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. 2023 May;68(5):1824-1834.
doi: 10.1007/s10620-022-07781-5. Epub 2022 Dec 7.

Ameliorating Role of Hydrogen-Rich Water Against NSAID-Induced Enteropathy via Reduction of ROS and Production of Short-Chain Fatty Acids

Yoshihiro Akita  1   2 , Masaaki Higashiyama  3 , Chie Kurihara  1 , Suguru Ito  1 , Shin Nishii  1 , Akinori Mizoguchi  1 , Kenichi Inaba  1 , Rina Tanemoto  1 , Nao Sugihara  1 , Yoshinori Hanawa  1 , Akinori Wada  1 , Kazuki Horiuchi  1 , Yoshikiyo Okada  1 , Kazuyuki Narimatsu  1 , Shunsuke Komoto  1 , Kengo Tomita  1 , Fumie Takei  4 , Yasushi Satoh  5 , Masayuki Saruta  2 , Ryota Hokari  1
Affiliations

Ameliorating Role of Hydrogen-Rich Water Against NSAID-Induced Enteropathy via Reduction of ROS and Production of Short-Chain Fatty Acids

Yoshihiro Akita et al. Dig Dis Sci. 2023 May.

Abstract

Background: Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy, the mechanism of which is involved in oxidative stress, can be lethal due to hemorrhage. Thus, we aimed to investigate the effect of hydrogen-rich water (HRW), in terms of oxidative stress, on intestinal mucosal damage as well as changes in the gut microbiome and the short-chain fatty acids (SCFAs) content in feces.

Methods: Hydrogen-rich water was orally administered for 5 days to investigate the effectiveness of indomethacin-induced enteropathy in mice. Small intestinal damage and luminal reactive oxygen species (ROS) were evaluated to investigate the ameliorating effects of hydrogen. Then, components of the gut microbiome were analyzed; fecal microbiota transplantation (FMT) was performed using the cecal contents obtained from mice drinking HRW. The cecal contents were analyzed for the SCFAs content. Finally, cells from the macrophage cell line RAW264 were co-cultured with the supernatants of cecal contents.

Results: Hydrogen-rich water significantly ameliorated IND-induced enteropathy histologically and reduced the expression of IND-induced inflammatory cytokines. Microscopic evaluation revealed that luminal ROS was significantly reduced and that HRW did not change the gut microbiota; however, FMT from HRW-treated animals ameliorated IND-induced enteropathy. The SCFA content in the cecal contents of HRW-treated animals was significantly higher than that in control animals. The supernatant had significantly increased interleukin-10 expression in RAW264 cells in vitro.

Conclusion: Hydrogen-rich water ameliorated NSAID-induced enteropathy, not only via direct antioxidant effects but also via anti-inflammatory effects by increasing luminal SCFAs. These results suggest that hydrogen may have therapeutic potential in small intestinal inflammatory diseases.

Keywords: Antioxidants; Hydrogen; IL-10; NSAIDs-induced enteropathy; Short-chain fatty acids.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Effects of hydrogen-rich water (HRW) on indomethacin-induced enteropathy. a Representative macroscopic features of the small intestine. b Small intestinal length (n = 8 per group). c Macroscopic ulcer area (n = 4 per group). d Representative histological features with hematoxylin eosin staining. e Ratio of crypt depth to villous height in the small intestine (n = 8 per group). f Myeloperoxidase activity in the small intestine (n = 4 per group). g mRNA expression of inflammatory cytokines in the small intestine (n = 5 per group). *P < 0.05, **P < 0.01. NW normalized water, HRW hydrogen-rich water
Fig. 2
Fig. 2
Intestinal permeability analyzed by plasma FITC-dextran concentration (n = 4 per group). *P < 0.05. NW normalized water, HRW hydrogen-rich water
Fig. 3
Fig. 3
Visual analysis of reactive oxygen species (ROS) in small intestinal mucosa. a Representative fluorescence images of each group. b Fluorescence intensity in the images of each group (n = 4 per group). *P < 0.05. NW normalized water, HRW hydrogen-rich water
Fig. 4
Fig. 4
Effects of fecal microbiota transplantation from hydrogen-rich water (HRW) mice on indomethacin-induced enteritis. a Small intestinal length (n = 8 per group). b Macroscopic ulcer area (n = 8 per group). c Representative histological features with hematoxylin eosin staining. d Ratio of crypt depth to villous height in the small intestine (n = 6 per group). e mRNA expression of inflammatory cytokines in the small intestine (n = 6 per group). *P < 0.05. FMT fecal microbiota transplantation, NW normalized water, HRW hydrogen-rich water
Fig. 5
Fig. 5
Concentration of short-chain fatty acids (SCFAs) in the enteral contents obtained from the small intestine or cecum of mice taking hydrogen-rich water (HRW). a Small intestine (n = 5 per group). b Cecum (n = 8 per group). *P < 0.05, **P < 0.01. NW normalized water, HRW hydrogen-rich water, ND not detected
Fig. 6
Fig. 6
The mRNA expressions in RAW264 cells stimulated by cecal contents supernatant from hydrogen-rich water (HRW) mice (n = 6 per group). *P < 0.05. CCS cecal content supernatant, NW normalized water, HRW hydrogen-rich water
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