Diagnostic efficacy of high-frequency ultrasound and X-ray contrast enema in colonic strictures after necrotizing enterocolitis: a retrospective study.

OBJECTIVE: To compare the efficacy of high-frequency ultrasound and X-ray contrast enema in the diagnosis of colonic strictures after necrotizing enterocolitis. METHODS: This study included pediatric patients who developed progressive abdominal distension or constipation after conservative treatment for necrotizing enterocolitis at our hospital between June 2012 and April 2020. All patients had high-frequency ultrasounds and X-ray contrast enema, and we used surgery, pathology, and telephone return visits as the reference standard. Patients with colonic strictures were confirmed by surgery and pathology. A patient was considered without colonic stricture if no stricture was reported or did not have related symptoms during telephone return visits. The areas under the Receiver operating characteristic (ROC) curves were used as evaluation indexes to compare the differential efficacy of high-frequency ultrasound and X-ray contrast enema. RESULTS: A total of 81 patients have been included in this study. Among them, 49 patients were diagnosed with colonic strictures after necrotizing enterocolitis. The AUCs for high-frequency ultrasound and X-ray contrast enema were 0.990 vs 0.938, respectively (p > 0.05). CONCLUSION: The diagnostic efficacy of high-frequency ultrasound was similar to that of X-ray contrast enema, furthermore this study also demonstrates the benefits of using high-frequency ultrasound to identify colonic strictures after necrotizing enterocolitis.

Probiotics: Versatile Bioactive Components in Promoting Human Health.

The positive impact of probiotic strains on human health has become more evident than ever before. Often delivered through food, dietary products, supplements, and drugs, different legislations for safety and efficacy issues have been prepared. Furthermore, regulatory agencies have addressed various approaches toward these products, whether they authorize claims mentioning a disease's diagnosis, prevention, or treatment. Due to the diversity of bacteria and yeast strains, strict approaches have been designed to assess for side effects and post-market surveillance. One of the most essential delivery systems of probiotics is within food, due to the great beneficial health effects of this system compared to pharmaceutical products and also due to the increasing importance of food and nutrition. Modern lifestyle or various diseases lead to an imbalance of the intestinal flora. Nonetheless, as the amount of probiotic use needs accurate calculations, different factors should also be taken into consideration. One of the novelties of this review is the presentation of the beneficial effects of the administration of probiotics as a potential adjuvant therapy in COVID-19. Thus, this paper provides an integrative overview of different aspects of probiotics, from human health care applications to safety, quality, and control.

Human milk fortification: the clinician and parent perspectives.

This study reports on the human milk fortification session at the 2019 NEC Society Symposium, which included clinicians and parents discussing the evidence comparing fortification options such as efficacy, safety, cost effectiveness, and the need for parents to be informed about fortifier choice. With the current literature available and the varying standard of care practices for human milk fortification, further studies are needed to determine the most complete diet for preterm infants. The optimal diet would not only provide key nutrients and energy for growth and development, but also improve short- and long-term outcomes. Parents, as advocates and providers for their infant, should be informed, educated, and included in the discussion and decisions regarding fortification of human milk for their infant.

Clinical features and management of post-necrotizing enterocolitis strictures in infants: A multicentre retrospective study.

