Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine

• Published in: Journal of gastroenterology 2024-08, Vol.59 (8), p.682-698
• Main Authors: Imazu, Noriyuki, Torisu, Takehiro, Yokote, Akihito, Umeno, Junji, Kawasaki, Keisuke, Fujioka, Shin, Matsuno, Yuichi, Nagasue, Tomohiro, Kawatoko, Shinichiro, Moriyama, Tomohiko, Nitahata, Tomoki, Uchida, Yushi, Aihara, Seishi, Taniguchi, Yoshiaki, Oda, Yoshinao, Kitazono, Takanari
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; Animals; Antioxidants; Antioxidants - pharmacology; Arginase; Arginase - metabolism; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colon - drug effects; Colon - metabolism; Colon - pathology; Colorectal Surgery; Dextran; Dextran Sulfate; Disease Models, Animal; Epithelial cells; Epithelium; Female; Gastroenterology; Hepatology; Humans; Inflammatory bowel disease; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Organoids; Original Article—Alimentary Tract; Oxidative stress; Oxidative Stress - drug effects; Rectum; Remission; Small intestine; Spermidine; Spermidine - metabolism; Spermidine - pharmacology; Surgical Oncology; Therapeutic targets; Ulcerative colitis
• ISSN: 0944-1174; 1435-5922; 1435-5922
• DOI: 10.1007/s00535-024-02104-z

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.