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

Michael L. Jensen, Thomas Thymann, Malene S. Cilieborg, Mikkel Lykke, Lars Mølbak, Bent B. Jensen, Mette Schmidt, Denise Kelly, Imke Mulder, Douglas G. Burrin, Per T. Sangild*

*Corresponding author for this work

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53-73%), and goblet cell densities (+110%) and lower myeloperoxidase (-51%) and colonic microbial density (10(5) vs. 10(10) colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs.

Original languageEnglish
Pages (from-to)G59-G71
Number of pages13
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume306
Issue number1
Early online date24 Oct 2013
DOIs
Publication statusPublished - Jan 2014

Keywords

  • immature
  • microbiota
  • necrotizing enterocolitis
  • neonates
  • premature

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    Jensen, M. L., Thymann, T., Cilieborg, M. S., Lykke, M., Mølbak, L., Jensen, B. B., Schmidt, M., Kelly, D., Mulder, I., Burrin, D. G., & Sangild, P. T. (2014). Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets. American journal of physiology. Gastrointestinal and liver physiology , 306(1), G59-G71. https://doi.org/10.1152/ajpgi.00213.2013