Neonatal necrotizing enterocolitis, a disease of the immature intestinal mucosal barrier

Necrotizing enterocolitis (NEC) is an enigmatic process in that one single etiologic factor has been sought and not found. Epidemiologic studies suggest that immaturity of the host plays a very important role. This article reviews the intestinal host defense system and its immature nature early in life in animal models and humans and suggests that it is this immaturity, along with other factors, which allows for the proliferation and invasion of antigens and organism, and the subsequent development of NEC. Data are presented which support the efficacy of pharmacologic maturation of the intestinal barrier with growth factors, either prenatally or postnatally, to decrease the incidence of NEC or, potentially, to provide a more benign course for the disease.     

Mechanisms of nitric oxide-mediated intestinal barrier failure in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the leading intestinal emergency in premature infants. The underlying etiology of NEC remains elusive, but hypoxic conditions and early enteral feeding are consistently implicated as the main risk factors in the pathogenesis of NEC. We postulate that nitric oxide (NO) plays a key role as a molecular signaling "hub" in the generation of gut barrier failure in NEC. Clinical studies suggest that inflammatory cytokines and excessive NO production may contribute to the pathogenesis of NEC. One of the major challenges in defining the critical signaling pathways that lead to the development of NEC is the lack of specific biochemical markers that consistently delineate the early stages of NEC. Intestinal pathology and molecular markers derived from late-stage NEC represent end-stage findings and thus provide little insight into the early events that led to intestinal inflammation. Such markers may not represent viable therapeutic targets for the treatment or prevention of NEC. Therefore, novel strategies are needed to identify the patients at risk for NEC and define the clinically relevant molecules that characterize the early stages of NEC. This review will examine the mechanisms of NO-mediated gut barrier failure and propose novel genetic-based approaches for elucidating the critical molecular pathways in NEC.     

肠屏障功能障碍与新生儿坏死性小肠结肠炎

坏死性小肠结肠炎( necrotizing enterocolitis,NEC)是严重危及新生儿生命的消化系统疾病,是导致新生儿,尤其是早产儿死亡的重要病因之一。新生儿,尤其是早产儿维持肠屏障功能的作用元件发育不成熟,极易受损,不能有效形成上皮细胞间的紧密连接,无法早期形成正常肠道蠕动以及分泌型IgA的减少,因此各种致病因素极易诱发肠屏障功能障碍,导致菌群移位和败血症,造成严重的肠道损害甚至并发症。缺氧缺血、炎症反应、病原体感染均可造成肠机械屏障损害,微生态屏障建立延迟、免疫屏障发育的不成熟以及病理情况下的肠微循环障碍均参与NEC的发生。此外,miRNA在肠上皮细胞的分化、结构和屏障功能调控中也发挥重要作用。 NEC的组织病理改变是肠屏障功能障碍的结果,而肠屏障功能的损害则加重NEC的病理改变。因此,认识肠屏障功能障碍在 NEC发病过程中的作用,对于防治NEC意义重大。     

Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates, and is characterized by the development of diffuse intestinal necrosis in the stressed, pre-term infant. Systemic stress causes a breakdown in the intestinal mucosal barrier, which leads to translocation of bacteria and endotoxin and the initiation of a signaling response within the enterocyte. This review summarizes recent evidence defining a clear role that defective enterocyte signaling plays in the pathogenesis of NEC through the following mechanisms: 1) The localized production of nitric oxide by villus enterocytes results in an increase in enterocyte apoptosis and impaired proliferation; 2) The translocation of endotoxin results in a PI3K-dependent activation of RhoA-GTPase within the enterocyte leading to decreased enterocyte migration and impaired restitution; 3) Dysregulated sodium-proton exchange within the enterocyte by endotoxin renders the enterocyte monolayer more susceptible to damage in the face of the acidic microenvironment characteristic of systemic sepsis; and 4) Endotoxin causes a p38-dependent release of the pro-inflammatory molecule COX-2 by the enterocyte, which potentiates the systemic inflammatory response. An understanding of the mechanisms by which disordered enterocyte signaling contributes to the pathogenesis of barrier failure and NEC--through these and other mechanisms--may lead to the identification of novel therapeutic approaches for this devastating disease.     

