Uptake of xenobiotic milk induces microRNA profile changes in the neonate intestine

ObjectiveExclusive breastfeeding is the best source of nutrition for most infants, but it is not always possible. Enteral nutrition influences intestinal gene regulation and the susceptibility for inflammatory bowel disorders, such as necrotizing enterocolitis (NEC). In modern neonatology it is observed that lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants. Since human breast milk has a high microRNA content in comparison to other body fluids, it is controversially discussed whether they could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals. DesignFollowing their discovery we utilized mammalian taxon-specific milk microRNA as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells (HIEC-6). ResultsMammals have in common a significant number of milk microRNAs yet exhibit taxon-specific microRNA fingerprints. We traced intact bovine-specific microRNAs from formula-nutrition in human preterm stool and 9 days after the onset of enteral feeding in intestinal cells of preterm piglets. Few hours after introducing enteral feeding in preterm piglets with supplemented reporter microRNAs (cel-miR-39-5p/-3p), we observed enrichment of the xenobiotic cel-miR in blood serum and in Ago2-immunocomplexes from intestinal biopsies. This points to a transmissibility of milk microRNA signals. We performed Adenovirus type 5-based microRNA-gene transfer into HIEC-6 and examined predicted bovine milk microRNA targets on the protein and transcriptome levels. ConclusionResults suggest that milk microRNAs could influence gene expression in intestinal epithelia of neonates under special conditions in vitro. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIEnteral nutrition influences intestinal gene regulation in neonates, e.g. lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants. C_LIO_LIHuman breast milk has a high microRNA content in comparison to other body fluids, thus it is discussed whether microRNAs could influence gene regulation in term and preterm neonates. C_LI What are the new findings?O_LIMammals have in common a significant number of milk miRNAs yet exhibit taxon-specific milk miRNA fingerprints. C_LIO_LITaxon-specific differences were used to trace xenobiotic microRNAs in human preterm neonates, who routinely received formula-supplemented nutrition in addition to breast milk. C_LIO_LIIn preterm piglets microRNA stably passed the GI tract and then accumulated in the bloodstream few hours post-feeding. C_LIO_LIPost-feeding reporter microRNAs were loaded to Ago2 in intestinal tissue samples. C_LIO_LIAdenovirus type 5-based bovine microRNA-gene transfer into HIEC-6 revealed deregulated microRNA targets on the protein and transcriptome levels. C_LI How might it impact on clinical practice in the foreseeable future?O_LIOur findings provide a line of evidence that a vertical transmission of maternal milk microRNA signals via GI transit to responsive cells and systemic bloodstream distribution is possible. Our discoveries will prompt the understanding about milk microRNA bioactivity with respect to intestinal maturation in term and preterm neonates and help to develop optimized nutritional strategies. C_LI