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

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-fatfed 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. Metabolic disorders, including Type 2 Diabetes Mellitus (T2DM) and obesity, pose a serious public health concern both nationally and globally. According to the Centers for Disease Control and Prevention (CDC), 9.4% of the population of the United States has Diabetes, including 25.2% of those aged 65 years or older 1. Obesity is also a major health concern, with more than one-third of American adults considered obese 2. Current treatment approaches, including intensive lifestyle modifications, diet intervention, and pharmacologics, have proven unsuccessful in controlling the global increase of metabolic disorders. Therefore, a novel approach to combat metabolic disorders is needed. A number of research groups have recently demonstrated the role of the human gut microbiota in metabolism and metabolic disease, leading to the attempt to develop microbial therapeutics. Bäckhed et al. initially spearheaded this research; using germ-free rodents, it was demonstrated that when the microbiota of conventionally raised animals was transplanted into germ-free rodents, the latter developed an increase in adiposity and insulin resistance 3. Studies by a number of different groups also demonstrated the importance of the microbiota in metabolism, described in a recent review 4. Specifically, the gut microbiota has been shown to play an important role in gut hormone modulation, including GLP-1. Administration of prebiotics, non-digestible food ingredients that stimulate the grow...

Antidiabetic Effects of Pediococcus acidilactici pA1c on HFD-Induced Mice

“…Even though we did not measure intestinal or fecal SCFA profile, it is likely that GM modulation, following pA1c treatment, may lead to an increased output of SCFAs that could directly affect GLP-1 secretion. Apart from the indirect effect on GLP-1 secretion through a SCFAs-mediated mechanism, pA1c could have also directly stimulated GLP-1 production through the release of microbial functional peptides or compounds, as previously described for a Staphylococcus epidermis strain in a recent investigation [ 82 ].…”

Role of Postbiotics in Diabetes Mellitus: Current Knowledge and Future Perspectives

“…Thus, other potential areas for future research may focus on intestinal permeability and integrity, as previously described in EVs from A. municiphila [40], intestinal peptides produced by modified probiotic bacteria [128], or soluble proteins such as p40 or p75 [20]. For example, one study identified a functional peptide from S. epidermidis JA1 supernatant that enhanced glucagon-like peptide-1 in NGN3-Human intestinal enteroid cells [129]. When the active bacteria was tested in vivo in HFD mice, it showed protection against metabolic disease.…”

Characteristics of Food Protein-Derived Antidiabetic Bioactive Peptides: A Literature Update

“…To date, only a few peptide sequences derived from bovine hemoglobin, casein, egg white, frog skin, and bacteria have been demonstrated to exhibit GLP-1 releasing effects in NCI-H716 [162,163], STC-1 [33,164,165], and GLUTag cell lines [153,[166][167][168], and in murine primary cultures [169]. Recently, M. Santos-Hernández published a paper regarding the fact that egg white proteins only had a modest effect in inducing GLP-1 production, while peptides (except free amino acids) released a significant amount [33].…”