To explore the clinical features and management of post-necrotizing enterocolitis strictures.Clinical data from 158 patients with post-necrotizing enterocolitis strictures were summarized retrospectively in 4 academic pediatric surgical centers between April 2014 and January 2019. All patients were treated conservatively in the internal medicine department. All patients underwent preoperative X-ray examinations, 146 patients underwent gastrointestinal contrast studies, and 138 patients underwent rectal mucosal biopsies. All of the patients were treated surgically.Of the 158 patients, 40 of them had necrotizing enterocolitis (NEC) Bell stage Ib, 104 had Bell stage IIa, and 14 had Bell stage IIb. In these patients, the clinical signs of intestinal strictures occurred at mean of 47.8 days after NEC. In 158 patients, 146 underwent barium enema examination, 116 demonstrated intestinal strictures, and 10 demonstrated microcolon and poor development. A total of 138 patients underwent rectal mucosal biopsies, and 5 patients had Hirschsprung disease. Intraoperative exploration showed that intestinal post-NEC strictures occurred in the ileal (17.7%, 28/158) and colon (82.3%, 130/158), including ascending colon, transverse colon and descending colon, and multiple strictures were detected in 36.1% (57/158) patients. Surgical resection of stricture segments in the intestine and primary end-to-end anastomosis were performed in 142 patients, and the remaining 16 patients underwent staged surgeries. In the 146 patients with complete follow-up data, 9 had postoperative adhesions: 4 of them received conservative treatment, and the others underwent a second operation. Fifteen patients were hospitalized 1 to 3 times for malnutrition and dehydration due to repeated diarrhea; these patients eventually recovered and were discharged smoothly. All the other patients had uneventful recoveries without stricture recurrence.Post-NEC strictures mostly occurred in the colon, and there were some cases of multiple strictures. A gastrointestinal contrast study was the preferred method of examination. Preoperative rectal mucosal biopsy resulted in a diagnosis of Hirschsprung disease, and then a reasonable treatment protocol was chosen. Surgical resection of stricture segments in the intestine and primary end-to-end anastomosis achieved good therapeutic effects with favorable prognoses in these patients.

Fecal microbiota transplantation by enema reduces intestinal injury in experimental necrotizing enterocolitis.

PURPOSE: Necrotizing Enterocolitis (NEC) is a devastating neonatal disease with a high mortality rate. Fecal Microbiota Transplantation (FMT) has been used to treat a variety of gastrointestinal diseases. We aimed to investigate the role of FMT in NEC. METHODS: NEC was induced by hypoxia, LPS, and hyperosmolar gavage feeding between postnatal days P5 and P9 (n = 8). Breastfed mice were used as control (n = 7). FMT (30 µl/g) was administered by gavage or enema at P6 during NEC induction. Distal ileum was harvested on P9. Disease severity was evaluated by H&E staining. Gene expression of inflammatory markers IL6 and TNFa was measured. Expression of intestinal barrier function was investigated by measuring Claudin-7. Microbiota composition in ileum and colon was analyzed by quantitative PCR. RESULTS: FMT by gavage further increased terminal ileum inflammation and did not improve the histological damage owing to experimental NEC. Conversely, FMT by enema decreased intestinal inflammation and improved histology of the NEC-like injury in the ileum. In addition, compared with NEC alone, FMT by enema increased Claudin-7 expression indicating an improvement in barrier function. These beneficial effects occurred despite no change in microbiota. CONCLUSION: Our results show that FMT by enema may be an effective strategy to reduce NEC progression as it attenuates intestinal inflammation and enhances intestinal barrier function. FMT by enema is a potential novel treatment for NEC. LEVEL OF EVIDENCE: Level IV, Evidence from well-designed case-control or cohort studies.

New Nutritional and Therapeutical Strategies of NEC.

Necrotizing enterocolitis (NEC) is an acquired severe disease of the digestive system affecting mostly premature babies, possibly fatal and frequently associated to systemic complications. Because of the severity of this condition and the possible long-term consequences on the child's development, many studies have aimed at preventing the occurrence of the primary events at the level of the bowel wall (ischemia and necrosis followed by sepsis) by modifying or manipulating the diet (breast milk versus formula) and/or the feeding pattern (time for initiation after birth, continuous versus bolus feeding, modulation of intake according clinical events). Feeding have been investigated so far in order to prevent NEC. However, currently well-established and shared clinical nutritional practices are not available in preventing NEC. Nutritional and surgical treatments of NEC are instead well defined. In selected cases surgery is a therapeutic option of NEC, requiring sometimes partial intestinal resection responsible for short bowel syndrome. In this paper we will investigate the available options for treating NEC according to the Walsh and Kliegman classification, focusing on feeding practices in managing short bowel syndrome that can complicate NEC. We will also analyze the proposed ways of preventing NEC.

Degradation of Extracellular DNA Significantly Ameliorates Necrotizing Enterocolitis Severity in Mice.

