Enteral but not parenteral antibiotics enhance gut function and prevent necrotizing enterocolitis in formula-fed newborn preterm pigs

Abstract

Birck MM, Nguyen DN, Cilieborg MS, Kamal SS, Nielsen DS, Damborg P, Olsen JE, Lauridsen C, Sangild PT, Thymann T. Enteral but not parenteral antibiotics enhance gut function and prevent necrotizing enterocolitis in formula-fed newborn preterm pigs. Am J Physiol Gastrointest Liver Physiol 310: G323-G333, 2016. First published December 17, 2015 doi:10.1152/ajpgi.00392.2015.-Preterm infants are susceptible to infection and necrotizing enterocolitis (NEC) and are often treated with antibiotics. Simultaneous administration of enteral and parenteral antibiotics during the first days after preterm birth prevents formula-induced NEC lesions in pigs, but it is unknown which administration route is most effective. We hypothesized that only enteral antibiotics suppress gut bacterial colonization and NEC progression in formula-fed preterm pigs. Caesarean-delivered preterm pigs (90 -92% of gestation) were fed increasing amounts of infant formula from birth to day 5 and given saline (CON) or antibiotics (ampicillin, gentamicin, and metronidazole) via the enteral (ENT) or parenteral (PAR) route (n ϭ 16 -17). NEC lesions, intestinal morphology, function, microbiology, and inflammatory mediators were evaluated. NEC lesions were completely prevented in ENT pigs, whereas there were high incidences of mild NEC lesions (59 -63%) in CON and PAR pigs (P Ͻ 0.001). ENT pigs had elevated intestinal weight, villus height/crypt depth ratio, and goblet cell density and reduced gut permeability, mucosal adherence of bacteria, IL-8 levels, colonic lactic acid levels, and density of Gram-positive bacteria, relative to CON pigs (P Ͻ 0.05). Values in PAR pigs were intermediate with few affected parameters (reduced lactic acid levels and density and adherence of Gram-positive bacteria, relative to CON pigs, P Ͻ 0.05). There was no evidence of increased antimicrobial resistance following the treatments. We conclude that enteral, but not parenteral, administration of antibiotics reduces gut bacterial colonization, inflammation, and NEC lesions in newborn, formula-fed preterm pigs. Delayed colonization may support intestinal structure, function, and immunity in the immediate postnatal period of formulafed preterm neonates.

Delayed development of systemic immunity in preterm pigs as a model for preterm infants

“…At birth and during the first week of life, preterm pigs showed very low blood neutrophil and lymphocyte counts, negligible NK cell frequency, low TLR-mediated cytokine production and impaired phagocytosis and NET responses. This may relate to the previously observed high incidence of bacteremia, osteomyelitis and NEC in formula-fed preterm pigs9252627. We identified a critical period during the second week of life where many innate immune parameters started to mature (blood neutrophil counts, NK cells and CD16 + monocyte frequencies, TLR-mediated cytokine production, phagocytosis and NET formation).…”

Brain Barrier Disruption and Region-Specific Neuronal Degeneration during Necrotizing Enterocolitis in Preterm Pigs

“…The reported data are observational and there is a need to substantiate whether a causal relationship exists between NEC-induced inflammation in the gut and blood, and subsequent brain injury. Further studies should investigate whether NEC-preventive interventions, such as enteral antibiotics, probiotics or beneficial milk diets, are neuroprotective in preterm neonates [22, 33, 34]. Our data suggest that during the acute phase of NEC, only severe clinical and pathological NEC lesions are associated with brain barrier disruption, neuroinflammation and neuron loss.…”

“…Enteral feeding across the first 5 days after birth consisted of rapidly increasing volumes of infant formula, containing maltodextrin as a main carbohydrate source, as described in our earlier publications [22, 23]. For the first 48 h, pigs were fed 24–48 mL/kg/day< of enteral nutrition + 32–48 mL/kg/day of intra-arterial Kabiven (Fresenius-Kabi).…”

Efficacy of a Triple Anti-Infective Regimen for Prevention of Complications in Critically Ill Term Neonates

“…Nevertheless, none of the gentamycin treated neonates developed NEC and none died in contrast to a 10% mortality rate in the controls (12). Recently, NEC lesions were completely prevented by antibiotics (ampicillin, gentamicin, and metronidazole) given via the enteral in contrast to the parenteral route in an animal model of preterm pigs (14). Our longlasting experience in the use of enteral gentamycin has revealed neither a change in ESBL producing enterobacteria in stool surveillance cultures nor in antimicrobial sensitivity patterns (22).…”

“…Oral aminoglycosides have successfully been investigated in the prevention of NEC in some small and old studies (12,13) and recently have been effective in preterm animal models of NEC prevention compared to parenteral antibiotics (14). And probiotics as summarized recently in a systematic meta-analysis showed significant benefits on NEC rates and all-cause neonatal mortality (15).…”