{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:10:18Z","timestamp":1789830618466,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Celiac disease (CD) is an autoimmune enteropathy associated with alterations of metabolism. Metabolomics studies, although limited, showed changes in choline, choline-derived lipids, and methionine concentrations, which could be ascribed to alterations in one-carbon metabolism. To date, no targeted metabolomics analysis investigating differences in the plasma choline\/methionine metabolome of CD subjects are reported. This work is a targeted metabolomic study that analyzes 37 metabolites of the one-carbon metabolism in 17 children with CD, treated with a gluten-free diet and 17 healthy control siblings, in order to establish the potential defects in this metabolic network. Our results demonstrate the persistence of defects in the transsulfuration pathway of CD subjects, despite dietary treatment, while choline metabolism, methionine cycle, and folate cycle seem to be reversed and preserved to healthy levels. These findings describe for the first time, a metabolic defect in one-carbon metabolism which could have profound implications in the physiopathology and treatment of CD.<\/jats:p>","DOI":"10.3390\/nu12123723","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T20:25:49Z","timestamp":1606940749000},"page":"3723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Alterations in One-Carbon Metabolism in Celiac Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0113-9904","authenticated-orcid":false,"given":"Rafael","family":"Mart\u00edn-Masot","sequence":"first","affiliation":[{"name":"Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de M\u00e1laga, 29011 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5937-7070","authenticated-orcid":false,"given":"Nat\u00e0lia","family":"Mota-Martorell","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariona","family":"Jov\u00e9","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Granada, 18071 Granada, Spain"},{"name":"Pediatric Gastroenterology and Nutrition Unit, Hospital Universitario Virgen de las Nieves, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs), 18071 Granada, Spain"},{"name":"Maternal and Child Health Network, Carlos III Health Institute, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-6107","authenticated-orcid":false,"given":"Reinald","family":"Pamplona","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9573-3244","authenticated-orcid":false,"given":"Teresa","family":"Nestares","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre (CIBM), Department of Physiology and \u201cJos\u00e9 MataixVerd\u00fa\u201d Institute of Nutrition and Food Technology (INYTA), University of Granada, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1056\/NEJMra010852","article-title":"Celiac Sprue","volume":"346","author":"Farrell","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0140-6736(03)14027-5","article-title":"Coeliac disease","volume":"362","author":"Green","year":"2003","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1053\/gast.2000.8521","article-title":"Current concepts of celiac disease pathogenesis","volume":"119","author":"Schuppan","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1172\/JCI30253","article-title":"Celiac disease: Pathogenesis of a model immunogenetic disease","volume":"117","author":"Kagnoff","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/S0140-6736(01)05554-4","article-title":"Mortality in patients with coeliac disease and their relatives: A cohort study","volume":"358","author":"Corrao","year":"2001","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa021687","article-title":"Prevalence of Celiac Disease among Children in Finland","volume":"348","author":"Mustalahti","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1053\/gast.2001.22123","article-title":"Current approaches to diagnosis and treatment of celiac disease: An evolving spectrum","volume":"120","author":"Fasano","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1111\/apa.14468","article-title":"Screening for coeliac disease in children","volume":"107","author":"Kurppa","year":"2018","journal-title":"Acta Paediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1053\/j.gastro.2009.05.040","article-title":"Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease","volume":"137","author":"Romanos","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1177\/2050640618765506","article-title":"The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population","volume":"6","author":"Thuesen","year":"2018","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1021\/pr800548z","article-title":"The Metabonomic Signature of Celiac Disease","volume":"8","author":"Bertini","year":"2009","journal-title":"J. Proteome Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1021\/pr100896s","article-title":"Are Patients with Potential Celiac Disease Really Potential? The Answer of Metabonomics","volume":"10","author":"Bernini","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Di Cagno, R., De Angelis, M., De Pasquale, I., Ndagijimana, M., Vernocchi, P., Ricciuti, P., Gagliardi, F., Laghi, L., Crecchio, C., and Guerzoni, M.E. (2011). Duodenal and faecal microbiota of celiac children: Molecular, phenotype and metabolome characterization. BMC Microbiol., 11.","DOI":"10.1186\/1471-2180-11-219"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sellitto, M., Bai, G., Serena, G., Fricke, W.F., Sturgeon, C., Gajer, P., White, J.R., Koenig, S.S.K., Sakamoto, J., and Boothe, D. (2012). Proof of Concept of Microbiome-Metabolome Analysis and Delayed Gluten Exposure on Celiac Disease Autoimmunity in Genetically At-Risk Infants. