Lacticaseibacillus paracasei LP-18 Alleviates Post-Semaglutide Weight Rebound and Metabolic Dysfunction in Obese Mice

Background: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, demonstrates significant anti-obesity and hypoglycemic effects in high-fat-diet (HFD)-induced obese models. However, both clinical and preclinical evidence indicates that semaglutide discontinuation inevitably leads to body weight rebound and progressive metabolic deterioration, severely compromising long-term therapeutic efficacy. Methods: To assess whether Lacticaseibacillus paracasei LP-18 alleviates post-semaglutide metabolic deterioration, we first confirmed its anti-obesity effect in HFD-fed mice, then used a three-stage model: HFD-induced obesity (4 weeks), semaglutide treatment (4 weeks), and withdrawal with or without L. paracasei LP-18 (4 weeks). Results:L. paracasei LP-18 supplementation effectively prevented post-discontinuation weight rebound and reduced cumulative energy intake while maintaining glucose homeostasis through decreased fasting and postprandial blood glucose levels. L. paracasei LP-18 also ameliorated dyslipidemia, reduced liver weight and hepatic lipid deposition, and attenuated white adipose tissue expansion and adipocyte hypertrophy. Mechanistically, L. paracasei LP-18 enriched beneficial taxa (Lacticaseibacillus, Bifidobacterium, Faecalibaculum) and depleted obesity-associated genera (Oribacterium, Anaerotruncus, Dorea), while restoring colonic barrier integrity via increased mucus layer thickness, goblet cell density, and upregulation of Muc2, ZO-1, and Occludin. Conclusions: These findings suggest that L. paracasei LP-18 is a promising probiotic strategy to alleviate post-semaglutide weight rebound and metabolic dysfunction, and its beneficial effects are associated with modulation of gut microbiota and preservation of intestinal barrier integrity.