Early Feeding, Antenatal Glucocorticoids, and Human Milk Decrease Intestinal Permeability in Preterm Infants

Shulman, Robert J.; Schanler, Richard J.; Lau, Chantal; Heitkemper, Margaret; Ou, Ching-Nan; Smith, E O

doi:10.1203/00006450-199810000-00009

Cited by 163 publications

(105 citation statements)

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“…This often overlooked conundrum of growth restriction is reinforced by the presence of 11 -hydroxysteroid dehydrogenase (an enzyme that reduces cortisol to a less biologically active form), which is expressed disproportionately in the distal intestine (Clairmont & Czech 1991, Pacha & Miksik 1994, Claus et al 2001. This enzyme limits glucocorticoid-induced maturation of tissue during neonatal development but the enzyme can be overwhelmed by exogenous administration of steroids which results in mucosal hypertrophy in preterm neonates and developmentally appropriate animal models (Shulman et al 1998, Schaeffer et al 2000, Gordon et al 2001d, Dilsiz et al 2003, Pacha et al 2003. In older neonates this effect has actually been found to be protective for neonatal gut disease, presumably because of improved barrier function against colonizing pathogens (Shulman et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme limits glucocorticoid-induced maturation of tissue during neonatal development but the enzyme can be overwhelmed by exogenous administration of steroids which results in mucosal hypertrophy in preterm neonates and developmentally appropriate animal models (Shulman et al 1998, Schaeffer et al 2000, Gordon et al 2001d, Dilsiz et al 2003, Pacha et al 2003. In older neonates this effect has actually been found to be protective for neonatal gut disease, presumably because of improved barrier function against colonizing pathogens (Shulman et al 1998). However, in extremely low birth weight infants, synthetic glucocorticoids result in spontaneous intestinal perforations because of the limited capacity of the bowel wall to accommodate mucosal hypertrophy (Garland et al 1999, Gordon et al 2001b, Stark et al 2001.…”

Section: Discussionmentioning

confidence: 99%

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The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells

Gordon

Paxton²,

Fox³

2005

Journal of Endocrinology

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Glucocorticoids induce hypertrophy of the neonatal ileal mucosa but the molecular mechanisms behind this growth induction remain poorly understood. Ileal epithelial cells (IECs) are dependent upon IGF-II for proliferation both in vivo and in culture. The type-2 IGF receptor (IGFR-2) is a lysosomal transport protein that attenuates IGF-IIdriven growth and is highly abundant in the ileum. The cellular repressor of E1A-stimulated genes (CREG) is a secreted phosphoglycoprotein that affects cell fate via ligand binding with IGFR-2, although the mechanism by which it does so is unknown. We hypothesized that glucocorticoids might facilitate IGF-mediated hypertrophy through CREG-mediated degradation of IGFR-2. To test this hypothesis, confluent rat IECs (IEC-18) were cultured for 72 h with or without dexamethasone (DEX) and harvested for Western blot, immunocytochemistry, gene array and CREG immunoneutralization experiments.IGFR-2 and CREG immunohistochemistry were also performed in archived ileal specimens from control and DEX-exposed newborn mice and extremely premature infants to investigate in vivo and clinical relevance. DEX exposure was found to diminish IGFR-2 immunolocalization in cultured rat IECs, newborn mouse ileal mucosa and human neonatal ileal mucosa. Gene array data indicated that IGFR-2 expression was unchanged with DEX treatment, suggesting a mechanism of protein degradation. CREG immunolocalization and abundance was found to be increased by DEX and immunoneutralization of CREG resulted in the abolition of IGFR-2 degradation. We have concluded that CREG is a secreted mediator by which DEX induces degradation of IGFR-2 and speculate that this is a fundamental mechanism of mucosal growth induction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells

Gordon

Paxton²,

Fox³

2005

Journal of Endocrinology

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“…Urine was kept on ice and after arrival at our laboratory was frozen at −70°C until analyzed. Urine was analyzed as we have described previously with slight modification for the analysis of sucralose (17). The sucralose is eluted with 5 mL HPLC grade acetonitrile.…”

Section: Methodsmentioning

confidence: 99%

Increased Gastrointestinal Permeability and Gut Inflammation in Children with Functional Abdominal Pain and Irritable Bowel Syndrome

