Energy-Metabolism-Enhancing Probiotics Enhance the Therapeutic Response to a Glucagon-like Peptide-1 Receptor Agonist

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for obesity, but substantial weight regain is common after therapy is discontinued. This study investigated whether probiotic strains with anti-obesity effects could enhance GLP-1RA-induced weight loss and attenuate post-treatment weight rebound. Methods: Candidate lactic acid bacteria were screened for anti-obesity efficacy in a high-fat-diet (HFD)-induced obese mouse model, and the selected strain was further characterized using metabolomic profiling of culture supernatants. To examine its interaction with GLP-1RA therapy, obese mice received dulaglutide for 4 weeks and were monitored for 2 weeks after treatment withdrawal, while the probiotic was orally administered for a total of 6 weeks. Body weight, glycemic parameters, and muscle strength were assessed throughout the study. Results: Limosilactobacillus fermentum GB102 reduced body weight and improved glycemic control in HFD-fed mice. These metabolic benefits were associated with alterations in circulating metabolic hormones, including adipokines, along with attenuated inflammatory responses in adipose tissue. Metabolomic profiling revealed that GB102 produced high levels of succinic acid, a metabolite previously linked to thermogenic activation. This strain increased whole-body energy expenditure in HFD-fed mice, produced glutamine, and showed enhanced conversion of arginine into ornithine and citrulline. When combined with dulaglutide, GB102 enhanced weight loss, preserved muscle strength, and attenuated both weight regain and glycemic rebound following dulaglutide withdrawal. Conclusions: These findings suggest that energy-metabolism-enhancing probiotics such as GB102 may enhance the metabolic effects of GLP-1RA therapy and help attenuate weight regain after treatment discontinuation.