New Insights Into the Pathogenesis and Treatment of Necrotizing Enterocolitis: Toll-Like Receptors and Beyond

Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
Pediatric Research (Impact Factor: 2.31). 03/2011; 69(3):183-8. DOI: 10.1203/PDR.0b013e3182093280
Source: PubMed


Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in the preterm infant. The dismal results of current treatment for NEC highlight the urgent need for greater understanding of the pathogenesis of this disease, and the importance of discovering novel, molecular-specific therapies for it. Current dogma indicates that NEC development reflects an abnormal response by the premature infant to the microbial flora that colonizes the gastrointestinal tract, although the mechanisms that mediate these abnormal bacterial-enterocyte interactions and the reasons for the particularly increased susceptibility of the premature infant to the development of NEC remain incompletely explained. Recent evidence has shed light on an emerging role for the Toll-like receptors (TLRs) of the innate immune system as central players in the pathways that signal in response to enteric bacteria resulting in the development of NEC. We now review recent advances in the field of NEC and identify several exciting potential avenues for novel treatments by focusing on abnormal TLR4 signaling in the premature intestine in the pathogenesis of NEC. In so doing, we seek to offer new hope to the patients and their families who are affected by this devastating disorder.

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    • "Survivors of NEC are at higher risk for developing short bowel syndrome, cholestatic liver disease as well as impaired growth and neurodevelopmental outcomes[4]. Several epidemiological risk factors have been proposed to play major roles in the pathogenesis of NEC, including preterm birth, enteral feeding and abnormal bacterial colonization[5,6]. Only prematurity has been recognized in the literature as an established risk factor for NEC, although the exact mechanism has not yet been fully elucidated[1,2]. "
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    ABSTRACT: Background: Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units. The challenge for neonatologists is to detect early clinical manifestations of NEC. One strategy would be to identify specific markers that could be used as early diagnostic tools to identify preterm infants most at risk of developing NEC or in the event of a diagnostic dilemma of suspected disease. As a first step in this direction, we sought to determine the specific gene expression profile of NEC. Methods: Deep sequencing (RNA-Seq) was used to establish the gene expression profiles in ileal samples obtained from preterm infants diagnosed with NEC and non-NEC conditions. Data were analyzed with Ingenuity Pathway Analysis and ToppCluster softwares. Results: Data analysis indicated that the most significant functional pathways over-represented in NEC neonates were associated with immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors for bacteria and viruses. Among the genes that were strongly modulated in neonates with NEC, we observed a significant degree of similarity when compared with those reported in Crohn's disease, a chronic inflammatory bowel disease. Conclusions: Gene expression profile analysis revealed a predominantly altered immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn's disease gene expression repertoires revealed a surprisingly high degree of similarity between these two conditions suggesting a new avenue for identifying NEC biomarkers.
    Full-text · Article · Jan 2016 · BMC Medical Genomics
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    • "Neonatal necrotizing enterocolitis (NEC) represents the most common intestinal disease of prematurely born babies. As it is associated with excessive morbidity and mortality [9,10], it remains a serious problem. Current treatment strategies include introduction of broad-spectrum antibiotics, discontinuation of enteral feedings, or intravenous hyper- alimentation [9]. "

    Full-text · Article · Jan 2015
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    • "NEC is the leading cause of death from gastrointestinal disease in premature infants, and is characterized by a marked increase in acute inflammation of the intestinal mucosa that leads to epithelial cell death and systemic sepsis [24]. Despite advances in neonatal care, overall survival has remained unchanged in the past two decades, in large part due to a lack of specific therapies for this devastating disease [25]. We [26] and others [27] recently determined that the development of NEC in mice, rats and humans reflects increased TLR4 signaling in the premature host, as exaggerated TLR4 signaling within the gut leads to increased enterocyte apoptosis and elevated pro-inflammatory cytokine release [3]. "
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    ABSTRACT: Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases.
    Full-text · Article · Jun 2013 · PLoS ONE
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