The human milk oligosaccharide 2′-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine

Abstract

Necrotising enterocolitis (NEC) is a common disease in premature infants characterised by intestinal ischaemia and necrosis. The only effective preventative strategy against NEC is the administration of breast milk, although the protective mechanisms remain unknown. We hypothesise that an abundant human milk oligosaccharide (HMO) in breast milk, 2′-fucosyllactose (2′FL), protects against NEC by enhancing intestinal mucosal blood flow, and we sought to determine the mechanisms underlying this protection. Administration of HMO-2′FL protected against NEC in neonatal wild-type mice, resulted in a decrease in pro-inflammatory markers and preserved the small intestinal mucosal architecture. These protective effects occurred via restoration of intestinal perfusion through up-regulation of the vasodilatory molecule endothelial nitric oxide synthase (eNOS), as administration of HMO-2′FL to eNOS-deficient mice or to mice that received eNOS inhibitors did not protect against NEC, and by 16S analysis HMO-2′FL affected the microbiota of the neonatal mouse gut, although these changes do not seem to be the primary mechanism of protection. Induction of eNOS by HMO-2′FL was also observed in cultured endothelial cells, providing a link between eNOS and HMO in the endothelium. These data demonstrate that HMO-2′FL protects against NEC in part through maintaining mesenteric perfusion via increased eNOS expression, and suggest that the 2′FL found in human milk may be mediating some of the protective benefits of breast milk in the clinical setting against NEC.

Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis

“…Currently, over 150 different HMO structures have been identified in humans and there seems to be considerable heterogeneity in the biological effects. For instance, HMOs that have sialyated or fucosylated side chains decrease pathogen burden, decrease NEC, and the addition of sialic acids to galacto‐oligosaccharides seem to confer NEC‐protection . Individual HMOs also seem to impart structure‐specific effects: for example, 2‐fucosyllactose (2’FL) dampens the activity of TLR‐4 signaling—a pathway involved in expression of PDI—whereas 6’‐sialyllactose (6’SL) can decrease the adherence of Escherichia coli .…”

Milk Glycans and Their Interaction with the Infant-Gut Microbiota

“…NEC is a common disease in premature infants characterized by abdominal distention and intestinal necrosis. 2′-FL has been shown to protect against NEC by enhancing mesenteric perfusion via increased endothelial nitric oxide synthase expression in the neonatal intestine, and these observations suggest that 2′-FL can mediate the protective benefits of milk in a clinical setting (Good et al 2016). …”

Prenatal and postnatal administration of prebiotics and probiotics

“…Specific HMO structures appear to impact the fecal microbiome in premature infants [49] and may explain a portion of the protective benefit of human milk against NEC. Studies of single HMO structures are thus far limited to animal studies, which demonstrate benefit in prevention of NEC [50,51]. …”