Decoupled Anti-Diabetic and Gut Microbiota Responses to Lactiplantibacillus plantarum LPJZ-658 in db/db Mice

This study was conducted to investigate the sex-dependent effect of Lactiplantibacillus plantarum LPJZ-658 on anti-diabetic efficacy and gut microbiota modulation in db/db mice. Eight-week-old male and female db/db diabetic mice were administered LPJZ-658 (1 × 109 CFU/day) or PBS for 4 weeks, with db/m mice as the healthy controls. Body weight, food intake, and fasting serum glucose were measured weekly. After intervention, serum levels of glucose, insulin, and lipid profile parameters (TG, T-CHO, NEFA, HDL, and LDL), as well as liver enzymes (AST and ALT), were determined. Histopathological changes in the kidney, pancreas, and liver were assessed, and the gut microbiota were analyzed. For most metabolic and histological parameters, the sex × treatment interaction was not significant. Nevertheless, post hoc multiple comparisons demonstrated that LPJZ-658 exerted marked anti-diabetic benefits predominantly in male db/db mice. In male db/db mice, LPJZ-658 reduced food intake, relative body weight, liver/body weight ratio, and serum glucose, insulin, TG, and ALT levels. Additionally, it alleviated histopathological damage to the kidney, pancreas, and liver. In contrast, female db/db mice showed no significant improvements in metabolic or histological parameters following LPJZ-658 treatment. Notably, gut microbiota indicators, including α-diversity and phylum-level and genus-level bacterial relative abundances exhibited significant sex × treatment interactions. Stratified analyses revealed that LPJZ-658 treatment showed a trend toward shifting the overall community structure toward the db/m phenotype and modulated multiple taxa at the phylum and genus levels in male db/db mice, whereas the microbial community structure and α-diversity remained largely unchanged in females. Additionally, functional prediction indicated that LPJZ-658 modulated gut microbial metabolic pathways in male mice, including membrane transport, carbohydrate metabolism, and amino acid metabolism pathways. LPJZ-658 exhibits sex-dependent anti-diabetic effects, with significant benefits likely associated with sex-specific modulation of the gut microbiota observed predominantly in males. Therefore, sex should be considered a critical factor in probiotic interventions for type 2 diabetes.