Preterm birth makes the immature intestine sensitive to feeding-induced intestinal atrophy

Abstract

Preterm birth and formula feeding predispose to small intestinal dysfunction, which may lead to necrotizing enterocolitis (NEC). In piglets, we tested whether the physiological and environmental transitions occurring at birth affect the response of the immature intestine to enteral feeding. Pig fetuses (106 days gestation, term = 115 days) were prepared with esophageal feeding tubes and fed either sow's colostrum (n = 8) or infant formula (n = 7) in utero. After 24 h of oral feeding, the pig fetuses were delivered by cesarean section and their gastrointestinal morphology and function were compared with those of preterm newborn (NB) littermates that were not fed (n = 8) or fed colostrum (n = 7) or formula (n = 13) for 24 h after birth. Before birth, both colostrum and formula feeding resulted in marked increases in intestinal mass, brush-border enzyme activities, and plasma glucagon-like peptide 2 concentrations, to levels similar to those in NB colostrum-fed piglets. In contrast, NB formula-fed piglets showed reduced intestinal growth, decreased brush-border enzyme activities, and intestinal lesions, reflecting NEC. NB formula-fed pigs also showed impaired enterocyte endocytotic function and decreased antioxidative capacity, whereas brush-border enzyme mRNA levels were unaltered, relative to NB colostrum-fed pigs. Our results indicate that the feeding-induced growth and enzyme maturation of the immature intestine are not birth dependent. However, with a suboptimal diet (milk formula), factors related to preterm birth (e.g., microbial colonization and metabolic and endocrine changes) make the immature intestine sensitive to atrophy and development of NEC.

Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets

“…Our current results show novel evidence that prophylactic treatment with antibiotics completely prevented NEC in premature pigs. This striking result further confirms our previous evidence (5,53) showing that bacterial colonization is a necessary element of NEC pathogenesis in preterm pigs. We suggest that the general inhibition of bacterial growth is key among the mechanisms whereby antibiotics prevent NEC although we cannot exclude that the antibiotics may have worked by specifically targeting bacterial species implicated in the pathogenesis of NEC.…”

“…Additionally, studies in fetal and germ-free preterm pigs, and in quails, show that the initial bacterial colonization is a prerequisite for the development of NEC (5,53,68). Regardless, no specific pathogen has been identified as the primary cause of NEC (47,69) although bacterial overgrowth may be a key element in the etiology of NEC (37).…”

Impact of gestational age on the clinical presentation and surgical outcome of necrotizing enterocolitis

“…17,20 Dysregulation or disruption of absorptive maturational processes by premature birth and by absent or discontinuous enteral feedings interrupts the stimuli for GI maturation and may also promote GI colonization by virulent microbes, further contributing to the risk of developing NEC. 16 The association between the age at onset of feedings and the age at onset of NEC has been reported by others. [8][9][10]14 We observed in our EP infants with NEC that feedings were initiated at a mean of 4 days of age, and the mean age of onset of NEC was 20 days (range, 0-45 days).…”

“…6 Although ileus may be a result of concurrent bacterial sepsis, a primary abnormality in motor function may promote a milieu in which the interaction of nutrients and immaturity of host-defense initiate and perpetuate a sequence of interactions that culminate in NEC. 3,6,[14][15][16][17] Greater maturity of intestinal motility in T infants might explain why ileus and abdominal distention were uncommon presenting signs in this group. Extremely premature infants are generally supported with mechanical ventilation and more frequently receive sedative medications.…”

Nutrient-intake-level-dependent regulation of intestinal development in newborn intrauterine growth-restricted piglets via glucagon-like peptide-2

“…The small intestine, which is the portal for absorption of virtually all nutrients into the blood stream, can be dramatically altered in IUGR neonates (D'Inca et al, 2010). This, along with compromised intestinal growth and development, can lead to atrophy of the intestine and impairment of nutrient absorption and utilization (Weaver et al, 1991;Baserga et al, 2004;Bjornvad et al, 2005). However, it remains unclear whether this impairment in intestinal development during the intrauterine growth phase will persist through the postnatal phase.…”