Effects of HMO on Intestinal Permeability

Necrotizing Enterocolitis (NEC) is one of the most common and often fatal intestinal disorders in premature infants. As many as 10% of premature infants with very-low-birth weight develop NEC; more than a quarter of them die. Most remarkably, breast-fed infants are at a six to ten fold lower risk to develop NEC compared to formula-fed infants. Most recent data from animal intervention studies conducted in the hosting laboratory in La Jolla, California, show that Human Milk Oligosaccharides (HMO), complex sugars highly abundant in human milk but not in infant formula, reduce NEC incidence and severity. The underlying mechanisms, however, are unknown. Here, we propose to elucidate one potential mechanism based on the following observations. An impaired intestinal barrier function plays a key role in NEC pathogenesis. The hosting laboratory has shown that glycosaminoglycans (GAG) are essential components of the intestinal barrier. Preliminary data from other groups indicate that HMO alter intestinal epithelial glycan expression in general. Here, we hypothesize that HMOs alter intestinal epithelial GAG expression in particular, augmenting the intestinal barrier function and thus contributing to the beneficial effects of breast-feeding on NEC incidence and severity. In Specific Aim 1 we will use an intervention study in a neonatal rat NEC model to assess whether HMOs modulate intestinal permeability. In Specific Aim 2 we will assess whether differences in intestinal permeability between formula-fed and `breast-fed` rats are due to an altered intestinal cell surface GAG expression pattern and whether HMO supplementation affects cell surface GAG amount and/or structural composition. The results of the proposed project will help us understand one potential mechanism underlying the beneficial effects of HMO in reducing NEC incidence and severity. On a broader perspective, the results may also guide our understanding of how HMO contribute to the beneficial effects of breast-feeding. Since GAG are involved in various physiological processes such as development, tissue repair, immunity, or host defense, HMO-mediated changes in the GAG-display of the intestine might have far more extensive effects on a functional intestine than solely sealing the barrier.