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Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model.

ABSTRACT: Necrotizing enterocolitis (NEC) is a complex disease involving prematurity, enteral feeding, and bacterial effects. We propose that the underlying initial condition in its pathogenesis is reduced ability of the neonatal gut epithelial cells (NGECs) to clear oxidative stress (OS), and that when such a NGEC population is exposed to enteral feeding, the increased metabolic OS tips the population toward apoptosis, inflammation, bacterial activation, and eventual necrosis. The multi-factorial complexity of NEC requires characterization with computational modeling, and herein, we used an agent-based model (ABM) to instantiate and examine our unifying hypothesis of the pathogenesis of NEC.An ABM of the neonatal gut was created with NGEC computational agents incorporating rules for pathways for OS, p53, tight junctions, Toll-like receptor (TLR)-4, nitric oxide, and nuclear factor-kappa beta (NF-?B). The modeled bacteria activated TLR-4 on contact with NGECs. Simulations included parameter sweeps of OS response, response to feeding, addition of bacteria, and alterations in gut mucus production.The ABM reproduced baseline cellular respiration and clearance of OS. Reduction in OS clearance consistent with clinical NEC led to senescence, apoptosis, or inflammation, with disruption of tight junctions, but rarely to NGEC necrosis. An additional "hit" of bacteria activating TLR-4 potentiated a shift to NGEC necrosis across the entire population. The mucus layer was modeled to limit bacterial-NGEC interactions and reduce this effect, but concomitant apoptosis in the goblet cell population reduced the efficacy of the mucus layer and limited its protective effect in simulated experiments. This finding suggests a means by which increased apoptosis at the cellular population level can lead to a transition to the necrosis outcome.Our ABM incorporates known components of NEC and demonstrates that impaired OS management can lead to apoptosis and inflammation of NGECs, rendering the system susceptible to an additional insult involving regionalized mucus barrier failure and TLR-4 activation, which potentiates the necrosis outcome. This type of integrative dynamic knowledge representation can be a useful adjunct to help guide and contextualize research.

SUBMITTER: Kim M

PROVIDER: S-EPMC3292758 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model.

Kim Moses M Christley Scott S Alverdy John C JC Liu Donald D An Gary G

Surgical infections 20120104 1

<h4>Background</h4>Necrotizing enterocolitis (NEC) is a complex disease involving prematurity, enteral feeding, and bacterial effects. We propose that the underlying initial condition in its pathogenesis is reduced ability of the neonatal gut epithelial cells (NGECs) to clear oxidative stress (OS), and that when such a NGEC population is exposed to enteral feeding, the increased metabolic OS tips the population toward apoptosis, inflammation, bacterial activation, and eventual necrosis. The mult ...[more]

PMID: 22217195

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Project description:ABSTRACT Necrotizing enterocolitis (NEC) is among the most relevant gastrointestinal diseases affecting mostly prematurely born infants with low birth weight. While intestinal dysbiosis has been proposed as one of the possible factors involved in NEC pathogenesis, the role of the gut microbiota remains poorly understood. In this study, the gut microbiota of preterm infants was explored to highlight differences in the composition between infants affected by NEC and infants prior to NEC development. A large-scale gut microbiome analysis was performed, including 47 shotgun sequencing data sets generated in the framework of this study, along with 124 retrieved from publicly available repositories. Meta-analysis led to the identification of preterm community state types (PT-CSTs), which recur in healthy controls and NEC infants. Such analyses revealed an overgrowth of a range of opportunistic microbial species accompanying the loss of gut microbial biodiversity in NEC subjects. Moreover, longitudinal insights into preterm infants prior to NEC development indicated Clostridium neonatale and Clostridium perfringens species as potential biomarkers for predictive early diagnosis of this disease. Furthermore, functional investigation of the enzymatic reaction profiles associated with pre-NEC condition suggested DL-lactate as a putative metabolic biomarker for early detection of NEC onset. IMPORTANCE Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease occurring predominantly in premature infants whose etiology is still not fully understood. In this study, the analysis of infant fecal samples through shotgun metagenomics approaches revealed a marked reduction of the intestinal (bio)diversity and an overgrowth of (opportunistic) pathogens associated with the NEC development. In particular, dissection of the infant’s gut microbiome before NEC diagnosis highlighted the potential involvement of Clostridium genus members in the progression of NEC. Remarkably, our analyses highlighted a gastrointestinal DL-lactate accumulation among NEC patients that might represent a novel potential functional biomarker for the early diagnosis of NEC.

Project description:BackgroundNecrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs).MethodsAn online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts.ResultsOut of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients.ConclusionsVarious pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients.ImpactThis study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units. Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries. A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU. The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

Dataset Information

Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model.

Publications

Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model.

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