Almost one third of all infants are not or cannot be breast-fed and receive infant formula. Formula-feeding significantly increases the risk to develop necrotizing enterocolitis (NEC), the most frequent and most lethal disorder in neonates. We hypothesize that oligosaccharides present in human milk but not in infant formula contribute to the protective effects in breast-fed infants by inhibiting P-selectin mediated neutrophil adhesion and activation, which are key events in NEC pathogenesis. To test this hypothesis, the PI will continue his training in glycobiology and receive additional intensive training in gastroenterology with a special emphasis on neonatal NEC. The PI will be strongly supported by his Career Development Training Committee, consisting of world-leading experts in their respective fields. The PI's scientific background, together with the additional training of this award, will bring novel ideas and innovative perspectives for an independent scientific career, which will benefit medical research on human infant nutrition, health and disease. Besides receiving intensive glycobiology and gastroenterology training, the PI will be trained in a rat model of NEC, learning how to induce and assess onset, progression and outcome of the disease.
AIM 1 uses this model to assess whether human milk oligosaccharides in general reduce NEC incidence and severity.
AIM 2 will use Frontal Affinity Chromatography Mass Spectrometry to identify individual milk oligosaccharides with high affinity for P-selectin and chemically synthesize them in sufficient amounts to be tested in vitro and in vivo.
AIM 3 will then assess the effects of these oligosaccharides on P-selectin-mediated neutrophil adhesion and activation in in vitro parallel flow chamber models and ex vivo whole blood assays.
AIM 4 will return to the rat model of NEC and assess the effects of these individual oligosaccharides in intervention studies.
We aim to identify bioactive human milk oligosaccharides lacking from infant formula that inhibit key events in NEC pathogenesis. Our results, combined with interdisciplinary training, will guide intervention studies that assess the effectiveness of individual milk oligosaccharides on reducing the risk of NEC in human neonates. Our studies will support the efforts to provide formula-fed infants with the same benefits that breast-fed infants receive with their mother's milk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK078668-02
Application #
7575724
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-04-01
Project End
2009-08-31
Budget Start
2009-04-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$90,000
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bode, Lars (2018) Human Milk Oligosaccharides in the Prevention of Necrotizing Enterocolitis: A Journey From in vitro and in vivo Models to Mother-Infant Cohort Studies. Front Pediatr 6:385
Lin, Ann E; Autran, Chloe A; Espanola, Sophia D et al. (2014) Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J Infect Dis 209:389-98
Jantscher-Krenn, Evelyn; Marx, Carolin; Bode, Lars (2013) Human milk oligosaccharides are differentially metabolised in neonatal rats. Br J Nutr 110:640-50
Bode, Lars; Jantscher-Krenn, Evelyn (2012) Structure-function relationships of human milk oligosaccharides. Adv Nutr 3:383S-91S
Jantscher-Krenn, Evelyn; Lauwaet, Tineke; Bliss, Laura A et al. (2012) Human milk oligosaccharides reduce Entamoeba histolytica attachment and cytotoxicity in vitro. Br J Nutr 108:1839-46
Bode, Lars (2012) Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 22:1147-62
Jantscher-Krenn, Evelyn; Zherebtsov, Monica; Nissan, Caroline et al. (2012) The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 61:1417-25