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most devastating diseases in neonates and is characterized by high morbidity and mortality. It has been suggested that neutrophils play a crucial role in NEC pathogenesis and contribute to the hyperinflammatory reaction after bacterial colonization, which ultimately induces NEC. The aim of this study was to investigate whether dissolution of neutrophil extracellular traps (NETs) by systemic DNase1 therapy reduces NEC manifestation and morbidity. METHODS: NEC was induced in neonatal mice by gavage feeding of lipopolysaccharide mixed in Neocate, followed by hypoxia q12 h for 5d. Inactivated DNase1 and DNase1 were administered intraperitoneally twice daily in the control and treatment groups, respectively, starting on day 5 for 72 h. Survival, NEC score, intestinal damage (Chiu score, malondialdehyde [MDA], glutathione peroxidase [GPx]), inflammation (neutrophil elastase [NE], myeloperoxidase [MPO], toll-like receptor 4 [TLR4]), and NETs markers (SYTOX orange, cell-free DNA [cfDNA], DNase, citrullinated Histone 3 [H3cit]) were then assessed. RESULTS: In total, 44 neonatal mice were used in the experiment. Mice in the treatment group demonstrated significantly reduced NEC rates (44 versus 86%, P = 0.029) and improved survival in comparison to controls (65 versus 35%, P = 0.01). Furthermore, mice treated with DNase1 showed significantly less tissue damage (cfDNA, Chiu score), oxidative stress (MDA, GPx), and inflammation (NE, MPO, H3cit, TLR4), which ultimately lead to a significant reduction in mortality. CONCLUSIONS: The results of the study indicate that systemic DNase1 treatment leads to a significant reduction in tissue damage, NEC severity, and mortality. Therefore, after validation of our findings in human subjects, DNase1 treatment should be considered as a therapeutic option in neonates diagnosed with NEC.

Gut microbiota and the pathogenesis of necrotizing enterocolitis in preterm neonates.

Necrotizing enterocolitis (NEC) remains a devastating intestinal disease in preterm neonates. In this population, disruption of the gut microbiota development, mainly due to organ immaturity, antibiotic use and hospital microbial environment, plays a key role in the pathogenesis of NEC. This gut dysbiosis has been associated with opportunistic pathogens overgrowth, expression of virulence factors, altered metabolic functions and inflammatory dysregulated responses. In this review, we provide an updated summary of the host and gut microbiota interactions during the formative early life. We also explore the key determinants of gut dysbiosis in preterm neonates with NEC. Finally, we discuss the promising role of bacteriotherapy in the management of NEC, the aim being to shape or restore the beneficial gut bacterial communities.

Microbiota y enfermedades gastrointestinales / Microbiota and gastrointestinal diseases

La colonización bacteriana se establece inmediatamente después del nacimiento, por contacto directo con la microbiota materna, y puede modificarse durante la lactancia. Están apareciendo datos indicativos de que modificaciones cuantitativas y cualitativas de la microbiota intestinal son capaces de estimular cambios en la activación del sistema inmune que pueden conducir a la aparición de enfermedades gastrointestinales o extraintestinales. El equilibrio entre la microbiota patógena y beneficiosa durante la niñez y la adolescencia es importante para la salud gastrointestinal, incluyendo la protección frente a patógenos, la inhibición de patógenos, el procesamiento de nutrientes (síntesis de vitamina K), el estímulo de la angiogénesis y la regulación del almacenamiento de la grasa corporal. También los probióticos pueden modular la microbiota intestinal para favorecer la salud del huésped. Este artículo es una revisión sobre la acción moduladora de la microbiota intestinal en la prevención y el tratamiento coadyuvante de las enfermedades gastrointestinales pediátricas

The bacterial colonisation is established immediately after birth, through direct contact with maternal microbiota, and may be influenced during lactation. There is emerging evidence indicating that quantitative and qualitative changes on gut microbiota contribute to alterations in the mucosal activation of the immune system, leading to intra- or extra-intestinal diseases. A balance between pathogenic and beneficial microbiota throughout childhood and adolescence is important to gastrointestinal health, including protection against pathogens, inhibition of pathogens, nutrient processing (synthesis of vitamin K), stimulation of angiogenesis, and regulation of host fat storage. Probiotics can promote an intentional modulation of intestinal microbiota favouring the health of the host. A review is presented on the modulation of intestinal microbiota on prevention, and adjuvant treatment of some paediatric gastrointestinal diseases

New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics.

