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)
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Special Emphasis Panel (ZHD1-DSR-A (18))
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Grave, Gilman D
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University of California Davis
Schools of Medicine
United States
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Patel, Ravi Mangal; Underwood, Mark A (2018) Probiotics and necrotizing enterocolitis. Semin Pediatr Surg 27:39-46
Kirmiz, Nina; Robinson, Randall C; Shah, Ishita M et al. (2018) Milk Glycans and Their Interaction with the Infant-Gut Microbiota. Annu Rev Food Sci Technol 9:429-450
Underwood, Mark A; Sohn, Kristin (2017) The Microbiota of the Extremely Preterm Infant. Clin Perinatol 44:407-427
Underwood, Mark A; Davis, Jasmine C C; Kalanetra, Karen M et al. (2017) Digestion of Human Milk Oligosaccharides by Bifidobacterium breve in the Premature Infant. J Pediatr Gastroenterol Nutr 65:449-455
Underwood, Mark A (2017) Impact of probiotics on necrotizing enterocolitis. Semin Perinatol 41:41-51
Huang, Jincui; Kailemia, Muchena J; Goonatilleke, Elisha et al. (2017) Quantitation of human milk proteins and their glycoforms using multiple reaction monitoring (MRM). Anal Bioanal Chem 409:589-606
Sohn, Kristin; Underwood, Mark A (2017) Prenatal and postnatal administration of prebiotics and probiotics. Semin Fetal Neonatal Med 22:284-289
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
Underwood, Mark A (2016) Missed Opportunities: The Cost of Suboptimal Breast Milk Feeding in the Neonatal Intensive Care Unit. J Pediatr 175:12-4
Underwood, Mark A (2016) Probiotics and Innate and Adaptive Immune Responses in Premature Infants. For Immunopathol Dis Therap 7:1-15

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