Dityrosine Aggravates Hepatic Insulin Resistance in Obese Mice by Altering Gut Microbiota and the LPS/TLR4/NF‐κB Inflammatory Pathway

Scope Dityrosine is the main product of protein oxidation, which has been proved to be a threat to human health. This study aims to investigate whether dityrosine exacerbates insulin resistance by inducing gut flora disturbance and associated inflammatory responses. Methods and results Mice fed with normal diet or high‐fat diet (HFD) received daily gavage of dityrosine (320 µg kg −1 BW) or saline for consecutive 13 weeks. The effects of dityrosine on gut microbiota are verified by in vitro fermentation using fecal microbiota from db/m mice and db/db mice. As a result, dityrosine causes the insulin resistance in mice fed normal diet, and aggravates the effects of HFD on insulin sensitivity. Dityrosine increases the levels of lipopolysaccharide (LPS), lipopolysaccharide‐binding protein (LBP), toll‐like receptor 4 (TLR4), nuclear factor kappa‐B (NF‐κB), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) but decreases levels of interleukin‐10 (IL‐10) in the plasma of CON and HFD‐fed mice. The changes of gut flora composition caused by dityrosine are significantly correlated with the changes of inflammatory biomarkers. Conclusion The effects of dityrosine on insulin resistance may be attributed to the reshaping of the gut microbiota composition and promoting the activity of the LPS/TLR4/NF‐κB inflammatory pathway in HFD‐induced obese individuals.