Mechanism of Activation of Probiotic Bifidobacteria by Prebiotic Milk Glycans

益生元乳聚糖激活益生菌双歧杆菌的机制

• 批准号: 8651901
• 负责人: Bruce German
• 金额: $ 41.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651901
• 关键词: Address; Allergic Reaction; American; Animals; Bacteria; Bifidobacterium; Bifidobacterium bifidum; Binding; Biological; Breast Feeding; Carbohydrates; Catabolism; Cattle; Cells; Clinical Trials; Complex; Complex Mixtures; Consumption; Diagnostic; Diarrhea; Disease; Environment; Epithelium; Feces; Food; Fractionation; Future; Gastrointestinal tract structure; Gene Cluster; Genomics; German population; Growth; Health; Human; Human Milk; Hydrolase; In Situ; In Vitro; Infant; Infant formula; Inflammatory disease of the intestine; Intervention; Intestines; Lactation; Lactobacillus; Link; Maps; Mass Spectrum Analysis; Measures; Metabolism; Methods; Milk; Modeling; Nucleotides; Oligosaccharides; Phenotype; Polysaccharides; Population Group; Probiotics; Production; Proteins; Research; Risk; Series; Shapes; Solid; Solutions; Source; Staging; Stream; Structure; System; Time; Training; Translating; Triad Acrylic Resin; Work; antimicrobial; base; enhancing factor; insight; intestinal epithelium; member; multidisciplinary; neonate; prebiotics; preference; programs; residence; response; tool

DESCRIPTION (provided by applicant): Probiotics and prebiotics are CAM interventions frequently employed by the American public to promote intestinal health and wellness. The presence of beneficial bacteria such as lactobacilli and bifidobacteria, whether delivered exogenously as probiotics or enriched via prebiotics, has been linked to positive health effects including reduction of gut inflammation, diarrhea and allergic reactions. At present however, our understanding of the mechanism of action underlying these biological effects is significantly lacking. Milk oligosaccharides are naturally-evolved prebiotic substrates that facilitate bifidobacterial enrichment and interaction within the infant host. Work from the UC Davis Milk Bioactives Program has shown that human milk oligosaccharides are utilized by select infant-borne bifidobacterial strains that demonstrated unique preferences in oligosaccharide consumption. In addition, genomic analysis of Bifidobacterium infantis and Bifidobacterium bifidum, two strains that grow well on milk oligosaccharides, has revealed unique gene clusters that are specifically induced during growth on these glycans. Further analysis has revealed that growth on milk glycans results in enhanced bifidobacterial interaction with the host epithelium. We hypothesize that the evolutionarily-driven relationship between milk oligosaccharides and cognate infant-borne bifidobacteria provides a model for enhanced probiotic persistence within, and interaction with, the human host. To address this hypothesis we will gain mechanistic insight into the specific catabolism of these unique milk glycans by bifidobacteria and comprehensively map their influence on bifidobacteria-host interaction via the following Specific Aims: 1. To comprehensively characterize human and bovine milk oligosaccharides and develop methods for their large scale fractionation and production for functional studies. 2. To completely characterize the bifidobacterial transporters and glycosyl hydrolases necessary to deconstruct these complex milk oligosaccharides. 3. To examine the influence of milk oligosaccharides on the interaction between bifidobacteria and the host. Successful completion of these Specific Aims will reveal specific mechanisms by which human milk oligosaccharides facilitate a protective enrichment of bifidobacteria in the gastrointestinal tract of breast fed infants. In addition, we will translate these findings to structurally and functionally equivalent bovine milk oligosaccharides, a commercially accessible substrate that can be easily delivered into CAM foods and therapies aimed at gut health. The significance of this application is a greater mechanistic understanding of the beneficial effects of synbiotic (milk oligosaccahrides plus cognate bifidobacteria) applications thereby providing both strategies and diagnostic measures to better address a variety of disorders marked by intestinal dysbiosis.

描述（由申请人提供）：益生菌和益生元是美国公众经常采用的CAM干预措施，以促进肠道健康和保健。有益细菌如乳酸杆菌和双歧杆菌的存在，无论是作为益生菌外源性递送还是通过益生元富集，都与积极的健康效应有关，包括减少肠道炎症，腹泻和过敏反应。然而，目前，我们对这些生物效应背后的作用机制的了解还非常缺乏。牛奶低聚糖是自然进化的益生元底物，有助于婴儿宿主内的益生菌富集和相互作用。加州大学戴维斯分校牛奶生物活性物质项目的工作表明，母乳低聚糖被选定的婴儿传播的双歧杆菌菌株利用，这些菌株在低聚糖消耗方面表现出独特的偏好。此外，对双歧杆菌和两歧双歧杆菌（两种在牛奶寡糖上生长良好的菌株）的基因组分析揭示了在这些聚糖上生长期间特异性诱导的独特基因簇。进一步的分析表明，乳汁聚糖上的生长导致双歧杆菌与宿主上皮细胞的相互作用增强。我们假设，牛奶低聚糖和同源的婴儿传播的益生菌之间的进化驱动的关系提供了一个模型，增强益生菌的持久性内，并与人类宿主的相互作用。为了解决这一假设，我们将获得对这些独特的乳聚糖被双歧杆菌特异性催化的机理洞察，并通过以下特定目的全面绘制它们对双歧杆菌-宿主相互作用的影响：1.全面表征人乳和牛乳低聚糖，并开发其大规模分离和生产方法，用于功能研究。2.为了完全表征解构这些复杂的乳寡糖所必需的生物活性细菌转运蛋白和糖基水解酶。3.研究乳寡糖对双歧杆菌与宿主相互作用的影响。这些特定目标的成功完成将揭示母乳低聚糖促进母乳喂养婴儿胃肠道中双歧杆菌保护性富集的特定机制。此外，我们将这些发现转化为结构和功能等效的牛乳低聚糖，这是一种商业上可获得的底物，可以很容易地输送到CAM食品和针对肠道健康的疗法中。本申请的重要性在于对合生元（乳寡糖加上同源益生菌）应用的有益效果的更大的机理理解，从而提供策略和诊断措施以更好地解决以肠道生态失调为标志的各种病症。