Grant Abstract: The UC Davis Milk Bioactives Center of Excellence in Research on CAM: Leveraging the Protective Properties of Milk to Enhance Probiotic Efficacy
Grant Number: 1P01AT008341-01
PI Name: German
Project Title: The UC Davis Milk Bioactives Center of Excellence in Research on CAM: Leveraging the Protective Properties of Milk to Enhance Probiotic Efficacy
Abstract: DESCRIPTION (provided by applicant): There is a gap in the knowledge in the field of CAM natural products, notably probiotics: a lack of understanding of mechanisms underlying probiotic action, as well as lack of strain selectivity and targeted function. The proposed strategy is based on the foundational knowledge of how human milk glycans enrich select Bifidobacterial strains that protect and guide development in healthy, breastfed human infants. The long- term objective of this project is to build a translational pipeline for the targeted development of effective synbiotics (prebiotic/probiotic combinations) for an array of first applications in the developing infant and child. To accomplish this objective the team will undertake 2 specific aims. First the research team will determine the structure-function relationships of the next set of glycan-Bifidobacteria combinations. In Project 1 the preferential utilization and specific mechanisms by which select Bifidobacteria catabolize bovine milk glycans will be examined, and the functional effects of glycan-fed Bifidobacteria on interactions with intestinal cells both n vitro and in vivo will be characterized. In Project 2 bovine milk glycoconjugate streams will be isolated and purified and chemo-enzymatically modified for testing in Project 1. In Project 2 accurate, sensitive and high- throughput methods will be developed to glycoprofile the utilization of these streams. These methods provide the means to build quantitative evidence of strain selectivity and function of synbiotics in vivo. Second, the research team will lay the foundation for future clinical efficacy studies in infants through a series of phase 0/I studies in healthy adults. In Project 3 the team will conduct a series of absorption, excretion, safety and tolerability, and dose-response studies of the first validated synbiotic. This synbiotic consists o bovine milk oligosaccharides paired with a genetically and functionally matched Bifidobacterial strain. In this project the team will employ several key innovations in study design and phenotyping to document selectivity and specificity of the synbiotic in vivo. The Glycomics & Metabolomics Core will provide analytical capabilities to assess targeted function of synbiotic interventions in Projects 1 (animals, cell media) and 3 (human studies). The Microbiology & Genomics Core will provide sequencing and microbial growth screening capabilities to support Projects 1 and 3. The Administrative Core will manage the overall center, provide logistical and bioinformatics/biostatistical support to the program, coordinate industrial partnerships and monitor progress for the entire program. By accomplishing these aims the research team will overcome several crucial obstacles in the field of probiotics: 1) a lack of understanding of mechanisms underlying strain-specific, glycan-based probiotic function, and 2) how to deal with high inter-individual variation in the gut microbiota. This center will establish a translational pipeline for developing safe, effective and mechanistically targeted CAM interventions (i.e. synbiotics) that modify the gut microbiome toward health and prevention, with a focus on applications in infancy and early childhood. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the gut microbiome is a crucial component of overall human health. Safe and effective approaches for correcting, maintaining, improving, and guiding the establishment of a healthy gut microbiota, particularly in infancy and early childhood, are needed. The project is relevant to NCCAM's mission because it supports translational research toward the goal of developing a portfolio of synbiotic interventions for improving health, with mechanistic signatures of biologica effects that harness state-of-the-art high throughput technologies.
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