Oral delivery of GLP-1 peptide using recombinant <i>Lactobacillus gasseri</i> for the treatment of type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is an effective therapeutic peptide for the treatment of type 2 diabetes mellitus (T2DM). Here, we constructed an effective probiotic-based oral GLP-1 delivery system by engineering the probiotic strain of <i>Lactobacillus gasseri</i> (<i>Lgs</i>^GPA) to secrete GLP-1 fusion peptide, which combines GLP-1 with protein transduction domain (PTD) and a serum albumin binding peptide (ABP), GLP-1-PTD-ABP (GPA). The supernatants of <i>Lgs</i>^GPA cultures significantly upregulated the expression of PDX-1 and stimulated insulin release in Min6 cells. Daily oral administration of <i>Lgs</i>^GPA in <i>db/db</i> mice significantly alleviated insulin resistance, hyperglycemia, and dyslipidemia. Simultaneously, the abundance of <i>unclassified_f_Erysipelotrichaceae</i> and <i>Intestinimonas</i> was significantly reduced in <i>db/db</i> mice, while the average abundance of <i>Akkermansia</i> increased in the SD rats. These findings demonstrate that the probiotic-based delivery system represents a versatile and effective strategy for the oral administration of therapeutic peptides. Collectively, our results highlight the potential of this probiotic-based approach as a promising therapeutic and preventive intervention for T2DM.IMPORTANCEIt is important to develop the oral delivery strategy for therapeutic peptides. Due to issues with patient adherence and the low oral bioavailability of current administration methods, researchers have been exploring oral delivery strategies for GLP-1 analogs for many years, including the use of advanced microbiome therapeutics (AMTs). AMTs offer the potential to use engineered microbes for innovative therapeutic applications, such as the oral delivery of GLP-1 analogs. Our approaches offer a general oral delivery strategy for therapeutic peptides. The probiotic-based approach represents a promising method for treating and preventing T2DM.