Discovery of a bacterial peptide as a modulator of GLP-1 and metabolic disease

Abstract

19Early work in germ-free rodents highlighted the gut microbiota's importance in 20 metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-21 like peptide-1 (GLP-1) is an incretin secreted by enteroendocrine L-cells lining the 22 gastrointestinal epithelium. GLP-1 has important functions including promoting insulin 23 secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and 24 appetite. We set out to elucidate how the microbiota can modulate GLP-1 secretion, 25with the goal to identify microbial strains with GLP-1 stimulatory activity as a metabolic 26 disease therapeutic. Over 1500 human-derived strains were isolated from fecal, breast 27 milk, and colon and intestinal biopsy samples from healthy individuals. . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Degradation of the Incretin Hormone Glucagon-Like Peptide-1 (GLP-1) by Enterococcus faecalis Metalloprotease GelE

“…1A). We also identified 45 isolates that dramatically increase GLP-1 levels; these were further characterized in a separate study (8).…”

“…Bacterial strain isolation. Bacterial strains for screening were isolated previously from fecal, breast milk, and ileum biopsy samples (8). Genetic mutant strains of Enterococcus faecalis (OG1RF, TX5266 [fsrB mutant], TX5264 [gelE mutant], TX5243 [sprE mutant], and TX5128 [gelE sprE mutant]) were generously gifted from the Danielle A. Garsin Laboratory (University of Texas, Health Science Center) (10).…”

Microbial regulation of enteroendocrine cells

“…142 Using an untargeted approach, screening of human-derived microbial strains identified a bacterial peptide from Staphylococcus epidermis that was able to stimulate GLP-1 from cultured cell lines in vitro. 143 In contrast, a secreted protease from Enterococcus faecalis (called GelE) was able to cleave and thus inactivate GLP-1 in vitro, 144 indicating that complex interactions exist between different members of gut microbiota to intricately regulate GLP-1 levels.…”

Confinement Alters the Structure and Function of Calmodulin

“…Protein confinement is not only a key aspect of many biological processes, including misfolding (chaperones), biosynthesis (ribosome tunnel), and transport (translocons), but also plays important roles in industrial applications, such as drug delivery, enzyme retrieval, and therapeutic product protection . Studies of confinement effects on proteins include modeling, simulations, and wet experiments .…”