Human gut bacterial cell surface polysaccharides as a microbial nutrient source and target of immunoregulatory proteins shape gut microbiota structure and function

人肠道细菌细胞表面多糖作为微生物营养源和免疫调节蛋白的靶标塑造肠道微生物群的结构和功能

• 批准号: 10379170
• 负责人: Darryl A Wesener
• 金额: $ 10.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379170
• 关键词: Award; Bacteria; Bacterial Polysaccharides; Bacterial RNA; Bacteroides; Binding Proteins; Bioinformatics; Biological; Biological Assay; Biological Process; Biosensor; Carbohydrates; Carbon; Cell surface; Chemistry; Communities; Consumption; Data Analyses; Development; Diet; Dietary Fiber; Dietary Polysaccharide; Dietary Supplementation; Disease; Environment; Formulation; Fractionation; Genetic; Genetic Screening; Genome; Genomics; Glycobiology; Gnotobiotic; Goals; Grant; Growth; Health; Health Promotion; Human; Immune; Immune Evasion; Immune system; Immunoglobulins; In Situ; In Vitro; Interdisciplinary Study; Intervention; Knowledge; Lead; Lectin; Libraries; Link; Mentors; Metabolic; Metabolism; Metagenomics; Methods; Microbe; Microscopic; Mus; Nutrient; Nutritional; Outcome; Phase; Phenotype; Plants; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Probiotics; Proteins; Regulation; Research; Resistance; Series; Shapes; Source; Structure; Students; Supervision; Supplementation; Systems Biology; Techniques; Testing; Therapeutic; Training; Translating; Universities; bacterial community; bacterial genome sequencing; base; carbohydrate structure; career development; combinatorial; dietary supplements; experimental study; extracellular; genome annotation; gut bacteria; gut microbes; gut microbiome; gut microbiota; human model; immune function; immunoregulation; improved; in vivo; innovation; member; microbial; microbial community; microbiota; mouse model; prebiotics; probiotic supplementation; skills; small molecule; therapeutic target; transcriptome sequencing

PROJECT SUMMARY The gut microbiota has been linked to many aspects of human health and disease. These finding have ignited efforts to precisely modulate gut microbiota composition and function to promote health-associated features. The nutrient landscape within the gut shapes, and is influenced by, the gut microbiota. Bacteria respond to available nutrients and utilize them to support their own metabolism, sharing the metabolic by-products with other bacteria and the host. Carbohydrates within the gut, both consumed in the diet and produced by the host, impact gut bacteria composition and function via their utilization as a carbon source. The biological function of the polysaccharides that cover gut bacteria however, remains unclear. Bacterial cell surface polysaccharides act as a barrier between the microbe and its environment, enhancing bacterial growth and survival through mechanisms that include resistance to toxic small molecules, nutrient adaptation, and immune evasion. The central hypothesis I will test in this proposal is that microbiota bacterial polysaccharides modulate gut community structure and function via utilization as a nutrient by other community members, and through interaction with soluble immunoregulatory proteins. AIM 1 will employ isolated bacterial polysaccharides and in vitro growth assays to identify genetic features that enable utilization of bacterial polysaccharides. AIM 2 will define whether bacterial polysaccharides are consumed in vivo by cultured, genome sequenced microbial communities installed in gnotobiotic mice using microscopic recoverable paramagnetic beads coated in polysaccharides. AIM3 will test whether cell surface polysaccharides from probiotic dietary supplements alter gut microbiota polysaccharide utilization and recognition of community members by immunoregulatory proteins in the gut lumen of gnotobiotic mice. This series of experiments that blends chemistry, glycobiology, genomics, and gnotobiotic mouse models will define mechanisms of bacterial polysaccharide utilization, increase understanding of how nutrients in the gut shape the microbiota, and suggest a bioactive component of bacterial dietary supplements. These combined finding should improve development of microbiota-derived and -directed therapeutics for targeted microbiota manipulation. This award will also support by career development. During completion of the supervised portion of this grant I will gain critical computational research skills that includes bacterial genome sequencing and annotation, bacterial RNA-sequencing to characterize function, and metagenomic analysis. Ultimately, this award will facilitate my successful transition into an independent academic position at a research-intensive university where I will lead, teach, and mentor an interdisciplinary group of students, postdocs, and clinicians defining mechanisms of microbiota assembly, function, and regulation with a goal to translate my findings into methods for targeted microbiota manipulation to improve human health.

项目摘要 肠道菌群与人类健康和疾病的许多方面有关。这些发现被点燃了 精确调节肠道菌群组成和功能以促进与健康相关的特征的努力。 肠形内的营养景观，受肠道菌群的影响。细菌反应 可用的营养成分并利用它们来支持自己的新陈代谢，与 其他细菌和宿主。肠道内的碳水化合物，均在饮食中消耗，并由宿主产生 通过利用作为碳源来影响肠道细菌的组成和功能。的生物学功能 然而，覆盖肠道细菌的多糖仍不清楚。细菌细胞表面多糖 充当微生物及其环境之间的障碍，增强细菌的生长并通过 包括对有毒小分子的耐药性，营养适应和免疫逃避的机制。这 中心假设I将在此提案中测试是微生物群细菌多糖调节肠道 社区结构和功能通过利用作为其他社区成员的营养，并 通过与可溶性免疫调节蛋白的相互作用。 AIM 1将采用孤立的细菌 多糖和体外生长试验，以识别能够利用细菌的遗传特征 多糖。 AIM 2将定义是否通过培养物在体内消耗细菌多糖， 基因组测序的微生物群落在gnotobiotic小鼠中使用微观可回收 涂在多糖中的顺磁珠。 AIM3将测试细胞表面多糖是否来自 益生菌饮食补充剂改变肠道菌群多糖的利用和对社区的认可 gnotobiotic小鼠肠道内腔中的免疫调节蛋白成员。这一系列实验 混合化学，糖生物学，基因组学和gnotobiotic小鼠模型将定义细菌的机制 多糖利用率，增加对肠道营养的理解 建议细菌饮食补充剂的生物活性成分。这些结合发现应该改善 针对靶向微生物群操纵的微生物群衍生和指导的治疗剂的开发。 该奖项还将支持职业发展。在完成本赠款的监督部分I 将获得关键的计算研究技能，包括细菌基因组测序和注释， 细菌RNA序列以表征功能和元基因组分析。最终，这个奖项将 促进我成功地过渡到研究密集于大学的独立学术职位 我将领导，教和指导一个跨学科的学生，博士后和临床医生定义 菌群组装，功能和调节的机制，其目标是将我的发现转化为方法 用于靶向微生物群的操纵以改善人类健康。