In high-fat diet-fed rats, the combination of dapagliflozin and 16:8 intermittent fasting normalizes the Firmicutes-to-Bacteroidetes ratio and increases gut microbiome diversity, which is associated with reduced adiposity and improved metabolic markers, suggesting gut microbial composition mediates metabolic benefits.

When rats eat a high-fat diet, their gut bacteria shift to favor fat-storing types, reducing beneficial acids that signal fullness. Giving them dapagliflozin and fasting 16 hours a day reverses this imbalance, increasing good bacteria that produce acetate and propionate. These acids bind to receptors in the gut and fat tissue, triggering signals that reduce hunger and activate cellular energy sensors. This turns off fat-making genes, turns on fat-burning pathways, and restores normal daily rhythms in metabolism, leading to less body fat and better liver and blood sugar control.