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

摘要 存在于将上皮表面与上皮细胞分离的粘蛋白层中的微生物。 胃肠道（GI）的大量微生物内容物在 维持宿主的代谢和免疫健康。比如说， 粘液溶解性革兰氏阴性专性厌氧细菌阿克曼氏菌 嗜粘蛋白菌与防止高脂诱导的肥胖有关。 与此同时，这种微生物的丰度在西方的人类中减少， 时尚饮食重要的是，在饮食诱导的肥胖症小鼠模型中，实验 定殖A.嗜粘蛋白菌导致较低的体重增加率和葡萄糖 阻力此外，A.嗜粘蛋白有助于抑制炎症， 增强粘蛋白的产生和促进肠屏障的完整性， 增强上皮细胞连接的形成。毫不奇怪，A。嗜粘蛋白是 被认为是潜在的商业益生菌。 不幸的是，之间相互作用的分子机制 阿克曼氏菌，其宿主，以及相关的微生物群落， 在这个应用中，我们建议应用遗传方法，我们最近 开发用于表征粘蛋白获取和降解的过程， A. mucinipihila，开发新的离体定殖模型以测试A. 嗜粘蛋白暴露对上皮细胞生理和功能的影响，并定义了 粘蛋白代谢在小鼠阿克曼菌定植中的作用及其 影响GI生态。 拟议的工作将产生新的遗传工具和宿主模型系统， 来了解这种新兴的有益微生物的分子基础 发挥其对宿主的健康促进作用，并有助于A. 具有增强的益生菌功能的嗜粘蛋白菌株。

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.