Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology

摘要 栖息在将上皮表面与表皮分开的粘蛋白层中的微生物 胃肠道 (GI) 中的大量微生物在 维持宿主的代谢和免疫健康。例如， 粘液溶解、革兰氏阴性、专性厌氧细菌 Akkermansia muciniphila 与预防高脂肪引起的肥胖有关。 与此同时，这种微生物在西方人类中的丰度下降 风格的饮食。重要的是，在饮食引起的肥胖小鼠模型中，实验 A. mucinophila 定植导致体重增加率和血糖降低 阻力。此外，A. muciniphila 通过以下方式有助于抑制炎症： 通过以下方式增强粘蛋白产生并促进肠道屏障完整性 增强上皮细胞连接的形成。毫不奇怪，A. muciniphila 是 被认为是一种潜在的商业益生菌。 不幸的是，两者之间相互作用的分子机制 阿克曼氏菌、其宿主和相关微生物群落主要是 未知 在这个应用中，我们建议应用我们最近的遗传方法 开发用于表征粘蛋白获取和降解的过程 A. mucinipihila，开发新的离体定植模型来测试 A. mucinipihila 的影响。 粘蛋白暴露对上皮细胞生理学和功能的影响，并定义 粘蛋白代谢在小鼠阿克曼氏菌定植中的作用及其 对地理标志生态的影响。 拟议的工作将产生新的遗传工具和宿主模型系统 了解这种新兴有益微生物的分子基础 对其宿主发挥其促进健康的作用，并有助于 A. 具有增强益生菌功能的粘蛋白菌株。

ABSTRACT Microbes that inhabit the mucin layer that separates epithelial surfaces from the bulk of microbial contents of the gastrointestinal tract (GI) play a critical role in maintaining the metabolic and immunological health of their host. For instance, the mucolytic, gram negative, obligate anaerobic bacterium Akkermansia muciniphila is associated with protection from high-fat induced obesity. Concomitantly, the abundance of this microbe decreases in humans on western style diets. Importantly, in mouse models of diet-induced obesity, experimental colonization with A. mucinophila leads to lower rates of weight gain and glucose resistance. In addition, A. muciniphila contributes to dampening inflammation by enhancing mucin production and promoting intestinal barrier integrity through enhanced formation of epithelial cell junctions. Not surprisingly, A. muciniphila is being considered as a potential commercial probiotic. Unfortunately, the molecular mechanisms underlying the interactions between Akkermansia, its host, and associated microbial communities are largely unknown In this application, we propose to apply genetic methods we recently developed to characterize the process of mucin acquisition and degradation by A. mucinipihila, develop new ex vivo colonization models to test the impact of A. muciniphila exposure on epithelial cell physiology and function, and define the role that mucin metabolism plays in Akkermansia colonization of mice and its impact on GI ecology. The proposed work will generate new genetic tools and host model systems with which to understand the molecular basis of how this emerging beneficial microbe exerts its health-promoting effects on its host, and aid in the engineering of A. muciniphila strains with enhanced probiotic functions.