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

Abstract

AbstractObesity 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 yeastSaccharomyces boulardiistrain 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 fromS. boulardiiwas characterisedex vivoon isolated pancreatic islets, demonstrating induced insulin secretion. Furthermore,in vivocharacterisation 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 thatS. boulardiican be genetically modified to secrete and deliver active therapeutic GLP-1R agonists in the gastrointestinal tract improving the metabolism of the host.