Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
Department of Chemistry, National Defense Medical College, Saitama, Japan.
Dig Dis Sci. 2022 Jan;67(1):121-133. doi: 10.1007/s10620-021-06848-z. Epub 2021 Feb 11.
Uric 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.
Inosinic 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.
IMP 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 in α-diversity and a significant difference in β-diversity from the control. Fecal microbiota transplantation from HUA mice ameliorated indomethacin-induced enteropathy.
The 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.
尿酸（UA）具有抗炎和促炎特性。我们之前发现，升高的血清 UA 水平可提供对小鼠小肠损伤的保护作用，可能是通过在小肠中分泌的管腔 UA 实现的。管腔 UA 可能作为抗氧化剂发挥作用，防止微生物群易受氧化应激的影响。然而，高尿酸血症下管腔 UA 是否增加，以及管腔 UA 是否以剂量依赖的方式发挥保护作用，以及管腔 UA 对肠病发挥保护作用的机制仍不清楚。
给予肌苷酸（IMP）（1000mg/kg，腹腔注射）以获得高血清 UA（HUA）和中等血清 UA（500mg/kgIMP，腹腔注射）小鼠。测量血清和肠组织中 UA 浓度和氧化应激标志物水平。给予吲哚美辛（20mg/kg，腹腔注射）以评估 UA 对吲哚美辛诱导的肠病的影响。分析回肠黏膜上的活性氧（ROS）。移植 HUA 小鼠的粪便微生物群，以研究其对吲哚美辛诱导的肠病的影响。
IMP 剂量依赖性地增加管腔 UA，同时增加管腔抗氧化标志物水平。两种 UA 升高组的吲哚美辛诱导的肠病均显著改善，同时降低了吲哚美辛诱导的管腔 ROS。HUA 小鼠的粪便微生物群在 α-多样性方面有显著增加，在 β-多样性方面与对照组有显著差异。从 HUA 小鼠移植的粪便微生物群改善了吲哚美辛诱导的肠病。
管腔 UA 在肠道损伤中的保护作用可能是通过消除氧化应激和调节微生物群组成来发挥的，这可能有利于肠道免疫。因此，使用抗氧化剂增强厌氧条件可能是一个潜在的治疗靶点。