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033387"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jaut.2016.05.006","article-title":"Investigating the early metabolic fingerprint of celiac disease\u2014A prospective approach","volume":"72","author":"Kirchberg","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00044-10","DOI":"10.14309\/ctg.0000000000000044","article-title":"Persistent Alterations in Plasma Lipid Profiles Before Introduction of Gluten in the Diet Associated With Progression to Celiac Disease","volume":"10","author":"Sen","year":"2019","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bekdash, R.A. (2019). Neuroprotective Effects of Choline and Other Methyl Donors. Nutrients, 11.","DOI":"10.3390\/nu11122995"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e13034","DOI":"10.1111\/acel.13034","article-title":"Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species","volume":"18","author":"Parkhitko","year":"2019","journal-title":"Aging Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41568-019-0187-8","article-title":"Methionine metabolism in health and cancer: A nexus of diet and precision medicine","volume":"19","author":"Sanderson","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Psychogios, N., Hau, D.D., Peng, J., Guo, A.C., Mandal, R., Bouatra, S., Sinelnikov, I., Krishnamurthy, R., Eisner, R., and Gautam, B. (2011). The Human Serum Metabolome. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016957"},{"key":"ref_21","first-page":"578","article-title":"Human Aging Is a Metabolome-related Matter of Gender","volume":"71","author":"Pamplona","year":"2016","journal-title":"J. Gerontol. Ser. A Boil. Sci. Med Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1194\/jlr.S087163","article-title":"MS-based lipidomics of human blood plasma: A community-initiated position paper to develop accepted guidelines","volume":"59","author":"Burla","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/MPG.0b013e31821a23d0","article-title":"European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease","volume":"54","author":"Husby","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1136\/bmj.320.7244.1240","article-title":"Establishing a standard definition for child overweight and obesity worldwide: International survey","volume":"320","author":"Cole","year":"2000","journal-title":"BMJ"},{"key":"ref_25","first-page":"138","article-title":"Specific Metabolomics Adaptations Define a Differential Regional Vulnerability in the Adult Human Cerebral Cortex","volume":"9","author":"Jove","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1007\/s00216-017-0272-3","article-title":"Development of a matrix-based candidate reference material of total homocysteine in human serum","volume":"409","author":"Liu","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/bph.14446","article-title":"Regulators of the transsulfuration pathway","volume":"176","author":"Sbodio","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jonsson, W., Margolies, N.S., and Anthony, T.G. (2019). Dietary Sulfur Amino Acid Restriction and the Integrated Stress Response: Mechanistic Insights. Nutrients, 11.","DOI":"10.3390\/nu11061349"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zuhra, K., Augsburger, F., Majtan, T., and Szab\u00f3, C. (2020). Cystathionine-\u03b2-synthase: Molecular Regulation and Pharmacological Inhibition. Biomolecules, 10.","DOI":"10.3390\/biom10050697"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1146\/annurev-nutr-071714-034330","article-title":"Direct and Functional Biomarkers of Vitamin B6 Status","volume":"35","author":"Ueland","year":"2015","journal-title":"Annu. Rev. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.biochi.2015.12.020","article-title":"Vitamin B6 nutritional status and cellular availability of pyridoxal 5\u2032-phosphate govern the function of the transsulfuration pathway\u2019s canonical reactions and hydrogen sulfide production via side reactions","volume":"126","author":"Gregory","year":"2016","journal-title":"Biochimie"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bcp.2017.11.019","article-title":"Gasotransmitter hydrogen sulfide signaling in neuronal health and disease","volume":"149","author":"Paul","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"654","DOI":"10.2174\/1871527317666180605072018","article-title":"Hydrogen Sulfide in Physiological and Pathological Mechanisms in Brain","volume":"17","author":"Kumar","year":"2018","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1161\/ATVBAHA.120.314084","article-title":"Reactive Sulfur Species: A New Redox Player in Cardiovascular Pathophysiology","volume":"40","author":"Kolluru","year":"2020","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1073\/pnas.1115634109","article-title":"Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production","volume":"109","author":"Fu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"140","DOI":"10.5195\/jmla.2018.253","article-title":"Malacards: The Human Disease Database","volume":"106","author":"Espe","year":"2018","journal-title":"J. Med. Libr. Assoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1097\/MCG.0b013e31802cb87a","article-title":"Hyper-CK-emia in Pediatric Celiac Disease","volume":"41","author":"Ertekin","year":"2007","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1002\/jcp.24002","article-title":"Challenges and opportunities of metabolomics","volume":"227","author":"Johnson","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1007\/s10620-020-06316-0","article-title":"Impact of a Child\u2019s Celiac Disease Diagnosis and Management on the Family","volume":"65","author":"Russo","year":"2020","journal-title":"Dig. Dis. Sci."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3723\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:40:42Z","timestamp":1760179242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["nu12123723"],"URL":"https:\/\/doi.org\/10.3390\/nu12123723","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}