Discovery of a Bacterial Peptide as a Modulator of GLP-1 and Metabolic Disease

Authors

Catherine Tomaro-Duchesneau
Stephanie L LeValley
Daniel Roeth
Liang Sun
Frank T Horrigan
Markus Kalkum
Joseph M Hyser
Robert A Britton

Publication Date

3-18-2020

Journal

Scientific Reports

DOI

10.1038/s41598-020-61112-0

PMID

32188864

PMCID

PMC7080827

PubMedCentral® Posted Date

5-18-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Bacterial Proteins, Biomarkers, Calcium, Calcium Signaling, Cell Line, Dose-Response Relationship, Drug, Female, Glucagon-Like Peptide 1, Humans, Intracellular Space, Metabolic Diseases, Mice, Peptides, Microbiology, Metabolism

Abstract

Early work in rodents highlighted the gut microbiota's importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1), an incretin secreted by L-cells lining the gastrointestinal epithelium, has important functions: promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to identify microbial strains with GLP-1 stimulatory activity as potential metabolic disease therapeutics. Over 1500 human-derived strains were isolated from healthy individuals and screened for GLP-1 modulation by incubating bacterial cell-free supernatants with NCI H716 L-cells. Approximately 45 strains capable of increasing GLP-1 were discovered. All GLP-1 positive strains were identified as Staphylococcus epidermidis by 16S rRNA sequencing. Mass spectrometry analysis identified a 3 kDa peptide, Hld (delta-toxin), present in GLP-1 positive supernatants but absent in GLP-1 neutral supernatants. Studies in NCI-H716 cells and human jejunal enteroids engineered to make more enteroendocrine cells demonstrated that Hld alone is sufficient to enhance GLP-1 secretion. When administered in high-fat-fed mice, Hld-producing S. epidermidis significantly reduced markers associated with obesity and T2DM. Further characterization of Hld suggests GLP-1 stimulatory action of Hld occurs via calcium signaling. The presented results identify a novel host-microbe interaction which may ultimately lead to the development of a microbial peptide-based therapeutic for metabolic disease.

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