Pathogenesis of NEC: Impact of an altered intestinal microbiome

Necrotizing enterocolitis (NEC), a disease most commonly seen in preterm infants, often presents without warning and is associated with very high mortality and morbidity. Progress in the prevention and treatment of NEC has been slow. In this article, we will discuss some of the reasons as to why this progress has been slow. We will describe some of the factors that appear to be highly associated and important components in the pathophysiology of NEC. We will discuss the intestinal microbial environment of the fetus as well as the preterm infant and how interaction of dysbiosis with an immature gastrointestinal tract combined with dietary factors play a role in the pathogenesis of NEC. Testable hypotheses are discussed as well as how these may lead to not only a better understanding of the pathophysiology of the disease but also the preventative strategies.     

Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response

Preeclampsia is characterized by generalized endothelial dysfunction as a result of an inappropriate maternal immune response against the fetus. It has been postulated that the adaptive immune system plays a key role in the etiology of preeclampsia by generating a pro-inflammatory Th1 type immune reaction. In this review, recent studies on Th1 and Th2 type cytokine mapping in preeclampsia are reviewed, as well as on the sources of pro-inflammatory cytokines and the role of regulatory cytokines and chemokines. In addition, we discuss the possible role of Toll-like receptors of the innate immune system in the pathophysiology of preeclampsia. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the newer concepts related to the pathogenesis of preeclampsia and explain the role of the maternal immune system and the role of pro-inflammatory and regulatory cytokines and chemokines in the pathophysiology of the disease.     

The immune system and aging: a review

The concept of immunosenescence reflects age-related changes in immune responses, both cellular and serological, affecting the process of generating specific responses to foreign and self-antigens. The decline of the immune system with age is reflected in the increased susceptibility to infectious diseases, poorer response to vaccination, increased prevalence of cancer, autoimmune and other chronic diseases. Both innate and adaptive immune responses are affected by the aging process; however, the adaptive response seems to be more affected by the age-related changes in the immune system. Additionally, aged individuals tend to present a chronic low-grade inflammatory state that has been implicated in the pathogenesis of many age-related diseases (atherosclerosis, Alzheimer's disease, osteoporosis and diabetes). However, some individuals arrive to advanced ages without any major health problems, referred to as healthy aging. The immune system dysfunction seems to be somehow mitigated in this population, probably due to genetic and environmental factors yet to be described. In this review, an attempt is made to summarize the current knowledge on how the immune system is affected by the aging process.     

Physiological effects of prebiotics and its role in prevention of necrotizing enterocolitis in preterm neonates

Necrotizing enterocolitis (NEC) is one of the most serious gastrointestinal emergencies in very low birth weight (VLBW) preterm neonates, affecting 7–14% of these neonates. Due to the seriousness of the disease, prevention of NEC is the most important goal. Current evidence from systematic review and meta-analysis revealed that probiotics are the most promising intervention in reduction of the incidence of NEC in VLBW neonates. As per the evidence, prebiotics modulate the composition of human intestine microflora to the benefit of the host by suppression of colonization of harmful microorganism and/or the stimulation of bifidobacterial growth, decreased stool viscosity, reduced gastrointestinal transit time, and better feed tolerance. Prebiotics may be potential alternatives or adjunctive therapies to probiotics, despite a lack of evidence supporting its clinical efficacy in prevention of NEC. In this article, we discuss evidence-based physiological effects of prebiotics and its therapeutic role in prevention of NEC.     

Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit. Here we review the epidemiology and pathophysiology of NEC, with an emphasis on the latest research findings and potential areas for future research. NEC continues to be one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, the pathogenesis of this disease remains unclear, and prevention and treatment strategies are limited. Hopefully, future studies aimed at understanding premature intestinal defenses, commensal or probiotic bacterial influences, and possible genetic predisposition will lead to the improvement of prevention and treatment strategies.     

