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

项目总结 肠道微生物区系与人类健康和疾病的许多方面有关。这些发现点燃了 努力精确地调节肠道微生物区系的组成和功能，以促进与健康相关的特征。 肠道内的营养景观塑造肠道微生物区系，并受其影响。细菌对以下物质有反应 并利用它们支持自己的新陈代谢，将代谢副产品与 其他细菌和宿主。肠道内的碳水化合物，既在饮食中消耗，也由宿主产生， 通过利用肠道细菌作为碳源来影响肠道细菌的组成和功能。它的生物学功能 然而，覆盖肠道细菌的多糖仍不清楚。细菌细胞表面多糖 作为微生物和环境之间的屏障，通过以下途径促进细菌生长和生存 这些机制包括对有毒小分子的抵抗、营养适应和免疫逃避。这个 我将在这项提议中检验的中心假设是微生物区系细菌多糖调节肠道 社区结构和功能，通过其他社区成员作为养分加以利用，以及 通过与可溶性免疫调节蛋白相互作用。AIM 1将使用分离的细菌 多糖和体外生长试验以确定使细菌能够利用的遗传特征 多糖类。目标2将定义细菌多糖是否在体内被培养的、 利用显微可恢复技术对灵知生菌小鼠体内的微生物群落进行基因组测序 包被多糖的顺磁珠。AIM3将测试细胞表面多糖是否来自 益生菌膳食补充剂改变肠道微生物区系多糖的利用和群落识别 GnotoBiotic小鼠肠道中的免疫调节蛋白。这一系列的实验 混合化学、糖生物学、基因组学和诺生菌小鼠模型将定义细菌的机制 多糖的利用，增加对肠道营养物质如何塑造微生物区系的理解，以及 建议使用细菌膳食补充剂中的生物活性成分。这些综合发现应该会有所改善 针对微生物区系靶向操作的微生物区系衍生和定向疗法的发展。 该奖项还将得到职业发展的支持。在完成本补助金的监督部分期间，我 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测序以确定功能，并进行元基因组分析。最终，这个奖项将 帮助我成功地过渡到一所研究密集型大学的独立学术职位 我将领导、教授和指导一个由学生、博士后和临床医生组成的跨学科小组，他们定义 微生物区系组装、功能和调节的机制，目的是将我的发现转化为方法 用于有针对性的微生物区系操纵以改善人类健康。

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.