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

item JENSEN, MICHAEL L - University Of Copenhagen
item THYMANN, THOMAS - University Of Copenhagen
item CILIEBORG, MALENE S. - University Of Copenhagen
item LYKKE, MIKKEL - University Of Copenhagen
item MOLBAK, LARS - University Of Copenhagen
item JENSEN, BENT B. - Aarhus University
item SCHMIDT, METTE - University Of Copenhagen
item KELLY, DENISE - University Of Aberdeen
item MULDER, IMKE - University Of Aberdeen
item Burrin, Douglas - Doug
item SANGILD, PER T - University Of Copenhagen

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/11/2013
Publication Date: 10/24/2013
Citation: Jensen, M., Thymann, T., Cilieborg, M., Lykke, M., Molbak, L., Jensen, B., Schmidt, M., Kelly, D., Mulder, I., Burrin, D.G., Sangild, P. 2013. Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets. American Journal of Physiology - Gastrointestinal and Liver Physiology. 306(1):G59-G71.

Interpretive Summary: Premature infants are at increased risk for an intestinal disease called necrotizing enterocolitis (NEC). Only a small percentage of infants develop NEC, but it has devastating effects on health, and can be fatal. The underlying cause of NEC is not established, but the presence of bacteria seems to be essential for the disease to occur. To test this question, we used premature formula-fed, piglets as a model of human preterm infants and treated the piglets with a cocktail of three antibiotics. We used antibiotic treatment in order to prevent the growth of bacteria in the intestine, which increases rapidly after birth. The results showed that antibiotic treatment effectively decreased the growth of bacteria and completely prevented NE, compared to pigs given a placebo. The antibiotic treatment also reduced the inflammation and tissue injury in the intestine. These findings are clinically relevant and demonstrate the effectiveness of using antibiotics to prevent the devastating disease of NEC.

Technical 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.