Bugs and the barrier: A review of the gut microbiome and intestinal barrier in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that affects premature neonates. It frequently results in significant morbidity and mortality for those affected. Years of research into the pathophysiology of NEC have revealed it to be a variable and multifactorial disease. However, there are risk factors associated with NEC including low birth weight, prematurity, intestinal immaturity, alterations in microbial colonization, and history of rapid or formula based enteral feeds (Fig. 1).1, 2, 3 An accepted generalization of the pathogenesis of NEC includes a hyperresponsive immune reaction to insults such as ischemia, starting formula feeds, or alterations in the microbiome with pathologic bacterial colonization and translocation. This reaction causes a hyperinflammatory response disrupting the normal intestinal barrier, allowing abnormal bacterial translocation and ultimately sepsis.^1,2,4 This review will focus specifically on the interactions with the microbiome and intestinal barrier function in NEC.     

微生态制剂对坏死性小肠结肠炎大鼠肠上皮细胞凋亡和增殖的影响

目的研究复方嗜酸乳杆菌对坏死性小肠结肠炎大鼠肠上皮细胞凋亡及增殖细胞核抗原(PCNA)表达的影响,为应用复方嗜酸乳杆菌防治新生儿坏死性小肠结肠炎(NEC)提供参考。方法36只出生48 h新生SD大鼠,采用随机数字表法分为正常组、模型组、干预组,每组12只。采用缺氧加冷刺激3 d建立NEC模型,干预组在建模同时给予复方嗜酸乳杆菌;于模型建立后禁食12 h处死所有大鼠,剖取其肠组织采用原位末端标记法(terminal-deoxynucleoitidyl transferase mediated nick end labeling,TUNEL)测定细胞凋亡情况,采用实时荧光定量PCR检测大鼠肠组织中PCNA基因表达情况。结果1.大鼠肠组织细胞凋亡的检测结果:模型组、正常组、干预组凋亡指数分别为(88.33±2.77)%、(4.75±0.75)%、(44.41±4.81)%,各组间两两比较差异均有统计学意义(均P<0.05)。2.大鼠肠组织中PCNA基因表达结果:模型组、正常组、干预组PCNA基因mRNA表达水平分别为(9.28±3.26)×10^-4、(15.35±1.91)×10^-4、(12.09±3.06)×10^-4,各组间两两比较差异均有统计学意义(均P<0.05)。结论NEC时新生大鼠肠上皮细胞凋亡增加,PCNA表达减少;复方嗜酸乳杆菌能减少细胞凋亡,促进肠上皮细胞增殖,可能有助于降低新生大鼠发生NEC的风险及严重程度。     

The role of the intestinal microcirculation in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) continues to be a devastating inflammatory disease of the newborn intestine. Despite advances in management, morbidity and mortality remain high. While it is clear that intestinal ischemia plays a large role in disease pathogenesis, attempts to link NEC to intestinal macrovascular derangement have been largely unsuccessful. More recently, there has been a concerted effort to characterize the pathologic changes of the intestinal microcirculation in response to intestinal injury, including NEC. This microcirculatory regulation is controlled by a balance of vasoconstrictor and vasodilator forces. Vasoconstriction is mediated primarily by endothelin-1 (ET-1), while vasodilation is mediated primarily by nitric oxide (NO). These chemical mediators have been implicated in many aspects of intestinal ischemic injury and NEC, with the balance shifting toward increased vasoconstriction associated with intestinal injury. With a proper understanding of these antagonistic forces, potential therapeutic avenues may result from improving this pathologic microcirculatory dysregulation.     

Late intestinal strictures following successful treatment of necrotizing enterocolitis

Between 1975 and 1992, in 16 infants (14%) out of 113 neonates with previous necrotizing enterocolitis (NEC) a total of 25 intestinal strictures had to be treated. Four (16%) were found in the ileum and 21 (84%) in the colon, and in 50% multiple strictures were present. In these 16 patients initial treatment for acute NEC included conservative treatment in 5, primary resection and enterostomies in 6 and proximal diverting enterostomies in 5. Therefore, the incidence of late strictures was 11% after conservative therapy, 11% after primary resection and 55% after primary proximal diverting enterostomies. An average of 49 days elapses between the recovery from NEC and the diagnosis of late strictures in conservatively treated patients. After initial surgical treatment, late strictures were detected on contrast studies on an average of 80 days. In pathologic specimens, marked fibrosis in the submucosa was consistently present in all strictures, whereas inflammatory changes in the mucosa, disruption or hypertrophy of the muscle layers or absence of ganglion cells were seen less frequently. All strictures were resected and primary end-to-end anastomosis was performed. But despite the development of late intestinal strictures, bowel preservation was improved after initial restrictive surgical therapy and aggressive medical treatment.     

Comparative study between isolated intestinal perforation and necrotizing enterocolitis.

