Protective Effect of Luminal Uric Acid Against Indomethacin-Induced Enteropathy: Role of Antioxidant Effect and Gut Microbiota

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

This research was supported by a Health and Labour Sciences research grant for research on intractable diseases from the Ministry of Health, Labour and Welfare, Japan. We thank Hanae Tsuchihashi (Meiji Co., Ltd.) for the technical support provided during the analysis of the microbiota.

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Correspondence to Masaaki Higashiyama.

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Ryota Hokari received commercial research funding from EA Pharma Co.

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Wada, A., Higashiyama, M., Kurihara, C. et al. Protective Effect of Luminal Uric Acid Against Indomethacin-Induced Enteropathy: Role of Antioxidant Effect and Gut Microbiota. Dig Dis Sci (2021). https://doi.org/10.1007/s10620-021-06848-z

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Keywords

  • Uric acid
  • Nonsteroidal anti-inflammatory drug-induced enteropathy
  • Antioxidants
  • Gut microbiota
  • Fecal microbiota transplantation