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Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine

  • Original Article—Alimentary Tract
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Abstract

Background

Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis.

Methods

The physiological role of ARG2 and spermidine was investigated using Arg2-deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients.

Results

In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2-deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2-deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2-deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients.

Conclusions

ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.

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Abbreviations

ARG2:

Arginase 2

DAPI:

4,6-Diamino-2-phenylindole

DSS:

Dextran sulfate sodium

GCL:

Glutamate–cysteine ligase

GCLC:

Glutamate–cysteine ligase catalytic subunit

GCLM:

Glutamate–cysteine ligase modifier subunit

HDAC2:

Histone deacetylase 2

HE:

Hematoxylin–eosin

HO-1:

Heme oxygenase-1

H2O2 :

Hydrogen peroxide

IBD:

Inflammatory bowel disease

KO:

Knockout

LPS:

Lipopolysaccharide

NQO1:

Nicotinamide quinone oxidoreductase 1

NRF2:

Nuclear factor erythroid 2-related factor 2

PCR:

Polymerase chain reaction

ROS:

Reactive oxygen species

SPD:

Spermidine

TNFα:

Tumor necrosis factor-α

TXNR:

Thioredoxin reductase 1

UC:

Ulcerative colitis

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Acknowledgements

The authors appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. The authors also thank Mr. M. Munakata and Mrs. M Tanaka at the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University for assistance with histology. The authors thank Ellen Knapp, PhD, from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript. The authors acknowledge BioRender.com to create graphic abstract.

Funding

This work was supported by JSPS KAKENHI [Grant No. JP21K06783] and a Grant-in-Aid for Scientific Research C.

Author information

Authors and Affiliations

  1. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Noriyuki Imazu, Takehiro Torisu, Akihito Yokote, Junji Umeno, Keisuke Kawasaki, Yuichi Matsuno, Tomohiro Nagasue, Shinichiro Kawatoko, Tomoki Nitahata, Yushi Uchida, Seishi Aihara & Takanari Kitazono

  2. Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan

    Shin Fujioka

  3. Department of International Medical Department, Kyushu University Hospital, Fukuoka, Japan

    Tomohiko Moriyama

  4. Department of Anatomic Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    Yoshiaki Taniguchi & Yoshinao Oda

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  1. Noriyuki Imazu
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  2. Takehiro Torisu
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Contributions

NI, and TT conceived the idea of the study. NI, AY, SK, T. Nitahata, YU, SA, and TT were involved in providing guidance on the animal experiments and data analysis. JU, KK, SF, YF, YM, T. Nagasue, TM, YT, and TT collected the clinical samples and contributed to interpretation of the data. TK, YO, and TT contributed to drafting of the manuscript and critical revision. All authors revised the manuscript, approved the manuscript to be published, and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Takehiro Torisu.

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Imazu, N., Torisu, T., Yokote, A. et al. Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine. J Gastroenterol (2024). https://doi.org/10.1007/s00535-024-02104-z

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