Human breast milk suppresses the transcriptional regulation of IL-1β-induced NF-κB signaling in human intestinal cells

Minekawa, Ryoko; Takeda, Takashi; Sakata, Masahiro; Hayashi, Masami; Isobe, Aki; Yamamoto, Takatsugu; Tasaka, Keiichi; Murata, Yuji

doi:10.1152/ajpcell.00471.2003

Cited by 58 publications

(44 citation statements)

References 43 publications

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“…Similarly, in the present piglet model and in human NEC, lesions occur preferentially in the caudal regions, especially when the intestine has to cope with an inferior feeding such as formula (2,31). Formula may be more provocative to the intestine, than colostrum, because it lacks the natural immunomodulatory factors (32), resulting in inflammatory responses (22) and bacterial overgrowth (3). The existence of such stress in premature formula-fed piglets was indicated by the presence of nuclear HIF1␣-IR, a stress-sensitive cellular marker.…”

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 67%

“…ENOS-IR was also reduced in the middle and caudal region of TPNϩFOR piglets, despite limited mucosal growth. It is therefore possible that formula-induced microbial changes or inflammatory responses are involved (3,22), as these factors are known to decrease eNOS-protein expression (23,24) and predominate in the caudal small intestine (25). Some compensation for this low eNOS density in enterally fed piglets may have occurred by an increased eNOS expression in terminal mesenteric arteries, as described previously in term piglets following enteral feeding (7).…”

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 79%

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Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

et al. 2008

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ABSTRACT:The initiation of enteral feeding represents a challenge to the neonatal intestinal microcirculation, especially in preterms where it predisposes to necrotizing enterocolitis (NEC). We hypothesized that a structural microvascular deficiency may occur when enteral feeding is initiated in preterm piglets susceptible to NEC. Stereologic volume densities of a pan-endothelial marker (vWF), and the main vasodilator endothelial nitric oxide synthase (eNOS), were determined along the small intestine of 1) unfed preterm piglets, 2) piglets receiving total parenteral nutrition (TPN) for 2-3 d, and 3) piglets fed 2 d sow's colostrum (TPNϩSOW) or milk formula (TPNϩFOR) following TPN. In the mucosa, vWF-density decreased in a cranio-caudal direction. A corresponding mucosal eNOS gradient appeared only after initiating enteral feeding. In TPNϩSOW, eNOS induction may lag behind the mucosal growth of the caudal region. In TPNϩFOR, formula-related factors (i.e. bacteria, cytokines) may suppress mucosal eNOS, indicated by increased stresssensitive nuclear HIF1␣ staining. The low mucosal endothelial eNOS density was related to the presence of NEC lesions, maybe via increased hypoxia-sensitivity, especially in the caudal region as indicated by nuclear HIF1␣-staining. Our results suggest an insufficient structural adaptation of the microvasculature to enteral feeding, especially of mucosal eNOS, which may lead to NEC. T he birth process converts the relatively dormant fetal intestine into an organ of intense metabolic activity and associated abundant perfusion, as it becomes the sole site for nutrient absorption. This profound transition is particularly problematic at premature birth, where it may result in NEC, a severe inflammatory bowel disease associated with the initiation of enteral feeding, especially formula (1-3). Therefore, a period of total parenteral nutrition (TPN) in preterm infants is often required before enteral feeding is tolerated (4). The etiology of NEC is unknown, but a dysfunctional intestinal microcirculation could contribute to the etiopathogenesis (5,6).The newborn intestinal circulation shows some unique features, up to now intensely studied from a functional point of view (5,7). Nitric oxide (NO), a gaseous free radical produced mainly by endothelial nitric oxide synthase (eNOS), is the most important vasodilator during the perinatal period in sheep (8) and pig (9). Although eNOS is constitutively expressed in the endothelium, both eNOS mRNA and protein expression can be modulated (10), including by nutrient intake (7). Furthermore, intestinal blood flow shows a cranial-tocaudal decrease along the small intestine in neonatal and adult dogs (11), pigs (12,13), and humans (14). It is, however, unknown whether this functional gradient in the small intestine is associated with a similar gradient in microvessel distribution and/or eNOS protein expression. Histologic analyses of the regional morphometrics of the intestinal endothelium and eNOS expression during the first days of life are therefore inte...

