Oral antibiotics increase blood neutrophil maturation and reduce bacteremia and necrotizing enterocolitis in the immediate postnatal period of preterm pigs

Abstract

Immature immunity may predispose preterm neonates to infections and necrotizing enterocolitis (NEC). Intravenous antibiotics are frequently given to prevent and treat sepsis, while oral antibiotics are seldom used. We hypothesized that oral antibiotics promote maturation of systemic immunity and delay gut bacterial colonization and thereby protect preterm neonates against both NEC and bacteremia in the immediate postnatal period. Preterm pigs were given formula and administered saline (CON) or broad-spectrum antibiotics orally (ORA) or systemically (SYS) for 5 d after birth. Temporal changes in blood parameters and bacterial composition in the intestine, blood and immune organs were analyzed. Newborn preterm pigs had few blood neutrophils and a high frequency of progenitor cells. Neutrophils gradually matured after preterm birth with increasing CD14 and decreasing CD172a expressions. Preterm neutrophil and monocyte TLR2 expression and TLR2-mediated blood cytokine responses were low relative to adults. ORA pigs showed enhanced blood neutrophil maturation with reduced cell size and CD172a expression. Only ORA pigs, but not SYS pigs, were protected from a high density of gut Gram-positive bacteria, high gut permeability, Gram-positive bacteremia and NEC. Neonatal oral antibiotics may benefit mucosal and systemic immunity via delayed gut colonization and enhanced blood neutrophil maturation just after preterm birth.

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

“…Total bacterial load in the colon, shown by log 10 of 16S rRNA copies, was similar between CON and PAR pigs but was reduced 100-fold in ENT pigs (P Ͻ 0.01, Fig. 5A), as also reported previously (32). Sequencing data revealed that the relative abundance of predominant genera in each treatment group was similar between distal intestinal and colon content (Fig.…”

“…and was colonized mainly by Enterobacteriaceae. The data also suggest that Gram-positive bacteria, in particular Enterococcus spp., may be the main bacteria group that affects the immature gut at this time and potentially leads to bacteremia via bacterial translocation across the gut barrier to the blood stream, as indicated in our study on systemic immunity (32). The cultures of frozen intestinal samples gave a preliminary indication of the risk for development of bacterial resistance genes following antibiotic treatment.…”

“…To test this hypothesis, we investigated intestinal structure, function, microbiology, and mucosal immunity in preterm pigs administered a combination of three commonly used antibiotics enterally or parenterally for 5 days after birth. The data on blood hematology and effects on systemic immunity have been published as a separate report, in which we showed that enteral antibiotics facilitated blood neutrophil maturation and reduced bacteremia and bacterial load in the bone marrow (32).…”

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

“…Late-onset sepsis (LOS) is defined as sepsis after day 3 and is more likely derived from postnatal acquisition of pathogens from the environment, including S. epidermidis , partly entering the body via indwelling catheters78. In addition, LOS may result from bacterial translocation across the immature gut, as blood cultures from neonates with LOS and bacteremia often reflects their gut bacterial composition9. Infection induced by bacterial translocation may be most prevalent shortly after preterm birth and before gut closure, especially when the immature gut has not yet been exposed to the maturational and barrier-supporting effects of mother’s milk (e.g.…”

“…immature function of many organ systems, including lungs, together with high sensitivity to NEC and LOS) when piglets are born at 90% gestation91718. Direct comparison of 90% gestation preterm pigs with preterm infants is difficult and depends on gestational age (e.g.…”