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

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

Posted 29 Jul 2018
bioRxiv DOI: 10.1101/379503 (published DOI: 10.1038/s41598-020-61112-0)

Early work in germ-free rodents highlighted the gut microbiota's importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1) is an incretin secreted by enteroendocrine L-cells lining the gastrointestinal epithelium. GLP-1 has important functions including promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to elucidate how the microbiota can modulate GLP-1 secretion, with the goal to identify microbial strains with GLP-1 stimulatory activity as a metabolic disease therapeutic. Over 1500 human-derived strains were isolated from fecal, breast milk, and colon and intestinal biopsy samples from healthy individuals. In vitro screening for GLP-1 modulation was performed by incubating bacterial cell-free supernatants with NCI H716 human L-cells. Approximately 45 strains capable of increasing GLP-1 levels, measured by ELISA, were discovered. Interestingly, all positive strains were identified as Staphylococcus epidermidis by 16S rRNA sequencing. Non-GLP-1 stimulatory S. epidermidis strains were also identified. Mass spectrometry analysis identified a 3 kDa peptide, termed GLP-1 stimulating peptide (GspA), present in GLP-1 positive but absent in GLP-1 neutral S. epidermidis. Studies in human L-cells and intestinal enteroids demonstrated that GspA alone is sufficient to enhance GLP-1 secretion. When administered in high-fat-fed mice, GspA-producing S. epidermidis significantly reduced markers associated with obesity and T2DM, including adiposity and hyperinsulinemia. Further characterization of GspA suggests a GLP-1 stimulatory action 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 obesity and T2DM.

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