Project Details

Human milk oligosaccharides promote intestinal homeostasis in experimental necrotizing enterocolitis

Bo Li, PhD

Summary

BACKGROUND: Necrotizing enterocolitis (NEC) is a disease characterized by inflammation and necrosis of the intestine that affects approximately 5-6% of preterm infants. The mortality rate of NEC has remained at 30-50%, with no substantial improvement to survivability over the past fifty years. Accordingly, there is an urgent need to elucidate the mechanisms involved in NEC development and to design an effective therapeutic intervention. GAP: Breast milk has been shown to decrease the incidence of NEC, human milk oligosaccharides (HMOs) are the most abundant constituent of human breast milk and seem to play an important role in attenuating intestinal injury in NEC, however, the underlying mechanism(s) for this attenuation has yet to be elucidated. HYPOTHESIS: HMOs attenuate intestinal injury and restore intestinal homeostasis in NEC, the effects of which may be independent of gut microbiota. METHODS: The impact of HMOs on a well-established murine model of NEC in the presence of normal or disrupted gut microbiome was assessed and findings validated using mouse intestinal organoids. RESULTS: In the presence of either normal or reduced gut microbiota, HMOs attenuated NEC-induced intestinal injury by rescuing intestinal epithelial proliferation and intestinal stem cell expression. Similarly, in murine intestinal organoids devoid of gut microbiota, HMOs increased intestinal proliferation and stem cell expression. The HMO-transcriptome clustered into multiple functional categories including: cell cycle, proliferation, and glycoproteins. IMPACT: This research provides a greater understanding of the mechanisms of action of HMOs in NEC, thus giving us the basis by which we can translate our findings into future clinical trials. Website Link: http://lab.research.sickkids.ca/pierro/