The gut microbiota has a significant role in human health and disease. Dysbiosis of the intestinal ecosystem contributes to the development of certain illnesses that can be reversed by favorable alterations by probiotics. The published literature was reviewed to identify scientific data showing a relationship between imbalance of gut bacteria and development of diseases that can be improved by biologic products. The medical conditions vary from infectious and antibiotic-associated diarrhea to obesity to chronic neurologic disorders. A number of controlled clinical trials have been performed to show important biologic effects in a number of these conditions through administration of prebiotics, probiotics, and synbiotics. Controlled clinical trials have identified a limited number of prebiotics, probiotic strains, and synbiotics that favorably prevent or improve the symptoms of various disorders including inflammatory bowel disease, irritable bowel syndrome, infectious and antibiotic-associated diarrhea, diabetes, nonalcoholic fatty liver disease, necrotizing enterocolitis in very low birth weight infants, and hepatic encephalopathy. Studies have shown that probiotics alter gut flora and lead to elaboration of flora metabolites that influence health through 1 of 3 general mechanisms: direct antimicrobial effects, enhancement of mucosal barrier integrity, and immune modulation. Restoring the balance of intestinal flora by introducing probiotics for disease prevention and treatment could be beneficial to human health. It is also clear that significant differences exist between different probiotic species. Metagenomics and metatranscriptomics together with bioinformatics have allowed us to study the cross-talk between the gut microbiota and the host, furthering insight into the next generation of biologic products.

Comparison of brainstem auditory evoked response at different click rates between preterm babies after neonatal necrotizing enterocolitis and healthy preterm babies.

BACKGROUND: Neonatal necrotizing enterocolitis (NEC) is associated with an increased incidence of poor neurodevelopment. The knowledge of underlying neurophysiology is very limited, and the influence of NEC on the preterm brainstem is very poorly understood. OBJECTIVE: To assess the effect of NEC on the immature auditory brainstem by excluding any possible confounding effect of preterm birth. METHODS: We recorded and analyzed brainstem auditory evoked response (BAER) at different click rates in preterm babies (30-34 weeks gestation) after NEC. The results were compared with those in age-matched healthy preterm babies who had no NEC. RESULTS: At click rate 21/s, the latencies of BAER waves I and III in the preterm NEC babies were similar to those babies without NEC. However, wave V latency was longer in the NEC babies than in those without NEC. The I-V interpeak interval was also longer in the NEC babies than in those without NEC. These abnormalities were persistent at higher click rates 51 and 91/s. Wave I amplitude in the preterm NEC babies did not differ significantly from that in those without NEC, but wave III and V amplitudes were smaller than in those without NEC at all 21-91/s clicks. CONCLUSIONS: Compared with healthy preterm babies, preterm babies after NEC showed a major increase in wave V latency and I-V interval at all 21-91/s clicks. Brainstem auditory function is impaired in preterm NEC babies after excluding the possible confounding effect of preterm birth. Neonatal NEC and associated perinatal conditions adversely affect the premature brainstem.

Lactobacillus paracasei subsp. paracasei F19 in Bell's stage 2 of necrotizing enterocolitis.

AIM: The aim of this trial is to evaluate the role Lactobacillus paracasei in Bell's stage 2 in order to prevent the clinical progression to stage 3. METHODS: A prospective study was approved and started in December 2008. Patients were infants with birth weight 600 to 1500 g. One group received probiotic supplementation (L. paracasei susp.paracasei F-19) and the control group received only standard medical treatment. The primary outcome was the progression to stage 3 as defined by Bell's modified criteria. Inclusion and exclusion criteria were created and discussed with parents before treatment. RESULTS: Thirty-two patients (stage 2 NEC) were considered eligible for the study. Group A: 18 patients and Group B: 14 patients. Three patients in group A and six patients in group B had a clinical history of Bell's stage 3 NEC (P<0.05); oral supplementation of L. paracasei reduced the clinical progression of NEC. It was considered that an improvement in intestinal motility might have contributed to this result. CONCLUSION: The use of Lactobacillus paracasei subsp. paracasei F-19 is safe; the low progression rate to stage 3 NEC suggests that the use of this probiotic in stage 2 NEC could be a valuable therapeutic option.