The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal disease encountered in the premature infant. Although the inciting events leading to NEC remain elusive, various risk factors, including prematurity, hypoxemia, formula feeding, and intestinal ischemia, have been implicated in the pathogenesis of NEC. Data from our laboratory and others suggest that NEC evolves from disruption of the intestinal epithelial barrier, as a result of a combination of local and systemic insults. We postulate that nitric oxide (NO), an important second messenger and inflammatory mediator, plays a key role in intestinal barrier failure seen in NEC. Nitric oxide and its reactive nitrogen derivative, peroxynitrite, may affect gut barrier permeability by inducing enterocyte apoptosis (programmed cell death) and necrosis, or by altering tight junctions or gap junctions that normally play a key role in maintaining epithelial monolayer integrity. Intrinsic mechanisms that serve to restore monolayer integrity following epithelial injury include enterocyte proliferation, epithelial restitution via enterocyte migration, and re-establishment of cell contacts. This review focuses on the biology of NO and the mechanisms by which it promotes epithelial injury while concurrently disrupting the intrinsic repair mechanisms.     

Management during the first 72 h of age of the periviable infant: An evidence-based review

After NICU admission the extremely immature newborn (EIN) requires evaluation and support of each organ system, and the integration of all those supports in a comprehensive plan of care. In this review, I attempt to analyze the evidence for treatment options after the initial transition, during the first 3 days of life, which have been shown to improve survival or short- or long-term morbidity. This review revealed several things: there is little available evidence from studies that have included significant numbers of EINs; interventions affecting different organ systems need to be co-ordinated as any intervention will have multiple effects; and future advances in treatment of this group of patients will require the installation of permanent research networks to have enough power to perform many studies needed to improve outcomes.     

人乳低聚糖与婴幼儿肠道健康研究进展

母乳中的低聚糖通过调节肠道内微生物菌群构成、抵御致病菌群对肠黏膜上皮细胞入侵及调控机体免疫反应等生理作用,维持婴幼儿肠道健康,并且对于一些肠道功能紊乱的疾病,如坏死性小肠结肠炎、腹泻等,也可有效预防及治疗.本文主要阐述近年来国内外有关人乳低聚糖与婴幼儿肠道健康方面的研究进展,进一步探讨人乳低聚糖与婴幼儿肠道健康的相关性...     

Importance of myeloid differentiation factor 88 in innate and acquired immune protection against genital herpes infection in mice

Toll-like receptors (TLRs) play an important role as pattern-recognition receptors to sense and respond to pathogens. Our laboratory and others have shown recently that activation of TLR/MyD88 signaling through vaginal administration of CpG oligodeoxynucleotides, either singly or in combination with recombinant glycoprotein from herpes simplex virus type 2 (HSV-2), confers immunity against genital herpes infection. In this study, we have investigated the importance of the myeloid differentiation factor 88 (MyD88), a critical adaptor protein shared by all TLRs, in innate and acquired immunity against genital HSV-2 infection in mice. We demonstrate that MyD88 is essential for innate immune resistance against HSV-2. Thus, MyD88 deficient (MyD88^−/−) mice show more vaginal HSV-2 titers, more rapid disease progression and earlier death compared to C57Bl/6 mice following a vaginal challenge with high (9 × 10⁴ PFU) or low (9 × 10³ PFU) virus dose. In contrast, use of MyD88 appears dispensable for induction of HSV-specific serum IgG antibody as well as local and systemic cell-mediated immune responses elicited by vaginal immunization with live attenuated thymidine kinase-deficient HSV-2 (HSV-2 TK⁻). Importantly, and similar to immunized C57Bl/6 mice, immunized MyD88^−/− mice were completely protected against subsequent vaginal challenge with a lethal dose of virulent strain of HSV-2. These results provide evidence that the adaptor protein MyD88 is important for innate early control of genital HSV-2 infection, and that use of MyD88 is not required for induction of acquired immunity following vaginal immunization with HSV-2 TK⁻.