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
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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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    • "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.
    PLoS ONE 06/2013; 8(6):e65779. DOI:10.1371/journal.pone.0065779 · 3.23 Impact Factor
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    • "We [5] and others [6] have shown that the initial injury to the small intestine primarily involves the loss of epithelial villi through apoptosis, which subsequently leads to the development of necrosis, a process that is consistent yet only incompletely explained. Loss of the epithelial barrier through apoptosis permits the translocation of bacteria and other antigens that are present within the lumen of the intestine, and which must normally be appropriately shielded from the immune system of the premature host in order to prevent the exaggerated inflammatory response, that is, typical of intestinal inflammatory conditions such as NEC [7] [8]. In response to the loss of epithelial continuity (which may be reflective of primary apoptosis or the early events that migh culminate in apoptosis), a multipronged healing program is initiated. "
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    ABSTRACT: Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host.
    Clinical and Developmental Immunology 05/2013; 2013(4):475415. DOI:10.1155/2013/475415 · 2.93 Impact Factor
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    • "The microbial community of preterm infants, compared to healthy, term infants, consists of dramatically fewer beneficial species, lower bacterial diversity, and more pathogens [9-12]. NEC does not occur in germ-free animals, lending credence to the importance of intestinal colonization to the development of NEC [13]. Several epidemiologic studies in preterm infants report an association between early empirical antibiotic use and subsequently increased risk of NEC, while randomized, controlled trials in preterm infants suggest that probiotic agents may reduce the risk of NEC [7,8,14]. "
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    ABSTRACT: Background: Necrotizing enterocolitis (NEC) is a devastating intestinal disease that afflicts 10% of extremely preterm infants. The contribution of early intestinal colonization to NEC onset is not understood, and predictive biomarkers to guide prevention are lacking. We analyzed banked stool and urine samples collected prior to disease onset from infants <29 weeks gestational age, including 11 infants who developed NEC and 21 matched controls who survived free of NEC. Stool bacterial communities were profiled by 16S rRNA gene sequencing. Urinary metabolomic profiles were assessed by NMR. Results: During postnatal days 4 to 9, samples from infants who later developed NEC tended towards lower alpha-diversity (Chao1 index, p=0.086) and lacked Propionibacterium (p=0.009) compared to controls. Furthermore, NEC was preceded by distinct forms of dysbiosis. During days 4 to 9, samples from four NEC cases were dominated by members of the Firmicutes (median relative abundance: >99% vs <17% in the remaining NEC and controls, p<0.001). During postnatal days 10 to 16, samples from the remaining NEC cases were dominated by Proteobacteria, specifically Enterobacteriaceae (median relative abundance >99% vs 38% in the other NEC cases and 84% in controls, p=0.01). NEC preceded by Firmicutes dysbiosis occurred earlier (onset, days 7 to 21) than NEC preceded by Proteobacteria dysbiosis (onset, days 19 to 39). All NEC cases lacked Propionibacterium and were preceded by either Firmicutes (>98% relative abundance, days 4 to 9) or Proteobacteria (>90% relative abundance, days 10 to 16) dysbiosis, while only 25% of controls had this phenotype (predictive value 88%, p=0.001). Analysis of days 4 to 9 urine samples found no metabolites associated with all NEC cases, but alanine was positively associated with NEC cases that were preceded by Firmicutes dysbiosis (p<0.001) and histidine was inversely associated with NEC cases preceded by Proteobacteria dysbiosis (p=0.013). A high urinary alanine:histidine ratio was associated with microbial characteristics (p<0.001) and provided good prediction of overall NEC (predictive value 78%, p=0.007). Conclusions: Early dysbiosis is strongly involved in the pathobiology of NEC. These striking findings require validation in larger studies but indicate that early microbial and metabolomic signatures may provide highly predictive biomarkers of NEC.
    04/2013; 1(1):13. DOI:10.1186/2049-2618-1-13
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