title: Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets.
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.
authors.affiliation: Dept. of Nutrition, Exercise and Sports, Faculty of Science, Univ. of Copenhagen, 30 Rolighedsvej, DK-1958 Frederiksberg C,. psa@life.ku.dk.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Jensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Thymann
authors.forename: Malene S
authors.initials: MS
authors.lastname: Cilieborg
authors.forename: Mikkel
authors.initials: M
authors.lastname: Lykke
authors.forename: Lars
authors.initials: L
authors.lastname: Mølbak
authors.forename: Bent B
authors.initials: BB
authors.lastname: Jensen
authors.forename: Mette
authors.initials: M
authors.lastname: Schmidt
authors.forename: Denise
authors.initials: D
authors.lastname: Kelly
authors.forename: Imke
authors.initials: I
authors.lastname: Mulder
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Burrin
authors.forename: Per T
authors.initials: PT
authors.lastname: Sangild
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000667:Ampicillin / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019072:Antibiotic Prophylaxis / Q000379:methods; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005839:Gentamicins / Q000494:pharmacology*; D018928:Immunity, Mucosal / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D008795:Metronidazole / Q000494:pharmacology*; D064307:Microbiota / Q000187:drug effects*; D007752:Obstetric Labor, Premature / Q000276:immunology; D011247:Pregnancy; D013552:Swine
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D008795:Metronidazole; D000667:Ampicillin
keywords: immature; microbiota; necrotizing enterocolitis; neonates; premature