBC) transfusions before NEC onset, pneumoperitoneum, earlier NEC onset age, postoperative ileus, acute kidney injury (AKI) by serum creatinine, postnatal steroids, hospital stay) and histopathological findings (necrosis, hemorrhage) had univariate associations with WMBI. Associations with RBC transfusion (odds ratio (OR) 23.6 [95% confidence interval (CI): 4.73-117.97]; p = 0.0001), age at NEC onset (OR 0.30 [95%CI: 0.11-0.84]; p = 0.021), necrosis (OR 0.10 [95%CI: 0.01-0.90]; p = 0.040), and bowel hemorrhage (OR 7.79 [95%CI: 2.19-27.72]; p = 0.002) persisted in multivariable association with grade 3-4 WMBI. The infants with WMBI had lower mean motor, cognitive, language scores, and higher ophthalmic morbidity at 2 years of age.ConclusionsThe WMBI was most likely associated with earlier NEC onset, higher RBC transfusions, and less necrosis and greater hemorrhage lesions on intestinal pathology in preterm infants with surgical NEC.ImpactIn preterm infants with surgical NEC, brain MRI showed injury in the white matter in 52%, gray matter in 10%, and cerebellar region in 30%. Preterm infants with severe WMBI (grade 3-4) had less necrosis and greater hemorrhagic lesions on histopathology of the bowel. Preterm infants with WMBI were more likely to have a more severe postoperative course, AKI, and longer length of hospitalization. Neuroprotective strategies to prevent brain injury in preterm infants with surgical NEC are needed with the goal of improving the neurodevelopmental outcomes.
| S-EPMC10308193 | biostudies-literature
Project description:BackgroundNecrotizing enterocolitis (NEC) is the leading cause of neonatal gastrointestinal-related death, while the etiology and pathogenesis are poorly understood.MethodsThe levels of CCL3 in intestinal tissue from modeling mice and patients were measured and analyzed. HE staining, TUNEL, Annexin and FCM were used to assess pathological changes and apoptosis in intestinal tissue and epithelial cells. CCL3, CCR4, cytokines, tight junction protein ZO-1, apoptosis-related genes and ERK1/2-NF-κB signaling pathway were detected by ELISA, Q-PCR, Western blotting and immunofluorescence.ResultsCCL3 levels in the intestinal tissue significantly elevated in patients with NEC and mouse models. Blockade of CCL3 significantly alleviated NEC-related intestinal tissue damage, while administration of recombinant CCL3 aggravated intestinal injury by exacerbating intestinal epithelial cell apoptosis in NEC mice. Importantly, CCR4 blockade reversed CCL3-mediated damage to intestinal tissue and intestinal epithelial cell apoptosis both in vivo and in vitro. Further mechanistic studies showed that CCL3 regulated apoptosis-related BAX/BCL-2 expression through the activation of the ERK1/2 and NF-κB pathways, which could be reversed by anti-CCR4 treatment. Furthermore, ERK1/2 inhibition reduced CCL3-mediated phosphorylation of NF-κB in IEC-6 cells, while inhibition of NF-κB had no obvious effect on ERK1/2 phosphorylation. As expected, inhibition of NF-κB regulated BAX/BCL-2 expression and alleviated CCL3-induced epithelial cell apoptosis. These results indicate that high expression of CCL3 in NEC lesions promotes intestinal epithelial apoptosis through the CCL3-CCR4-ERK1/2-NFκB-BAX/BCL2 signalling axis, thereby exacerbating NEC-related intestinal injury.ConclusionsOur study represents an important conceptual advance that CCL3 may be one of the key culprits of intestinal tissue damage in NEC patients, and blocking either CCL3, CCR4, or NF-κB may represent a novel effective immunotherapy for NEC.
| S-EPMC9073010 | biostudies-literature
Project description:BackgroundNecrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.MethodsFecal samples from human neonates and mouse pups were analyzed by HPLC - MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.ResultsThe levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.ConclusionSuccinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.
| S-EPMC9742382 | biostudies-literature
Project description:Although currently available data are variable, it appears that the incidence of surgical necrotizing enterocolitis (NEC) has not decreased significantly over the past decade. Pneumoperitoneum and clinical deterioration despite maximal medical therapy remain the most common indications for operative treatment. Robust studies linking outcomes with specific indications for operation are lacking. Promising biomarkers for severe NEC include fecal calprotectin and S100A12; serum fatty acid-binding protein; and urine biomarkers. Recent advances in ultrasonography make this imaging modality more useful in identifying surgical NEC and near-infrared spectroscopy (NIRS) is being actively studied. Another fairly recent finding is that regionalization of care for infants with NEC likely improves outcomes. The neurodevelopmental outcomes after surgical treatment are known to be poor. A randomized trial near completion will provide robust data regarding neurodevelopmental outcomes after laparotomy versus drainage as the initial operative treatment for severe NEC.
| S-EPMC5777619 | biostudies-other
Project description:AimsThe objective of this study is to determine the incidence of and risk factors for necrotizing enterocolitis (NEC) and transfusion-associated NEC (TANEC) in very-low-birth-weight (VLBW) infants pre/post implementation of a peri-transfusion feeding protocol.Study designA retrospective cohort study was conducted including all inborn VLBW infants admitted to the Duke intensive care nursery from 2002 to 2010. We defined NEC using Bell's modified criteria IIA and higher and TANEC as NEC occurring within 48h of a packed red blood cell (pRBC) transfusion. We compared demographic and laboratory data for TANEC vs. other NEC infants and the incidence of TANEC pre/post implementation of our peri-transfusion feeding protocol. We also assessed the relationship between pre-transfusion hematocrit and pRBC unit age with TANEC.ResultsA total of 148/1380 (10.7%) infants developed NEC. Incidence of NEC decreased after initiating our peri-transfusion feeding protocol: 126/939 (12%) to 22/293 (7%), P=0.01. The proportion of TANEC did not change: 51/126 (41%) vs. 9/22 (41%), P>0.99. TANEC infants were smaller, more likely to develop surgical NEC, and had lower mean pre-transfusion hematocrits prior to their TANEC transfusions compared with all other transfusions before their NEC episode: 28% vs. 33%, P<0.001. Risk of TANEC was inversely related to pre-transfusion hematocrit: odds ratio 0.87 (0.79-0.95).ConclusionsPre-transfusion hematocrit is inversely related to risk of TANEC, which suggests that temporally maintaining a higher baseline hemoglobin in infants most at risk of NEC may be protective. The lack of difference in TANEC pre-/post-implementation of our peri-transfusion feeding protocol, despite an overall temporal decrease in NEC, suggests that other unmeasured interventions may account for the observed decreased incidence of NEC.
| S-EPMC4050434 | biostudies-literature
Project description:In this review, we summarize existing knowledge regarding the effects of probiotics on necrotizing enterocolitis (NEC). We review the role of the microbiome in NEC and pre-clinical data on mechanisms of probiotic action. Next, we summarize existing randomized controlled trials and observational studies of probiotics to prevent NEC. We also summarize findings from several recent meta-analyses and report a new cumulative meta-analysis of probiotic trials. Finally, we review data from cohorts routinely using commercially available probiotics. Our goal is to inform clinicians about the risks and benefits of probiotics, which may be helpful for those considering use in preterm infants to prevent NEC, death, or sepsis.
| S-EPMC5844696 | biostudies-literature
Project description:BackgroundNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.Methods3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.ResultsAdult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.ConclusionsOur study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.
| S-EPMC5560643 | biostudies-literature