Dose-Related Effects of Sambucus nigra Fruit Extract on Metabolic Dysfunction, Gut-Barrier and Endocrine Markers, Redox Homeostasis, and Multiorgan Histology in High-Fat-Diet-Fed Rats

Background: This study examined associations between Sambucus nigra fruit extract (SNE) co-administration and metabolic, endocrine, gut-barrier-related, redox, and histological outcomes during high-fat-diet (HFD) exposure. Methods: Sixty-four male Wistar albino rats were assigned to a 2 × 4 factorial design (n = 8/group), receiving standard diet or HFD with vehicle or SNE at 100, 200, or 400 mg/kg/day for 16 weeks. Diet and SNE administration began concurrently. The extract profile included cyanidin-3-O-sambubioside (68.42 mg/g), cyanidin-3-O-glucoside (42.15 mg/g), total monomeric anthocyanins (122.42 mg/g), and total phenolics (198.50 mg GAE/g). Biochemical endpoints were assessed using clinical chemistry, immunoassay, and spectrophotometric methods; histology was evaluated descriptively. Biochemical data were analyzed using two-way ANOVA followed by Tukey’s HSD test. Results: HFD groups showed higher metabolic and organ injury markers and lower antioxidant measures than standard-diet controls. SNE co-administration was associated with lower body weight, fasting glucose, insulin, HOMA-IR, atherogenic lipid fractions, selected hepatorenal injury markers, circulating LPS/zonulin, and oxidative damage markers. Many outcomes showed their largest numerical differences from HFD controls at 400 mg/kg, although BDNF peaked at 200 mg/kg in HFD-fed animals. Energy intake also declined across HFD-SNE groups. Representative sections showed less conspicuous lesions with SNE. Conclusions: SNE co-administration was associated with attenuation of HFD-related abnormalities during concurrent exposure. Because no pair-fed comparator was included, effects independent of reduced energy intake cannot be established. Descriptive histology does not demonstrate quantitative structural recovery, and the selected tolerability endpoints do not establish comprehensive safety or clinical efficacy.