Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine.
Antioxidant effect
Arginase 2
Spermidine
Ulcerative colitis
Journal
Journal of gastroenterology
ISSN: 1435-5922
Titre abrégé: J Gastroenterol
Pays: Japan
ID NLM: 9430794
Informations de publication
Date de publication:
02 May 2024
02 May 2024
Historique:
received:
31
08
2023
accepted:
13
04
2024
medline:
2
5
2024
pubmed:
2
5
2024
entrez:
2
5
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 38695904
doi: 10.1007/s00535-024-02104-z
pii: 10.1007/s00535-024-02104-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. Japanese Society of Gastroenterology.
Références
Kobayashi T, Siegmund B, Le Berre C, et al. Ulcerative colitis. Nat Rev Dis Primers. 2020;6:74.
pubmed: 32913180
doi: 10.1038/s41572-020-0205-x
Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769–78.
pubmed: 29050646
doi: 10.1016/S0140-6736(17)32448-0
Nakase H, Sato N, Mizuno N, et al. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev. 2022;21: 103017.
pubmed: 34902606
doi: 10.1016/j.autrev.2021.103017
Beaugerie L, Rahier JF, Kirchgesner J. Predicting, preventing, and managing treatment-related complications in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2020;18(1324–35): e2.
Ihara Y, Torisu T, Miyawaki K, et al. Ustekinumab improves active Crohn’s disease by suppressing the T helper 17 pathway. Digestion. 2021;102:946–55.
pubmed: 34350861
doi: 10.1159/000518103
Imazu N, Torisu T, Ihara Y, et al. Ustekinumab decreases circulating Th17 cells in ulcerative colitis. Intern Med. 2023;63:153.
pubmed: 37197955
pmcid: 10864063
doi: 10.2169/internalmedicine.1724-23
Madeo F, Hofer SJ, Pendl T, et al. Nutritional aspects of spermidine. Annu Rev Nutr. 2020;40:135–59.
pubmed: 32634331
doi: 10.1146/annurev-nutr-120419-015419
Zou D, Zhao Z, Li L, et al. A comprehensive review of spermidine: safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing. Compr Rev Food Sci Food Saf. 2022;21:2820–42.
pubmed: 35478379
doi: 10.1111/1541-4337.12963
Eisenberg T, Knauer H, Schauer A, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11:1305–14.
pubmed: 19801973
doi: 10.1038/ncb1975
Timmons J, Chang ET, Wang JY, et al. Polyamines and gut mucosal homeostasis. J Gastrointest Dig Syst. 2012. https://doi.org/10.4172/2161-069X.S7-001 .
doi: 10.4172/2161-069X.S7-001
pubmed: 25237589
pmcid: 4165078
Weiss TS, Herfarth H, Obermeier F, et al. Intracellular polyamine levels of intestinal epithelial cells in inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:529–35.
pubmed: 15472512
doi: 10.1097/00054725-200409000-00006
Obayashi M, Matsui-Yuasa I, Matsumoto T, et al. Polyamine metabolism in colonic mucosa from patients with ulcerative colitis. Am J Gastroenterol. 1992;87:736–40.
pubmed: 1590311
Gobert AP, Latour YL, Asim M, et al. Protective role of spermidine in colitis and colon carcinogenesis. Gastroenterology. 2022;162(813–27): e8.
Nakamura A, Kurihara S, Takahashi D, et al. Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon. Nat Commun. 2021;12:2105.
pubmed: 33833232
pmcid: 8032791
doi: 10.1038/s41467-021-22212-1
Yu H, Yoo PK, Aguirre CC, et al. Widespread expression of arginase I in mouse tissues. Biochemical and physiological implications. J Histochem Cytochem. 2003;51:1151–60.
pubmed: 12923240
doi: 10.1177/002215540305100905
Choi S, Park C, Ahn M, et al. Immunohistochemical study of arginase 1 and 2 in various tissues of rats. Acta Histochem. 2012;114:487–94.
pubmed: 21975054
doi: 10.1016/j.acthis.2011.09.002
Coburn LA, Gong X, Singh K, et al. L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. PLoS ONE. 2012;7: e33546.
pubmed: 22428068
pmcid: 3299802
doi: 10.1371/journal.pone.0033546
Zwintscher NP, Shah PM, Salgar SK, et al. Hepatocyte growth factor, hepatocyte growth factor activator and arginine in a rat fulminant colitis model. Ann Med Surg (Lond). 2016;7:97–103.
pubmed: 27144006
doi: 10.1016/j.amsu.2016.03.039
Kudo T, Matsumoto T, Nakamichi I, et al. Recombinant human granulocyte colony-stimulating factor reduces colonic epithelial cell apoptosis and ameliorates murine dextran sulfate sodium-induced colitis. Scand J Gastroenterol. 2008;43:689–97.
pubmed: 18569986
doi: 10.1080/00365520701864627
Hara M, Torisu K, Tomita K, et al. Arginase 2 is a mediator of ischemia-reperfusion injury in the kidney through regulation of nitrosative stress. Kidney Int. 2020;98:673–85.
pubmed: 32739205
doi: 10.1016/j.kint.2020.03.032
Sakuma S, Abe M, Kohda T, et al. Hydrogen peroxide generated by xanthine/xanthine oxidase system represses the proliferation of colorectal cancer cell line Caco-2. J Clin Biochem Nutr. 2015;56:15–9.
pubmed: 25678748
doi: 10.3164/jcbn.14-34
Kawano S, Torisu T, Esaki M, et al. Autophagy promotes degradation of internalized collagen and regulates distribution of focal adhesions to suppress cell adhesion. Biol Open. 2017;6:1644–53.
