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.

• Authors: Akinori Wada, Masaaki Higashiyama, Chie Kurihara, Suguru Ito, Rina Tanemoto, Akinori Mizoguchi, Shin Nishii, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Kazuki Horiuchi, Naoki Shibuya, Misaki Akiyama, Yoshikiyo Okada, Chikako Watanabe, Shunsuke Komoto, Kengo Tomita, Fumie Takei, Ryota Hokari
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 67 Issue 1 Pg. 121-133 (01 2022) ISSN: 1573-2568 [Electronic] United States
• PMID: 33569665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antioxidants
• Reactive Oxygen Species
• Uric Acid
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antioxidants (metabolism)
• Disease Models, Animal
• Fecal Microbiota Transplantation (methods)
• Gastrointestinal Microbiome (drug effects, immunology)
• Indomethacin (pharmacology)
• Intestinal Diseases (chemically induced, metabolism, microbiology, therapy)
• Intestine, Small (metabolism, microbiology)
• Mice
• Oxidative Stress (drug effects)
• Protective Factors
• Reactive Oxygen Species (analysis)
• Treatment Outcome
• Uric Acid (blood, metabolism)