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

Weil, P. P.; Reincke, S.; Hirsch, C. A.; Giachero, F.; Aydin, M.; Scholz, J.; Jönsson, F.; Hagedorn, C.; Nguyen, D. N.; Thymann, T.; Jiang, P.; Pembaur, A.; Orth, V.; Wünsche, V.; Wirth, S.; Jenke, A. C. W. C. W.; Sangild, P. T.; Kreppel, F.; Postberg, J.

Objective: Exclusive 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. Design: Following 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). Results: Mammals 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. Conclusion: Results suggest that milk microRNAs could influence gene expression in intestinal epithelia of neonates under special conditions in vitro.