{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:00:11Z","timestamp":1792789211396,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DK95491"],"award-info":[{"award-number":["DK95491"]}]},{"name":"NIH","award":["DK104713"],"award-info":[{"award-number":["DK104713"]}]},{"name":"NIH","award":["DK129410"],"award-info":[{"award-number":["DK129410"]}]},{"name":"NIH","award":["DK133994"],"award-info":[{"award-number":["DK133994"]}]},{"name":"NIH","award":["BX006475"],"award-info":[{"award-number":["BX006475"]}]},{"name":"NIH","award":["BX002182"],"award-info":[{"award-number":["BX002182"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["DK95491"],"award-info":[{"award-number":["DK95491"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["DK104713"],"award-info":[{"award-number":["DK104713"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["DK129410"],"award-info":[{"award-number":["DK129410"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["DK133994"],"award-info":[{"award-number":["DK133994"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["BX006475"],"award-info":[{"award-number":["BX006475"]}]},{"name":"Veteran\u2019s Administration Merit Awards","award":["BX002182"],"award-info":[{"award-number":["BX002182"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to microbiota dysbiosis, resulting in the loss of microbiota-derived metabolites, which the epithelium relies on for energy procurement. The role of microbiota-sourced purines, such as hypoxanthine, as substrates salvaged by the colonic epithelium for nucleotide biogenesis and energy balance, has recently been appreciated for homeostasis and wound healing. Allopurinol, a synthetic hypoxanthine isomer commonly prescribed to treat excess uric acid in the blood, inhibits the degradation of hypoxanthine by xanthine oxidase, but also inhibits purine salvage. Although the use of allopurinol is common, studies regarding how allopurinol influences the gastrointestinal tract during colitis are largely nonexistent. In this work, a series of in vitro and in vivo experiments were performed to dissect the relationship between allopurinol, allopurinol metabolites, and colonic epithelial metabolism and function in health and during disease. Of particular significance, the in vivo investigation identified that a therapeutically relevant allopurinol dose shifts adenylate and creatine metabolism, leading to AMPK dysregulation and disrupted proliferation to attenuate wound healing and increased tissue damage in murine experimental colitis. Collectively, these findings underscore the importance of purine salvage on cellular metabolism and gut health in the context of IBD and provide insight regarding the use of allopurinol in patients with IBD.<\/jats:p>","DOI":"10.3390\/cells13050373","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T08:43:48Z","timestamp":1708505028000},"page":"373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Allopurinol Disrupts Purine Metabolism to Increase Damage in Experimental Colitis"],"prefix":"10.3390","volume":"13","author":[{"given":"Corey S.","family":"Worledge","sequence":"first","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6529-3831","authenticated-orcid":false,"given":"Rachael E.","family":"Kostelecky","sequence":"additional","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geetha","family":"Bhagavatula","sequence":"additional","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0431-8887","authenticated-orcid":false,"given":"Sean P.","family":"Colgan","sequence":"additional","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Scott","family":"Lee","sequence":"additional","affiliation":[{"name":"Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3748\/wjg.v20.i1.91","article-title":"Inflammatory bowel disease: Pathogenesis","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e0016","DOI":"10.1097\/IN9.0000000000000016","article-title":"Revisiting the \u201cstarved gut\u201d hypothesis in inflammatory bowel disease","volume":"5","author":"Colgan","year":"2023","journal-title":"Immunometabolism"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1880241","DOI":"10.1080\/19490976.2021.1880241","article-title":"Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic","volume":"13","author":"Lee","year":"2021","journal-title":"Gut Microbes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101226","DOI":"10.1016\/j.isci.2020.101226","article-title":"Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function","volume":"23","author":"Lee","year":"2020","journal-title":"iScience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1074\/jbc.RA117.000269","article-title":"Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function","volume":"293","author":"Lee","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s00109-017-1557-x","article-title":"Layered defense: How mucus and tight junctions seal the intestinal barrier","volume":"95","author":"Capaldo","year":"2017","journal-title":"J. