Metabolic diseases, including type 2 diabetes and obesity, have become increasingly prevalent global health concerns. Studies over the past decade have established connections between the gastrointestinal microbiota and host metabolism, but the mechanisms behind these connections are only beginning to be understood. We were interested in identifying microbes that have the ability to modulate the levels of the incretin hormone glucagon-like peptide-1 (GLP-1). Using a human-derived cell line that is capable of secreting GLP-1 in response to stimulatory ligands (NCI-H716), we identified supernatants from several bacterial isolates that were capable of decreasing GLP-1 levels, including several strains of Enterococcus faecalis We further identified the secreted protease GelE, an established virulence factor from E. faecalis, as being responsible for GLP-1 inhibition via direct cleavage of GLP-1 by GelE. Finally, we demonstrated that E. faecalis supernatants can disrupt a colonic epithelial monolayer and cleave GLP-1 in a gelE-dependent manner. This work suggests that a secreted factor from an intestinal microbe can traverse the epithelial barrier and impact levels of an important intestinal hormone.IMPORTANCE Humans have a complex and interconnected relationship with their gastrointestinal microbiomes, yet our interest in the microbiome tends to focus on overt pathogenic or probiotic activities, leaving the roles that commensal species may have on host physiology and metabolic processes largely unexplored. Commensal organisms in the microbiome produce and secrete many factors that have an opportunity to interact with the gastrointestinal tract and host biology. Here, we show that a secreted protease from E. faecalis, GelE, is able to degrade the gastrointestinal hormone GLP-1, which is responsible for regulating glucose homeostasis and appetite in the body. The disruption of natural GLP-1 signaling by GelE may have significant consequences for maintaining healthy blood glucose levels and in the development of metabolic disease. Furthermore, this work deepens our understanding of specific host-microbiome interactions.

中文翻译：

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粪肠球菌金属蛋白酶 GelE 降解肠促胰岛素胰高血糖素样肽-1 (GLP-1)。

代谢性疾病，包括 2 型糖尿病和肥胖症，已成为越来越普遍的全球健康问题。过去十年的研究已经建立了胃肠道微生物群和宿主代谢之间的联系，但这些联系背后的机制才刚刚开始被了解。我们有兴趣鉴定能够调节肠促胰岛素激素胰高血糖素样肽-1 (GLP-1) 水平的微生物。使用能够分泌 GLP-1 以响应刺激性配体 (NCI-H716) 的人源细胞系，我们鉴定了来自几种能够降低 GLP-1 水平的细菌分离株的上清液，包括几种粪肠球菌菌株。进一步鉴定了分泌的蛋白酶 GelE，这是一种来自粪肠球菌的已确定的毒力因子，通过 GelE 直接裂解 GLP-1 来抑制 GLP-1。最后，我们证明了粪肠球菌上清液可以破坏结肠上皮单层并以依赖于凝胶的方式切割 GLP-1。这项工作表明，来自肠道微生物的分泌因子可以穿过上皮屏障并影响一种重要肠道激素的水平。或益生菌活动，留下共生物种可能对宿主生理和代谢过程的作用在很大程度上未被探索。微生物组中的共生生物产生和分泌许多有机会与胃肠道和宿主生物学相互作用的因子。这里，我们表明，粪肠球菌分泌的蛋白酶 GelE 能够降解胃肠激素 GLP-1，后者负责调节体内葡萄糖稳态和食欲。GelE 对天然 GLP-1 信号的破坏可能对维持健康的血糖水平和代谢疾病的发展产生重大影响。此外，这项工作加深了我们对特定宿主-微生物组相互作用的理解。