A flavonoid-rich extract of bergamot juice improves high-fat diet-induced intestinal permeability and associated hepatic damage in mice

Consumption of high-fat diets (HFDs) is a contributing factor to obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD). Several studies suggested the protective role of bioactives present in Citrus fruits against the above mentioned chronic metabolic conditions. In this study, we evaluated if a flavonoid-rich extract of Citrus bergamia (bergamot) juice (BJe) could inhibit HFD-induced intestinal permeability and endotoxemia and, through this mechanism, mitigate the associated hepatic damage in C57BL/6J mice. After 12 weeks of the treatment, HFD consumption caused high body weight (BW) gain, hyperinsulinemia, hyperglycemia, and dyslipidemia, which were mitigated by BJe (50 mg per kg BW) supplementation. Furthermore, supplementation with BJe prevented HFD-induced liver alterations, including increased plasma alanine aminotransferase (ALT) activity, increased hepatic lipid deposition, high NAS, and fibrosis. Mice fed a HFD for 12 weeks showed (i) a decrease in small intestine tight junction protein levels (ZO-1, occludin, and claudin-1), (ii) increased intestinal permeability, and (iii) endotoxemia. All these adverse events were mitigated by BJe supplementation. Linking the capacity of BJe to prevent HFDassociated endotoxemia, supplementation with this extract decreased the HFD-induced overexpression of hepatic TLR-4, downstream signaling pathways (MyD88, NF-κB and MAPK), and the associated inflammation, evidenced by increased MCP-1, TNF-α, IL-6, iNOS, and F4/80 levels. Overall, we suggest that BJe could mitigate the harmful consequences of western style diet consumption on liver physiology by protecting the gastrointestinal tract from permeabilization and associated metabolic endotoxemia.