Oral Administration of Lactobacillus acidophilus Expressing GLP-1 Peptide Variants with N-Terminal Extensions in Mice with Streptozotocin-Induced Hyperglycemia

Engineered bacteria are being explored as oral delivery systems for therapeutic peptides. This study examined Lactobacillus acidophilus expressing two GLP-1 peptide variants with N-terminal extensions, M-GLP-1 and M-6HIS-GLP-1, in male C57BL/6J mice with moderate streptozotocin (STZ)-induced hyperglycemia. Both purified peptides increased insulin concentrations in MIN6 conditioned medium after 24 h, but neither significantly attenuated the STZ-associated reduction in metabolic activity. Cage-level analysis showed lower average post-treatment glucose concentrations in mice receiving L. acidophilus expressing M-GLP-1 (Lacto-M-GLP-1) or M-6HIS-GLP-1 (Lacto-M-6HIS-GLP-1) than in STZ controls, but neither group differed significantly from mice receiving empty-vector L. acidophilus. The intraperitoneal glucose tolerance test showed numerically lower late-phase glucose concentrations and incremental area under the curve in both groups than in controls. Mice receiving Lacto-M-6HIS-GLP-1 showed greater body-weight change than those receiving Lacto-M-GLP-1 or empty-vector L. acidophilus. Pancreatic histology showed a lower pancreatic glucagon-positive signal area and a higher insulin-to-glucagon signal-area ratio than in STZ controls and Lacto-M-GLP-1. The findings demonstrate cellular responses to purified GLP-1 variants and metabolic changes associated with administering L. acidophilus expressing the peptides.