INTRODUCTION: Intestinal perforations in the neonatal period are usually related to necrotizing enterocolitis (NEC) or intestinal occlusion. Intestinal perforation in the absence of these conditions is called isolated perforation (IP). Several risk factors and pathogenic mechanisms have been suggested, and most of them are common to those classically attributed to NEC. AIM: To identify and compare the clinical and pathological features of IP and NEC. MATERIAL AND METHODS: We reviewed all cases of neonatal intestinal perforation and NEC in the last five years. Thirty-three patients were retrospectively classified into Group NEC: 24 cases, and Group IP: 9 cases. We collected multiple data as study variables: 1) General features; 2) Obstetric history; 3) Neonatal treatment; 4) Comorbidity; 5) Perforation features; 6) Treatment and outcome. RESULTS: Comparing the groups, we found statistical significant differences in isolated perforation cases with these risk factors: extreme prematurity, very low birth weight, abruptio placenta, intubation and neonatal mechanical ventilation, umbilical catheterization, precocious sepsis, and indomethacin therapy. A more precocious operation and a good prognosis also reached statistical significance. In the other hand, we found statistically significant differences in NEC with congenital cardiopathy (excluding isolated patent ductus arteriosus), with intestinal pneumatosis, with diffuse bowel involvement and a worse prognosis. Risk factors and pathologic findings seem to support an ischaemic pathogenesis in both diseases.     

Spontaneous intestinal perforation and Candida peritonitis presenting as extensive necrotizing enterocolitis

Spontaneous intestinal perforation (SIP) has been increasingly reported in very-low-birthweight (VLBW) infants, although it is still less common than necrotizing enterocolitis (NEC). In around one-third of cases, SIP is associated with systemic candidiasis. We describe a case of SIP and Candida peritonitis in a VLBW infant, which was mistakenly diagnosed as NEC during the infant's short life. At laparotomy, the bowel surface was black and thought to be necrotic. As the infant was thought to have whole-bowel necrosis due to NEC, her condition was deemed incompatible with survival. At postmortem, however, the bowel wall was found to be healthy apart from a very localized patch of necrosis associated with a single perforation. The bowel was covered by a thick, black, serosal exudate consisting of fungal elements from Candida albicans. CONCLUSION: This case reinforces the fact that a markedly discoloured bowel is not necessarily necrotic and that the discoloration can potentially recover.     

Probiotics and necrotizing enterocolitis

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.     

Feeding and necrotizing enterocolitis

Twenty-six infants had necrotizing enterocolitis (NEC) in the neonatal unit of the Long Island Jewish-Hillside Medical Center, New Hyde Park, NY, between 1964 and 1976; 25 of these cases occurred between 1973 and 1976. The relationship of feeding practices to this clustering of NEC cases was investigated in two ways: (1) A 10% sample of all admissions, 1964 to 1976, was studied. A striking correlation was found between the yearly incidence of NEC and the percentage of infants in that year who had received large increases in daily feeding volume. The highest mean daily feeding volume occurred in 1974 and 1975, the two years of peak NEC incidence. (2) The feeding records of the 26 NEC cases were studied. Thirteen NEC patients had had large increases in feeding volume within two days of NEC onset. Seven others received greater than 150 mL of formula per kilogram per day prior to NEC onset. Rapid increase in feeding volume and the use of large volumes are suggested as important etiologic factors of NEC.     

促红细胞生成素与坏死性小肠结肠炎

新生儿坏死性小肠结肠炎(necrotizing enterocolitis,NEC)是新生儿期最常见的严重的胃肠道疾病,也是危及早产儿、低出生体重儿生命的疾病.NEC的发生与许多因素有关,但其确切的发病机制目前尚不十分清楚,临床上也缺少预防和治疗NEC较为有效的方法.促红细胞生成素是一种糖蛋白激素,具有抗氧化、抗凋亡、促进血管增殖等多种功能,对NEC的预防和治疗有一定的作用.     

Neonatal necrotizing enterocolitis

Necrotizing enterocolitis (NEC) remains a major cause of morbidity and death in neonates. The 30% to 50% mortality rate for NEC with perforation has not changed appreciably in the past 30 years. The critical relevant outcomes following NEC include survival, gastrointestinal function, and neurodevelopmental status. In each of these areas, initial anecdotal and case-series analysis has been followed by studies using more sophisticated methods of analysis. The single most important predictor of outcome, besides gestational age, is whether or not the disease has progressed to the point requiring surgical intervention. Patients with NEC requiring operation have a high mortality. Moreover, the vast majority of morbidity following NEC occurs in the patients who survive following operation. The purpose of this review is to examine the evolution of evidence regarding outcomes for patients with NEC and to provide an update on our current state of knowledge.