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.