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.tem.2022.01.002","article-title":"Gut barrier disruption and chronic disease","volume":"33","author":"Martel","year":"2022","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/s41577-021-00538-7","article-title":"Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?","volume":"21","author":"Akdis","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41575-019-0258-z","article-title":"Gut microbiota-derived metabolites as key actors in inflammatory bowel disease","volume":"17","author":"Lavelle","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.3748\/wjg.v28.i30.4053","article-title":"Gut microbiota, inflammatory bowel disease and colorectal cancer","volume":"28","author":"Quaglio","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12970-021-00412-w","article-title":"Common questions and misconceptions about creatine supplementation: What does the scientific evidence really show?","volume":"18","author":"Antonio","year":"2021","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41385-022-00514-x","article-title":"Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury","volume":"15","author":"Rath","year":"2022","journal-title":"Mucosal Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev.physiol.010908.163145","article-title":"Stem cells, self-renewal, and differentiation in the intestinal epithelium","volume":"71","author":"Clevers","year":"2009","journal-title":"Annu. Rev. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17719","DOI":"10.1074\/jbc.272.28.17719","article-title":"Amidophosphoribosyltransferase limits the rate of cell growth-linked de novo purine biosynthesis in the presence of constant capacity of salvage purine biosynthesis","volume":"272","author":"Yamaoka","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10409238.2020.1832438","article-title":"Human de novo purine biosynthesis","volume":"56","author":"Pareek","year":"2021","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_16","first-page":"73","article-title":"Nucleotide metabolism and cell-cell interactions","volume":"341","author":"Eltzschig","year":"2006","journal-title":"Methods Mol. Biol."},{"key":"ref_17","unstructured":"Qurie, A., Preuss, C.V., and Musa, R. (2024). StatPearls [Internet], StatPearls Publishing."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E827","DOI":"10.1152\/ajpendo.00378.2020","article-title":"New insights into purine metabolism in metabolic diseases: Role of xanthine oxidoreductase activity","volume":"319","author":"Furuhashi","year":"2020","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0009-8981(90)90107-4","article-title":"Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol","volume":"187","author":"Reiter","year":"1990","journal-title":"Clin. Chim. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/clpt.1991.61","article-title":"Pharmacokinetics and metabolism of allopurinol riboside","volume":"49","author":"Shapiro","year":"1991","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/978-1-4684-4553-4_31","article-title":"Metabolic studies of high doses of allopurinol in humans","volume":"165","author":"Nelson","year":"1984","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/0006-2952(83)90222-8","article-title":"On the metabolism of allopurinol. Formation of allopurinol-1-riboside in purine nucleoside phosphorylase deficiency","volume":"32","author":"Reiter","year":"1983","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/0076-6879(90)92082-O","article-title":"Established intestinal cell lines as model systems for electrolyte transport studies","volume":"192","author":"Dharmsathaphorn","year":"1990","journal-title":"Methods Enzymol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"C282","DOI":"10.1152\/ajpcell.00564.2005","article-title":"Transcriptional repression of Na-K-2Cl cotransporter NKCC1 by hypoxia-inducible factor-1","volume":"291","author":"Ibla","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1938380","DOI":"10.1080\/19490976.2021.1938380","article-title":"Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor","volume":"13","author":"Wang","year":"2021","journal-title":"Gut Microbes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1046\/j.1365-2249.1998.00728.x","article-title":"Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines","volume":"114","author":"Dieleman","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1124\/dmd.117.077552","article-title":"Species-Specific Involvement of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of the Pyrimidine-Containing mGlu5-Negative Allosteric Modulator VU0424238 (Auglurant)","volume":"45","author":"Crouch","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jjcc.2020.01.011","article-title":"The serum uric acid level in females may be a better indicator of metabolic syndrome and its components than in males in a Japanese population","volume":"76","author":"Tani","year":"2020","journal-title":"J. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/15257770.2018.1460477","article-title":"High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients","volume":"37","author":"Meijer","year":"2018","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.metabol.2007.04.013","article-title":"Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency","volume":"56","author":"Torres","year":"2007","journal-title":"Metabolism"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1750-1172-2-48","article-title":"Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome","volume":"2","author":"Torres","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/bjh.13403","article-title":"Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology","volume":"169","author":"Jones","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1136\/gutjnl-2011-300767","article-title":"Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation","volume":"61","author":"Rath","year":"2012","journal-title":"Gut"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1177\/0022034509359125","article-title":"Factors Affecting Wound Healing","volume":"89","author":"Guo","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Olivier, S., Diounou, H., Pochard, C., Frechin, L., Durieu, E., Foretz, M., Neunlist, M., Rolli-Derkinderen, M., and Viollet, B. (2022). Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis. Cells, 11.","DOI":"10.3390\/cells11040590"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hrncir, T. (2022). Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options. Microorganisms, 10.","DOI":"10.3390\/microorganisms10030578"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1172\/JCI111068","article-title":"Regulation of de novo purine synthesis in human bone marrow mononuclear cells by hypoxanthine","volume":"72","author":"King","year":"1983","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Taylor, S.J., Winter, M.G., Gillis, C.C., Silva, L.A.d., Dobbins, A.L., Muramatsu, M.K., Jimenez, A.G., Chanin, R.B., Spiga, L., and Llano, E.M. (2022). Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis. Microbiome, 10.","DOI":"10.1186\/s40168-022-01389-7"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1017\/S0029665114001463","article-title":"Links between diet, gut microbiota composition and gut metabolism","volume":"74","author":"Flint","year":"2015","journal-title":"Proc. Nutr. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev-biochem-032620-105728","article-title":"The Purinosome: A Case Study for a Mammalian Metabolon","volume":"91","author":"Pedley","year":"2022","journal-title":"Annu. Rev. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1126\/science.aac6054","article-title":"Spatial colocalization and functional link of purinosomes with mitochondria","volume":"351","author":"French","year":"2016","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1007\/BF02065554","article-title":"Influence of intestinal inflammation (IBD) and small and large bowel length on fecal short-chain fatty acids and lactate","volume":"40","author":"Hove","year":"1995","journal-title":"Dig. Dis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"120179","DOI":"10.1016\/j.lfs.2021.120179","article-title":"Lactate-utilizing bacteria ameliorates DSS-induced colitis in mice","volume":"288","author":"Chen","year":"2022","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1056072","article-title":"Principles for the buffering of genetic variation","volume":"291","author":"Hartman","year":"2001","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1016\/j.febslet.2005.01.063","article-title":"Robustness, evolvability, and neutrality","volume":"579","author":"Wagner","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"i981","DOI":"10.1093\/bioinformatics\/bty604","article-title":"Understanding the evolution of functional redundancy in metabolic networks","volume":"34","author":"Sambamoorthy","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/S0016-5085(88)80078-7","article-title":"Fecal lactate and ulcerative colitis","volume":"95","author":"Vernia","year":"1988","journal-title":"Gastroenterology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1365-2036.2004.02047.x","article-title":"Review article: The aetiopathogenesis of inflammatory bowel disease--immunology and repair mechanisms","volume":"20","author":"Dignass","year":"2004","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1007\/BF02051922","article-title":"The starved colon\u2014Diminished mucosal nutrition, diminished absorption, and colitis","volume":"33","author":"Roediger","year":"1990","journal-title":"Dis. Colon Rectum"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"672182","DOI":"10.3389\/fphar.2021.672182","article-title":"Metabolic Aspects of Adenosine Functions in the Brain","volume":"12","author":"Camici","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5382","DOI":"10.1007\/s10620-022-07719-x","article-title":"Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo","volume":"67","author":"Turbayne","year":"2022","journal-title":"Dig. Dis. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1177\/1756283X17733657","article-title":"Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD","volume":"10","author":"Moreau","year":"2017","journal-title":"Therap Adv. Gastroenterol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1136\/flgastro-2016-100738","article-title":"A practical guide to thiopurine prescribing and monitoring in IBD","volume":"9","author":"Warner","year":"2018","journal-title":"Frontline Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/apt.17831","article-title":"Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study)","volume":"59","author":"Vasudevan","year":"2024","journal-title":"Aliment. Pharmacol. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/5\/373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:02:27Z","timestamp":1760104947000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/5\/373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,21]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cells13050373"],"URL":"https:\/\/doi.org\/10.3390\/cells13050373","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,21]]}}}