Abstract
BackgroundThe appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms.Methodology/Principal FindingsPreterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization-dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased.Conclusions/SignificanceDepressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria-associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates.
Highlights
Intestinal microbiota, prematurity and inappropriate enteral feeding are regarded as three key risk factors for the onset and progression of necrotizing enterocolitis (NEC), a serious intestinal inflammatory disease in preterm infants with high morbidity and mortality [1]
We deliberately aimed to analyze the intestine of pigs prior to the time when they would become severely affected with NEC pathological lesions, as this would make the interpretation of the proteomic data less meaningful and indicate intestinal proteome of NEC pathology rather than initial events of NEC progression
The healthier state of the AB intestines was indicated by higher villi, absence of hemorrhage and no separation of different layers (Figure 1C), whereas, the untreated pigs showed various features related to NEC in different individual pig from villous atrophy, hemorrhage (Figure 1A) to separation of mucosa layers (Figure 1B)
Summary
Intestinal microbiota, prematurity and inappropriate enteral feeding are regarded as three key risk factors for the onset and progression of necrotizing enterocolitis (NEC), a serious intestinal inflammatory disease in preterm infants with high morbidity and mortality [1]. The intestinal microbiota in preterm neonates is less diverse than in term neonates, especially when delivered by caesarean section [2], and this may predispose the gut to pathogenic E. coli, Clostridium, Klebsiella and Bacterioides species [2,3,4] Overgrowth of these pathogenic species triggers inappropriate inflammatory processes in the immature intestine which sensitize to further translocation of pathogenic bacteria and toxins, leading to sepsis and necrosis. Antibiotic regimens in clinical neonatology are highly variable and empirical and mainly used with the aim to prevent and treat systemic sepsis Antibiotics such as ampicillin plus cefotaxime or aminoglycoside, clindamycin and/or metronidazole have been recommended for NEC treatment in the USA [6,7], while penicillin, gentamicin and metronidazole are sometimes used in the UK [8]. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms
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