Use of hyperbaric oxygenation in neonatal patients: a pilot study of 8 patients.

This article presents a pilot study to determine the value of hyperbaric oxygenation (HBO2) in the acute management of neonatal hypoxia (hypoxic ischemic encephalopathy) and necrotizing enterocolitis. Neonates with hypoxic-ischemic encephalopathy and NE were treated in a Sechrist monoplace chamber. Electroencephalogram, evoked potential, ophthalmic evaluation, ultrasonograph, laboratory exams, and radiographs were obtained before and after HBO2. Treatment protocol was 2.0 atm abs/45 minutes. Preventive myringotomies were conducted in all patients. A follow-up was done at 3 and 6 months. All patients (n = 8) were ventilator-dependent and required bag-valve-mask ventilation by a neonatologist during the treatment. All showed a resolution after HBO2. There was also a dramatic improvement (P < .05) in hemoglobin, hematocrit, total proteins, serum sodium, triglycerides, and pH. There were favorable changes in all other studies although they did not meet statistical significance. There was a marked reduction of the morbidity and mortality. There were no adverse effects on the ophthalmologic or Central Nervous System. When used promptly, HBO2 can modify the local and systemic inflammatory response caused by intestinal inflammation or cerebral or systemic hypoxia. It helps to preserve the marginal tissue and recover the ischemic and metabolic penumbra. This pilot study suggests that HBO2 could be a safe and effective treatment in the acute management of neonatal necrotizing enterocolitis or hypoxic ischemic encephalopathy. There is a need for a prospective, randomized, controlled, and double-blinded study to determine the real use of HBO2 in these cases.

Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates.

Preterm neonates are susceptible to gastrointestinal disorders such as necrotizing enterocolitis (NEC). Maternal milk and colostrum protects against NEC via growth promoting, immunomodulatory, and antimicrobial factors. The fetal enteral diet amniotic fluid (AF), contains similar components, and we hypothesized that postnatal AF administration reduces inflammatory responses and NEC in preterm neonates. Preterm pigs (92% gestation) were delivered by caesarean section and fed parental nutrition (2 days) followed by enteral (2 days) porcine colostrum (COLOS, n = 7), infant formula (FORM, n = 13), or AF supplied before and after introduction of formula (AF, n = 10) in experiment 1, and supplied only during the enteral feeding period in experiment 2 (FORM, n = 16; AF, n = 14). The NEC score was reduced in both AF and COLOS pigs, relative to FORM, when AF was provided prior to full enteral feeding (9.9 and 7.7 compared with 17.3, P < 0.05). There was no effect of AF when provided only during enteral feeding. AF pigs showed decreased bacterial abundance in colon and intestinal inflammation-related genes (e.g., TNF-α, IL-1α, IL-6, NOS) were downregulated, relative to FORM pigs with NEC. Anti-inflammatory properties of AF were supported by delayed maturation and decreased TNF-α production in murine dendritic cells, as well as increased proliferation and migration, and downregulation of IL-6 expression in intestinal cells (IEC-6, IPEC-J2). Like colostrum, AF may reduce NEC development in preterm neonates by suppressing the proinflammatory responses to enteral formula feeding and gut colonization when provided before the onset of NEC.

Lactoferrin and necrotizing enterocolitis.

Lactoferrin (LF) is a multifunctional protein and a member of the transferrin family. LF and lysozyme in breast milk kill bacteria. In the stomach, pepsin digests and releases a potent peptide antibiotic called lactoferricin from native LF. The antimicrobial characteristics of LF may facilitate a healthy intestinal microbiome. LF is the major whey in human milk; its highest concentration is in colostrum. This fact highlights early feeding of colostrum and also fresh mature milk as a way to prevent necrotizing enterocolitis.