Blueberry juice counteracts metabolic dysregulation in a rat model of prediabetes by targeting hepatic mitochondrial bioenergetics and metabolic pathways

Background and aims: This study aimed to assess the effects of blue- berry juice (BJ) on metabolic profile, gut microbiota composition, gut barrier integrity and metabolic endotoxemia, as well as on hepatic metab- olism and mitochondrial-related parameters, in a prediabetic rat model. Materials and methods: A prediabetic rat model [Male Wistar rats, 8 weeks old] was established by ingestion of a high-sucrose (HSu, 35%) diet for 9 weeks (W9), supplemented with a high-fat diet (HF, 60%) for further 14 weeks (HSuHF, W23), vs control with standard diet. Half of the animals (n=10/group) daily received BJ (25g/Kg BW, orally) between W9 and W23 (HSuHF+BJ). Along with metabolic characterization, a 1H NMR-based metabolomic approach was performed to elucidated BJ effects on serum and hepatic metabolic surrogates. Gut microbiota composition, colonic ultra‐structural morphology, intestinal permeability, and systemic inflam- mation were analyzed. Morphological and functional markers of liver damage were assessed by ultrasonography, immunohistochemical staining techniques and mitochondrial bioenergetics assays; RT-qPCR was performed to analyze hepatic expression profile of gene involved in chief metabolic pathways. Values are means ± S.E.M (ANOVA followed by post-hoc tests). Results: BJ treatment prevented diet-evoked metabolic dysregulation. Notably, HSuHF+BJ rats ameliorated (p<0.05) glucose tolerance, insulin sensitivity and hypertriglyceridemia, together with attenuation of liver impairment, as seen by reduced steatosis and by improved mitochondrial function, without affecting gut microbiota composition and related barrier properties. Apart from restoring hepatic antioxidant metabolites, BJ posi- tively affected the hepatic mRNA expression of key targets involved in fatty acid oxidation, insulin signaling, inflammatory response, as well as mitochondrial respiratory chain-related genes, which were all downregulat- ed (p<0.05) in HSuHF animals’livers. Conclusion: BJ can be a useful nutraceutical for preventing prediabetes progression induced by hypercaloric diet, due to beneficial effects against hepatic steatosis and mitochondria dysfunction, independent of gut microbiota modulation at this early stage of disease.