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Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 67%

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 79%

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

et al. 2008

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“…Dexamethasone suppresses NF-B activation by inducing the NF-B inhibitor IB (26) and by direct protein-protein interactions that prevent NF-B from inducing transcription in a promoter site-specific fashion (27). Breast milk might contribute to decreased intestinal inflammation, as human breast milk has been shown to suppress the activation of the IL-8 gene promoter induced by IL-1␤ through NF-B in intestinal epithelial cells (28). In these cells, human breast milk induces the production of IB␣ (28).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

et al. 2007

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Necrotizing enterocolitis (NEC) is a major cause of morbidity and death in premature infants. NEC is associated with increased levels of pro-inflammatory cytokines in plasma and tissues that are regulated by the transcription factor nuclear factor-B (NF-B). It remains unknown, however, whether NF-B mediates injury in neonatal NEC. We therefore examined the activation status of NF-B perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-B is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-B remains strongly activated at both d 1 and d 2 in stressed animals, and this is accompanied by a significant decrease in the levels of the endogenous NF-B inhibitor protein IB␣ and IB␤ at d 2. To determine the importance of elevated NF-B activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream IB kinase (IKK). NBD but not a control peptide decreased mortality and bowel injury in this model, supporting the hypothesis that bowel injury in NEC results from elevated NF-B activity. Our findings therefore lead us to conclude that selective NF-B inhibition represents a promising therapeutic strategy for NEC.

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“…The cell lines are often intestinal-derived and immortal such as CaCo-2, a human colon carcinoma cell line [138] . Inflammatory stimulants such as LPS and pro-inflammatory cytokines can be added to cell cultures which can then be analyzed to determine the presence or absence of specific cytokines.…”

Section: Nec Modelsmentioning

confidence: 99%

Necrotizing enterocolitis: A multifactorial disease with no cure

Schnabl

Aerde²,

Thomson³

et al. 2008

WJG

160

120

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INTRODUCTIONNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of neonates and remains one of the most common gastrointestinal emergencies in newborn infants [1] . Onset of NEC is often within the first three months of life and neonates who are of extremely low birth weight (< 1000 g) and under 28 wk gestation are the most susceptible [2] . Full term neonates account for 10% of all NEC cases while premature infants account for 90% [3] . With an incidence rate of 1%-5% for all newborns admitted to the NICU [1] , a prevalence of 7%-14% of very low birth weight infants (VLBW, 500-1500 g) [4] and a mortality rate approaching 20%-50% [5] , NEC continues to represent a significant clinical problem. In Canada, the incidence rate is 1.8 per 100 live births with a prevalence of 7% of VLBW infants [1] . Advances in obstetric and neonatal care have improved survival rates for smaller, more immature infants, and as more VLBW preterm infants survive the neonatal period, the population at risk for NEC increases [1] .No consistent association between sex, race, and rates of NEC has been identified. However, male VLBW infants and black infants are at greater risk of death [6] . Due to inadequate treatments and no effective preventative strategy, an estimated 20%-40% of babies with NEC require surgery [1] and 10%-30% experience significant morbidity including neurodevelopmental impairment, vision and hearing impairment, failure to thrive, feeding abnormalities, diarrhea, bowel obstruction, and short bowel syndrome [1,2,7] . The case fatality rate with surgical intervention is as high as 50% [1] . NEC is also a financial burden to the health care system with yearly hospital charges reported to be as high as $6.5 million in the US [8] . Thus, NEC continues to be an important health issue for preterm neonates. DIAGNOSIS Clinical signs and symptomsThe onset of NEC can occur suddenly within a few AbstractNecrotizing enterocolitis is an inflammatory bowel disease of neonates with significant morbidity and mortality in preterm infants. Due to the multifactorial nature of the disease and limitations in disease models, early diagnosis remains challenging and the pathogenesis elusive. Although preterm birth, hypoxic-ischemic events, formula feeding, and abnormal bacteria colonization are established risk factors, the role of genetics and vasoactive/inflammatory mediators is unclear. Consequently, treatments do not target the specific underlying disease processes and are symptomatic and surgically invasive. Breast-feeding is the most effective preventative measure. Recent advances in the prevention of necrotizing enterocolitis have focused on bioactive nutrients and trophic factors in human milk. Development of new disease models including the aspect of prematurity that consistently predisposes neonates to the disease with multiple risk factors will improve our understanding of the pathogenesis and lead to discovery of innovative therapeutics.

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Human breast milk suppresses the transcriptional regulation of IL-1β-induced NF-κB signaling in human intestinal cells

Cited by 58 publications

References 43 publications

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

Necrotizing enterocolitis: A multifactorial disease with no cure

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