Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established treatments for obesity and type 2 diabetes mellitus, but gastrointestinal barriers constrain oral delivery of peptide therapeutics. Genetically engineered microorganisms have been investigated as intestinal sources of GLP-1-related therapeutic molecules. These platforms produce GLP-1 or GLP-1-derived peptides, express modified GLP-1RAs or fusion proteins, or release effectors that stimulate endogenous GLP-1 secretion. Preclinical studies have reported improvements in glycemic measures and, in some models, reductions in body weight or weight gain. However, recombinant product expression and treatment-associated effects are more consistently demonstrated than exposure to intact biologically active products in vivo, receptor or pathway dependence, and the contribution of the engineered construct relative to the microbial chassis. Proteolysis, mucus interactions, restricted epithelial permeability, and receptor localization constrain access to intestinal and systemic targets. This review critically evaluates the preclinical evidence for GLP-1-oriented engineered microorganisms, with emphasis on intestinal target accessibility, local and systemic mechanisms, microbial chassis and genetic design, and the safety, manufacturing, and regulatory requirements for clinical translation.