Long-Term Sucralose Consumption Alters Gut Microbiota and Hepatic Lipid Metabolism and Increases Depressive-like Behavior in Young Mice

Background: Sucralose is widely used as a non-nutritive sweetener, yet its systemic consequences of long-term exposure remain incompletely understood. This study investigated the effects of long-term sucralose consumption on metabolic homeostasis and neurobehavioral outcomes. Methods: Male C57BL/6J mice were treated with 5 mg/kg body weight sucralose under non-stressed and unpredictable chronic mild stress conditions for 14 weeks. Results: Sucralose altered hepatic cholesterol regulation without significantly increasing serum triglyceride or total cholesterol relative to water controls. Significant treatment–stress interactions were detected for hepatic Srb1 (F = 6.511, p = 0.004) and intestinal Npc1l1 (F = 3.763, p = 0.032), indicating stress-dependent modulation of cholesterol absorption. Hepatic inflammation also showed significant interactions for Il6 (p < 0.001) and Tnfa (p = 0.003). In addition, the sucralose group exhibited heightened neuroinflammation, cerebral endoplasmic reticulum stress, and increased depressive-like behaviors. 16S rRNA sequencing demonstrated reduced α-diversity and a shift in microbial composition and predicted carbohydrate processing and transport functions. Spearman correlation analysis linked microbial, intestinal, hepatic, neuroinflammatory, and behavioral variables within sucralose-treated mice. Conclusions: Long-term sucralose consumption altered gut microbial composition, hepatic cholesterol regulation, and neuroinflammatory and behavioral outcomes.