二酪氨酸是蛋白质氧化的主要产物，被证实对人体健康构成威胁。本研究旨在调查二酪氨酸是否通过引起肠道菌群紊乱和相关炎症反应来恶化胰岛素抵抗性。接连13周，喂养正常饮食或高脂饮食（HFD）的小鼠每日接受口服二酪氨酸（320 µg kg-1 BW）或生理盐水。通过使用db/m小鼠和db/db小鼠的粪便菌群进行体外发酵验证二酪氨酸对肠道菌群的影响。结果显示，二酪氨酸导致正常饮食小鼠出现胰岛素抵抗，且加重了HFD对胰岛素敏感性的影响。二酪氨酸增加了正常饮食小鼠和HFD小鼠体内血浆内脂多糖（LPS）、脂多糖结合蛋白（LBP）、Toll样受体4（TLR4）、核因子κ-B（NF-κB）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-8（IL-8）的水平，但降低了白细胞介素-10（IL-10）的水平。二酪氨酸引起的肠道菌群组成变化与炎症生物标志物变化显著相关。二酪氨酸对胰岛素抵抗的影响可能归因于肠道菌群组成的重塑，以及在HFD诱导的肥胖个体中促进LPS/TLR4/NF-κB炎症途径的活化。© 2023 Wiley-VCH GmbH.

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.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.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.© 2023 Wiley-VCH GmbH.