The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats
- Evelyn Jantscher-Krenn1,2,3,
- Monica Zherebtsov2,
- Caroline Nissan1,2,
- Kerstin Goth4,
- Yigit S Guner4,
- Natasha Naidu5,
- Biswa Choudhury5,
- Anatoly V Grishin4,
- Henri R Ford4,
- Lars Bode1,2
- 1Division of Neonatal Medicine, Department of Pediatrics, University of California–San Diego, San Diego, California, USA
- 2Division of Gastroenterology and Nutrition, Department of Pediatrics, University of California-San Diego, San Diego, California, USA
- 3Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Graz, Austria
- 4Saban Research Institute, Children's Hospital, Los Angeles, California, USA
- 5Glycotechnology Core, University of California–San Diego, San Diego, California, USA
- Correspondence to Dr Lars Bode, University of California–San Diego, Department of Pediatrics, Division of Neonatal Medicine, Division of Gastroenterology and Nutrition, 200 West Arbor Drive, MC 8450, San Diego, CA 92103-8450, USA;
Contributors LB, AVG and HRF designed the research; LB, EJK, MZ, KG and YSG conducted the rat intervention studies; LB, YSG and AVG analysed the data; EJK and LB analysed glycans by HPLC-FL; CN and LB conducted the sequential endoglycosidase digestion studies; NN and BC analysed glycans by MALDI-TOF-MS and GC-MS; LB wrote the manuscript. All authors read and approved the final manuscript.
- Revised 3 November 2011
- Accepted 13 November 2011
- Published Online First 3 December 2011
Background Necrotising enterocolitis (NEC) is one of the most common and fatal intestinal disorders in preterm infants. Breast-fed infants are at lower risk for NEC than formula-fed infants, but the protective components in human milk have not been identified. In contrast to formula, human milk contains high amounts of complex glycans.
Objective To test the hypothesis that human milk oligosaccharides (HMO) contribute to the protection from NEC.
Methods Since human intervention studies are unfeasible due to limited availability of HMO, a neonatal rat NEC model was used. Pups were orally gavaged with formula without and with HMO and exposed to hypoxia episodes. Ileum sections were scored blindly for signs of NEC. Two-dimensional chromatography was used to determine the most effective HMO, and sequential exoglycosidase digestions and linkage analysis was used to determine its structure.
Results Compared to formula alone, pooled HMO significantly improved 96-hour survival from 73.1% to 95.0% and reduced pathology scores from 1.98±1.11 to 0.44±0.30 (p<0.001). Within the pooled HMO, a specific isomer of disialyllacto-N-tetraose (DSLNT) was identified to be protective. Galacto-oligosaccharides, currently added to formula to mimic some of the effects of HMO, had no effect.
Conclusion HMO reduce NEC in neonatal rats and the effects are highly structure specific. If these results translate to NEC in humans, DSLNT could be used to prevent or treat NEC in formula-fed infants, and its concentration in the mother's milk could serve as a biomarker to identify breast-fed infants at risk of developing this disorder.
EJK and MZ made equal contributions.
Funding The study was funded by NIH grants K99/R00 DK078668 (LB), R03 HD059717S1 (LB), R21 AI083612 (AVG) and R01 AI014032 (HRF) and in part by Abbott Nutrition. The funding sources were not involved in the study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication.
Competing interests None.
Ethics approval IRB of the University of California–San Diego.
Provenance and peer review Not commissioned; externally peer reviewed.