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

项目摘要 肠道微生物群与人类健康和疾病的许多方面有关。这些发现点燃了 努力精确调节肠道微生物群组成和功能，以促进健康相关特征。 肠道内的营养景观塑造了肠道微生物群，并受其影响。细菌对 可利用的营养素并利用它们来支持自己的新陈代谢，并与他人分享代谢副产物 其他细菌和宿主。肠道内的碳水化合物，既在饮食中消耗，又由宿主产生， 影响肠道细菌组成和功能。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 作为微生物与其环境之间的屏障，通过以下方式促进细菌生长和存活 这些机制包括对有毒小分子的抗性、营养适应和免疫逃避。的 在这个提议中，我将检验的中心假设是，微生物群细菌多糖调节肠道 群落结构和功能，通过利用作为一种营养物质的其他社区成员，和 通过与可溶性免疫调节蛋白的相互作用。AIM 1将使用分离的细菌 多糖和体外生长测定，以鉴定能够利用细菌 多糖AIM 2将确定细菌多糖是否被培养的， 基因组测序的微生物群落安装在gnotobiotic小鼠使用显微镜可回收 包裹着多糖的顺磁珠。AIM3将测试细胞表面多糖 益生菌膳食补充剂改变肠道微生物群多糖的利用和对群落的识别 成员通过gnotobiotic小鼠肠腔中的免疫调节蛋白。这一系列的实验 混合物化学，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，增加对肠道中营养物质如何塑造微生物群的理解， 表明细菌膳食补充剂的生物活性成分。这些综合发现应该会改善 开发用于靶向微生物群操纵的微生物群衍生和定向疗法。 该奖项还将支持职业发展。在完成本补助金的监督部分期间， 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测序以表征功能，以及宏基因组分析。最终，该奖项将 帮助我成功过渡到一所研究型大学的独立学术职位 在那里，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， 微生物群组装，功能和调节的机制，目标是将我的发现转化为方法 用于有针对性的微生物群操纵，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.