Oral delivery of GLP-1R agonist by an engineered probiotic yeast strain has anti-obesity effects in mice

Obesity is rapidly increasing within the global population and is one of the leading causes of chronic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver disease, and cardiovascular diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as promising therapeutic agents for treating T2D and obesity. However, the route of administration of the GLP-1R agonists is currently by injection or high oral dosages of the therapeutic combined with absorption enhancers. Oral delivery of GLP-1R agonists remains the preferred administration route due to convenience and high patient compliance. Thus, strategies to improve the oral delivery of this therapeutic are needed. In this study, we engineered the probiotic yeast Saccharomyces boulardii strain to produce Exendin-4, a GLP-1R agonist, in the gastrointestinal tract to reduce the adverse effects of diet-induced obesity in male C57BL/6 mice. The biological efficiency of the secreted Exendin-4 from S. boulardii was characterised ex vivo on isolated pancreatic islets, demonstrating induced insulin secretion. Furthermore, in vivo characterisation of the engineered strain identified a synergistic effect of cold exposure and Sb-Exe4 by successfully inhibiting appetite and promoting body weight loss under cold exposure (8°C). In addition, the combination of cold and Sb-Exe4 improved the glucose and lipid homeostasis in the mice by increasing the circulating glucagon level and reducing the inflammatory marker TNF-α. Our results demonstrate that S. boulardii can be genetically modified to secrete and deliver active therapeutic GLP-1R agonists in the gastrointestinal tract improving the metabolism of the host.