The human milk oligosaccharide 2'-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine.
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.
1Divisions of Newborn Medicine,Children's Hospital of Pittsburgh,Pittsburgh,PA 15224,USA.
Misty
http://orcid.org/0000-0002-0264-5721
M
Good
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Chhinder P
CP
Sodhi
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Yukihiro
Y
Yamaguchi
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Hongpeng
H
Jia
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Peng
P
Lu
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
William B
WB
Fulton
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Laura Y
LY
Martin
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Thomas
T
Prindle
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Diego F
DF
Nino
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
Qinjie
Q
Zhou
1Divisions of Newborn Medicine,Children's Hospital of Pittsburgh,Pittsburgh,PA 15224,USA.
Congrong
C
Ma
5Pediatric Pathology,Children's Hospital of Pittsburgh,Pittsburgh,PA 15224,USA.
John A
JA
Ozolek
7Abbott Nutrition,Columbus,OH 43215,USA.
Rachael H
RH
Buck
7Abbott Nutrition,Columbus,OH 43215,USA.
Karen C
KC
Goehring
3General Pediatric Surgery,Johns Hopkins University and Bloomberg Children's Center,Johns Hopkins Hospital,Baltimore,MD 21287,USA.
David J
DJ
Hackam
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000187:drug effects; D008895:Milk, Human / Q000737:chemistry*; D009569:Nitric Oxide / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects*; D014312:Trisaccharides / Q000008:administration & dosage*
D014312:Trisaccharides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C031420:2'-fucosyllactose
 2′FL 2′-fucosyllactose;  HMO human milk oligosaccharide;  LPS lipopolysaccharide;  NEC necrotising enterocolitis;  TLR4 toll-like receptor 4;  eNOS endothelial nitric oxide synthase; 2′-Fucosyllactose; Breast milk; Endothelial nitric oxide synthase; Human milk oligosaccharides; Necrotising enterocolitis