pubmed: 28970230
pmcid: 5703610
Li B, Alli R, Vogel P, et al. IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis. Mucosal Immunol. 2014;7:869–78.
pubmed: 24301657
doi: 10.1038/mi.2013.103
Torisu T, Torisu K, Lee IH, et al. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nat Med. 2013;19:1281–7.
pubmed: 24056772
pmcid: 3795899
doi: 10.1038/nm.3288
Bajic D, Niemann A, Hillmer AK, et al. Gut microbiota-derived propionate regulates the expression of Reg3 mucosal lectins and ameliorates experimental colitis in mice. J Crohns Colitis. 2020;14:1462–72.
pubmed: 32227170
pmcid: 8921751
doi: 10.1093/ecco-jcc/jjaa065
Ren W, Yin J, Wu M, et al. Serum amino acids profile and the beneficial effects of L-arginine or L-glutamine supplementation in dextran sulfate sodium colitis. PLoS ONE. 2014;9: e88335.
pubmed: 24505477
pmcid: 3914992
doi: 10.1371/journal.pone.0088335
Andrade ME, Santos RD, Soares AD, et al. Pretreatment and treatment with L-arginine attenuate weight loss and bacterial translocation in dextran sulfate sodium colitis. JPEN J Parenter Enteral Nutr. 2016;40:1131–9.
pubmed: 25855577
doi: 10.1177/0148607115581374
Singh K, Gobert AP, Coburn LA, et al. Dietary arginine regulates severity of experimental colitis and affects the colonic microbiome. Front Cell Infect Microbiol. 2019;9:66.
pubmed: 30972302
pmcid: 6443829
doi: 10.3389/fcimb.2019.00066
Coburn LA, Horst SN, Allaman MM, et al. L-Arginine availability and metabolism is altered in ulcerative colitis. Inflamm Bowel Dis. 2016;22:1847–58.
pubmed: 27104830
doi: 10.1097/MIB.0000000000000790
Wallace HM, Fraser AV, Hughes A. A perspective of polyamine metabolism. Biochem J. 2003;376:1–14.
pubmed: 13678416
pmcid: 1223767
doi: 10.1042/bj20031327
Niechcial A, Schwarzfischer M, Wawrzyniak M, et al. Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis. J Crohns Colitis. 2023;17:1489.
pubmed: 36995738
pmcid: 10588784
doi: 10.1093/ecco-jcc/jjad058
Liu P, de la Vega MR, Dodson M, et al. Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated noncanonical mechanism. Hepatology. 2019;70:372–88.
pubmed: 30873635
doi: 10.1002/hep.30616
Aihara S, Torisu K, Uchida Y, et al. Spermidine from arginine metabolism activates Nrf2 and inhibits kidney fibrosis. Commun Biol. 2023;6:676.
pubmed: 37380734
pmcid: 10307812
doi: 10.1038/s42003-023-05057-w
Yan J, Yan JY, Wang YX, et al. Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway. Br J Pharmacol. 2019;176:3126–42.
pubmed: 31077347
pmcid: 6692641
doi: 10.1111/bph.14706
Xu TT, Li H, Dai Z, et al. Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice. Aging (Albany NY). 2020;12:6401–14.
pubmed: 32268299
doi: 10.18632/aging.103035
Medina CB, Mehrotra P, Arandjelovic S, et al. Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020;580:130–5.
pubmed: 32238926
pmcid: 7217709
doi: 10.1038/s41586-020-2121-3
Murray Stewart T, Dunston TT, Woster PM, et al. Polyamine catabolism and oxidative damage. J Biol Chem. 2018;293:18736–45.
pubmed: 30333229
pmcid: 6290137
doi: 10.1074/jbc.TM118.003337
Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2-an update. Free Radic Biol Med. 2014;66:36–44.
pubmed: 23434765
doi: 10.1016/j.freeradbiomed.2013.02.008
Piotrowska M, Swierczynski M, Fichna J, et al. The Nrf2 in the pathophysiology of the intestine: molecular mechanisms and therapeutic implications for inflammatory bowel diseases. Pharmacol Res. 2021;163: 105243.
pubmed: 33080322
doi: 10.1016/j.phrs.2020.105243
Loboda A, Damulewicz M, Pyza E, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73:3221–47.
pubmed: 27100828
pmcid: 4967105
doi: 10.1007/s00018-016-2223-0
Lillig CH, Berndt C, Holmgren A. Glutaredoxin systems. Biochim Biophys Acta. 2008;1780:1304–17.
pubmed: 18621099
doi: 10.1016/j.bbagen.2008.06.003
Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med. 2014;66:75–87.
pubmed: 23899494
doi: 10.1016/j.freeradbiomed.2013.07.036
Dowling JK, Afzal R, Gearing LJ, et al. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages. Nat Commun. 2021;12:1460.
pubmed: 33674584
pmcid: 7936006
doi: 10.1038/s41467-021-21617-2
Geiger R, Rieckmann JC, Wolf T, et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167(829–42): e13.
Middleton SJ, Shorthouse M, Hunter JO. Increased nitric oxide synthesis in ulcerative colitis. Lancet. 1993;341:465–6.
pubmed: 8094492
doi: 10.1016/0140-6736(93)90211-X
Rachmilewitz D, Stamler JS, Bachwich D, et al. Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn’s disease. Gut. 1995;36:718–23.
pubmed: 7541008
pmcid: 1382676
doi: 10.1136/gut.36.5.718
Yasukawa K, Tokuda H, Tun X, et al. The detrimental effect of nitric oxide on tissue is associated with inflammatory events in the vascular endothelium and neutrophils in mice with dextran sodium sulfate-induced colitis. Free Radic Res. 2012;46:1427–36.
pubmed: 22998024
doi: 10.3109/10715762.2012.732698