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细胞表面分开的粘蛋白层中的微生物 胃肠道(GI)的大量微生物内容物在 维持宿主的新陈代谢和免疫健康。例如, 嗜粘性革兰氏阴性厌氧菌阿克曼氏菌 粘液与防止高脂肪诱导的肥胖有关。 随之而来的是，在西方的人类中，这种微生物的丰度减少了。 时尚饮食。重要的是，在饮食诱导肥胖的小鼠模型中，实验性 嗜粘杆菌的定植导致较低的体重增加率和血糖 抵抗。此外，粘液假单胞菌有助于通过以下途径抑制炎症 通过促进粘蛋白的产生和促进肠道屏障的完整性 促进上皮细胞连接的形成。不足为奇的是，粘液嗜酸杆菌 被认为是潜在的商业益生菌。 不幸的是，相互作用背后的分子机制 它的宿主阿克曼西亚和相关的微生物群落在很大程度上 在这个未知的应用中，我们建议应用我们最近 用来描述粘蛋白的获取和降解过程 发展新的体外定植模型来测试粘液曲霉的影响。 接触粘液对上皮细胞的生理和功能的影响，并定义 粘蛋白代谢在阿克曼原虫在小鼠体内定植中的作用 对胃肠道生态的影响。 拟议的工作将产生新的遗传工具和宿主模型系统 以了解这种新出现的有益微生物如何 在寄主上发挥促进健康的作用，并协助A. 具有增强益生菌功能的粘液杆菌菌株。

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.