Abstract
An excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.
Highlights
An excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants
We found that the signal transducer and activator of transcription 1 (STAT1) cell signaling pathway is involved in IL-1β-induced inflammation in H4 cells and indole-3-lactic acid (ILA) has a regulatory effect on the STAT1 signaling pathway in the prevention of inflammation
We found that the STAT1 cell signaling pathway plays an important role in IL-1β-induced inflammation in H4 cells and ILA has a regulatory effect on the STAT1 signaling pathway in prevention of inflammation
Summary
An excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated These findings may be helpful in preventing NEC for premature infants. This laboratory has a longstanding interest in examining the effect of colonizing bacteria, probiotics and their metabolites, on the protection of immature intestine from excessive inflammation. H4 cells, a well-characterized human fetal primary small intestinal epithelial cell line[19,20,21], were used to investigate the molecular mechanisms including the signaling pathway of ILA in protection of immature enterocytes from excessive inflammation. Immature and mature enterocytes have been noted to have different reactions upon ILA treatment with or without IL-1β stimulation suggesting that the effects of ILA on enterocytes are developmentally regulated
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