Protective Effect of Luminal Uric Acid Against Indomethacin-Induced Enteropathy: Role of Antioxidant Effect and Gut Microbiota
Protective Effect of Luminal Uric Acid Against Indomethacin-Induced Enteropathy: Role of Antioxidant Effect and Gut Microbiota
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DOI：
10.1007/s10620-021-06848-z
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发表时间：
2021-02
影响因子：
3.1
通讯作者：
Akinori Wada;Masaaki Higashiyama;C. Kurihara;Suguru Ito;Rina Tanemoto;Akinori Mizoguchi;S. Nishii;Kenichi Inaba;N. Sugihara;Yoshinori Hanawa;Kazuki Horiuchi;N. Shibuya;Misaki Akiyama;Y. Okada;C. Watanabe;S. Komoto;K. Tomita;F. Takei;R. Hokari
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文献类型：
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作者：
Akinori Wada;Masaaki Higashiyama;C. Kurihara;Suguru Ito;Rina Tanemoto;Akinori Mizoguchi;S. Nishii;Kenichi Inaba;N. Sugihara;Yoshinori Hanawa;Kazuki Horiuchi;N. Shibuya;Misaki Akiyama;Y. Okada;C. Watanabe;S. Komoto;K. Tomita;F. Takei;R. Hokari
背景尿酸（UA）具有抗炎和促炎特性。我们之前发现，血清 UA 水平升高可能通过小肠分泌的管腔 UA 来防止小鼠小肠损伤。 Luminal UA 可以作为一种抗氧化剂，防止微生物群对氧化应激的脆弱性。然而，管腔UA是否在高尿酸血症下增加并以剂量依赖性方式发挥保护作用，以及管腔UA对肠病发挥保护作用的机制仍不清楚。方法给予肌苷酸（IMP）（1000mg/kg，腹腔注射）获得高血清UA（HUA）和中度血清UA（500mg/kg IMP，腹腔注射）小鼠。测量了血清和肠道中的 UA 浓度和氧化应激标记物的水平。小鼠接受吲哚美辛（20 mg/kg，腹腔注射）以评估 UA 对吲哚美辛诱发的肠病的影响。分析回肠粘膜上的活性氧（ROS）。移植HUA小鼠粪便微生物群，研究其对吲哚美辛诱导的肠病的影响。结果IMP剂量依赖性地增加管腔UA，并具有更高水平的管腔抗氧化标记物。在两个 UA 升高的组中，吲哚美辛诱发的肠病均显着改善，吲哚美辛诱发的管腔 ROS 减少。 HUA 小鼠的微生物群与对照组相比，α-多样性显着增加，β-多样性显着差异。 HUA 小鼠粪便微生物群移植可改善吲哚美辛诱导的肠病。结论 管腔 UA 在肠道损伤中的保护作用可能是通过氧化应激消除和微生物群组成调节发挥的，尤其是肠道免疫。因此，使用抗氧化剂增强厌氧条件是一个潜在的治疗目标。
BackgroundUric acid (UA) has anti- and pro-inflammatory properties. We previously revealed that elevated serum UA levels provide protection against murine small intestinal injury probably via luminal UA secreted in the small intestine. Luminal UA may act as an antioxidant, preventing microbiota vulnerability to oxidative stress. However, whether luminal UA is increased under hyperuricemia and plays a protective role in a dose-dependent manner as well as the mechanism by which luminal UA exerts its protective effects on enteropathy remains unknown.MethodsInosinic acid (IMP) (1000 mg/kg, i.p.) was administered to obtain high serum UA (HUA) and moderate serum UA (500 mg/kg IMP, i.p.) mice. UA concentrations and levels of oxidative stress markers in the serum and intestine were measured. Mice received indomethacin (20 mg/kg, i.p.) to evaluate the effects of UA on indomethacin-induced enteropathy. Reactive oxygen species (ROS) on the ileal mucosa were analyzed. The fecal microbiota of HUA mice was transplanted to investigate its effect on indomethacin-induced enteropathy.ResultsIMP increased luminal UA dose-dependently, with higher levels of luminal antioxidant markers. Indomethacin-induced enteropathy was significantly ameliorated in both UA-elevated groups, with decreased indomethacin-induced luminal ROS. The microbiota of HUA mice showed a significant increase inα-diversity and a significant difference inβ-diversity from the control. Fecal microbiota transplantation from HUA mice ameliorated indomethacin-induced enteropathy.ConclusionsThe protective role of luminal UA in intestinal injury is likely exerted via oxidative stress elimination and microbiota composition modulation, preferably for gut immunity. Therefore, enhancing anaerobic conditions using antioxidants is a potential therapeutic target.