Shulman¹,

Eakin

Czyzewski³

et al. 2008

The Journal of Pediatrics

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158

118

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Objectives-To determine GI permeability and fecal calprotectin concentration in children 7-10 years of age with functional abdominal pain and irritable bowel syndrome (FAP/IBS) vs Controls and ascertain potential relationships with pain symptoms and stooling.Study design-GI permeability and fecal calprotectin concentration were measured. Children kept a two-week diary of pain episodes and stooling pattern.Results-Proximal GI permeability was greater in the FAP/IBS group (n = 93) compared with controls (n = 52) (0.59 ± 0.50 vs. 0.36 ± 0.26, respectively; mean ± SD; P < 0.001) as was colonic permeability (1.01 ± 0.67 vs. 0.81 ± 0.43, respectively; P < 0.05). Gastric and small intestinal permeability were similar. Fecal calprotectin concentration was greater in children with FAP/IBS compared with control children (65.5 ± 75.4 µg/g stool vs. 43.2 ± 39.4, respectively; P < 0.01). Fecal calprotectin concentration correlated with pain interference with activities (P = 0.01, r 2 = 0.36). There was no correlation between GI permeability and pain related symptoms. Neither permeability nor fecal calprotectin correlated with stool form.Conclusions-Children with FAP/IBS have evidence of increased GI permeability and low grade GI inflammation with the latter relating to the degree to which pain interferes with activities.Surveys suggest that 10% -17% of children between the ages of 4 and 16 years meet the criteria for recurrent abdominal pain (1-3). It has been suggested that the term recurrent abdominal pain be replaced by the terms functional abdominal pain (FAP) and irritable bowel syndrome (IBS) (4;5). FAP/IBS in children bear many similarities to IBS in adults and may be precursors for IBS (6-8). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. GI permeability is increased in adults with IBS (9;10); however, the limited data in children are unclear. Similarly, a few studies report GI inflammation (i.e., increased fecal calprotectin concentration) in adults with IBS (9). Little data are available regarding calprotectin in children (11;12). To our knowledge no pediatric studies have sought to determine if changes in GI permeability and/or fecal calprotectin concentration relate to FAP/IBS symptoms (e.g., pain severity or frequency, stooling pattern). NIH Public AccessThe objectives of this study were to measure permeability throughout the GI tract (using sugar permeability tests) and gut inflammation (using fecal calprotectin) in a large group of well characterized children with FAP/IBS and to compare the results to healthy children without GI complaints. We used a site-speci...

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“…19 In this way, corticosteroids assist in achieving a successful transition from fetal to extra-uterine life, accelerating fetal maturation as a whole. [20][21][22][23][24][25][26][27] The acceleration of lung development leads to a reduction in the incidence of respiratory distress syndrome and its severity. 17,[28][29][30] The structural and biochemical alterations induced by corticosteroids translate into a diminution of the need for and duration of mechanical ventilation for newborns with respiratory insufficiency.…”

Section: Introductionmentioning

confidence: 99%

Antenatal treatment with corticosteroids for preterm neonates: impact on the incidence of respiratory distress syndrome and intra-hospital mortality

et al. 2003

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CONTEXT: Although the benefits of antenatalcorticosteroids have been widely demonstrated in other countries, there are few studies among Brazilian newborn infants. OBJECTIVE:To evaluate the effectiveness of antenatal corticosteroids on the incidence of respiratory distress syndrome and intra-hospital mortality among neonates with a gestational age of less than 34 weeks. TYPE OF STUDY:Cross-sectional. SETTING:A tertiary-care hospital. PARTICIPANTS:Neonates exposed to any dose of antenatal corticosteroids for fetal maturation up to 7 days before delivery, and newborns paired by sex, birth weight, gestational age and time of birth that were not exposed to antenatal corticosteroids. The sample obtained consisted of 205 exposed newborns, 205 non-exposed and 39 newborns exposed to antenatal corticosteroids for whom it was not possible to find an unexposed pair. PROCEDURES:Analysis of maternal and newborn records. MAIN MEASUREMENTS:The primary clinical outcomes for the two groups were compared: the incidence of respiratory distress syndrome and intra-hospital mortality; as well as secondary outcomes related to neonatal morbidity. RESULTS:Antenatal corticosteroids reduced the occurrence of respiratory distress syndrome (OR: 0.33; 95% CI: 0.21-0.51) and the protective effect persisted when adjusted for weight, gestational age and the presence of asphyxia (adjusted OR: 0.27; 95% CI: 0.17-0.43). The protective effect could also be detected through the reduction in the need for and number of doses of exogenous surfactant utilized and the number of days of mechanical ventilation needed for the newborns exposed to antenatal corticosteroids. Their use also reduced the occurrence of intra-hospital deaths (OR: 0.51: 95% CI: 0.38-0.82). However, when adjusted for weight, gestational age, presence of prenatal asphyxia, respiratory distress syndrome, necrotizing enterocolitis and use of mechanical ventilation, the antenatal corticosteroids did not maintain the protective effect in relation to death. With regard to other outcomes, antenatal corticosteroids reduced the incidence of intraventricular hemorrhage grades III and IV (OR: 0.28; 95% CI: 0.10-0.77). CONCLUSIONS:Antenatal corticosteroids were effective in the reduction of morbidity and mortality among premature newborns in the population studied, and therefore their use should be stimulated within our environment.

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Early Feeding, Antenatal Glucocorticoids, and Human Milk Decrease Intestinal Permeability in Preterm Infants

Cited by 163 publications

References 13 publications

The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells

The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells

Increased Gastrointestinal Permeability and Gut Inflammation in Children with Functional Abdominal Pain and Irritable Bowel Syndrome

Antenatal treatment with corticosteroids for preterm neonates: impact on the incidence of respiratory distress syndrome and intra-hospital mortality

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