Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Effective preventive agents and biomarkers predictive of high-risk infants are significant clinical needs. The most promising interventions shown to prevent NEC are breast milk feedings and probiotic microorganisms, although the mechanisms of action are unknown. Our proposal draws from the integrated, multi-disciplinary Milk Bioactives Consortium at the University of California Davis and includes exciting preliminary data: a clinical trial of two probiotic products in premature infants, evidence that human milk oligosaccharides selectively stimulate growth of specific bifidobacteria, and a novel potential biomarker of infant susceptibility. We hypothesize that a regimen of prebiotic oligosaccharides and/or probiotic microbes, which increases bifidobacteria colonization to mimic that of healthy term breast-fed infants, will improve infant growth and lead to an attractive regimen for larger trials of prevention of NEC. We further hypothesize that a low ?-defensin gene copy number polymorphism predisposes some premature infants to development of an intestinal microbiota low in bifidobacteria and the consequent deficit in normal microflora protection increases their susceptibility to NEC.
Specific Aim 1 will conduct Phase 1 and Phase 2 clinical trials to identify and evaluate a preferred dietary supplement regimen to achieve a predominance of bifidobacteria in the fecal microbiota of preterm infants.
Specific Aim 2 will conduct a series of in vitro experiments to (a) analyze biochemical and genetic properties of the bifidobacteria in the feces of infants receiving prebiotic oligosaccharides and/or probiotic microbes and (b) analyze the prebiotic properties of components of human milk.
Specific Aim 3 will analyze the potential of a novel genetic biomarker for susceptibility to NEC: ?-defensin gene copy number. The proposed clinical trials and in vitro experiments are designed to answer important questions regarding the development of the intestinal microbiota, the effect of breast milk components on the developing intestinal microbiota, and the effect of changes in the intestinal microbiota on the health and growth of the premature infant.

Public Health Relevance

Having more healthy bacteria in the intestines may improve growth and prevent infections in premature infants. By giving different doses and combinations of live healthy bacteria (probiotics) and fiber (prebiotics) to premature infants, we aim to find the best way to change the bacteria in the intestines to be more like those of healthy breast-fed term infants. The genes of premature infants who get intestinal infections may be slightly different from those who don't;we will test one group of particularly promising genes to see if that is true.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-A (18))
Program Officer
Grave, Gilman D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Underwood, Mark A (2016) Response to Letter to the Editor Regarding ""Probiotic Administration in Infants With Gastroschisis: A Pilot Randomized Placebo-Controlled Trial"". J Pediatr Gastroenterol Nutr 63:e210
Vongbhavit, Kannikar; Underwood, Mark A (2016) Prevention of Necrotizing Enterocolitis Through Manipulation of the Intestinal Microbiota of the Premature Infant. Clin Ther 38:716-32
Powell, Weston T; Borghese, Robyn A; Kalanetra, Karen M et al. (2016) Probiotic Administration in Infants With Gastroschisis: A Pilot Randomized Placebo-Controlled Trial. J Pediatr Gastroenterol Nutr 62:852-7
Underwood, Mark A; German, J Bruce; Lebrilla, Carlito B et al. (2015) Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. Pediatr Res 77:229-35
De Leoz, Maria Lorna A; Kalanetra, Karen M; Bokulich, Nicholas A et al. (2015) Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of-concept study. J Proteome Res 14:491-502
Underwood, Mark A; Gaerlan, Stephanie; De Leoz, Maria Lorna A et al. (2015) Human milk oligosaccharides in premature infants: absorption, excretion, and influence on the intestinal microbiota. Pediatr Res 78:670-7
Grapov, Dmitry; Lemay, Danielle G; Weber, Darren et al. (2015) The human colostrum whey proteome is altered in gestational diabetes mellitus. J Proteome Res 14:512-20
Frese, Steven A; Mills, David A (2015) Should infants cry over spilled milk? Fecal glycomics as an indicator of a healthy infant gut microbiome. J Pediatr Gastroenterol Nutr 60:695
Pacheco, Alline R; Barile, Daniela; Underwood, Mark A et al. (2015) The impact of the milk glycobiome on the neonate gut microbiota. Annu Rev Anim Biosci 3:419-45
Spevacek, Ann R; Smilowitz, Jennifer T; Chin, Elizabeth L et al. (2015) Infant Maturity at Birth Reveals Minor Differences in the Maternal Milk Metabolome in the First Month of Lactation. J Nutr 145:1698-708

Showing the most recent 10 out of 76 publications