{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T18:01:29Z","timestamp":1781028089039,"version":"3.54.1"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sungkyunkwan University School of Medicine, Samsung Changwon Hospital"},{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2025-RISE-13-JJU"],"award-info":[{"award-number":["2025-RISE-13-JJU"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Oral manifestations can be the initial sign of systemic diseases such as Behcet\u2019s disease (BD) and Sjogren\u2019s syndrome (PSS). Their frequency and morphology vary widely, and recurrent aphthous stomatitis (RAS) often mimics BD ulcers, complicating differentiation on clinical grounds. Nonspecific aphthoid lesions are also seen in PSS. This study aimed to identify distinctive metabolic patterns in saliva that could discriminate BD, PSS, and RAS using global metabolite profiling. Saliva samples were collected from 43 patients (BD, n\u2009=\u200924; PSS, n\u2009=\u200910; RAS, n\u2009=\u20099) after fasting and abstaining from oral activities for at least 90 minutes. Gas chromatography-mass spectrometry (GC\/MS) was employed for metabolite profiling. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) were used to distinguish groups. Variable importance in projection (VIP) scores were calculated from partial least squares discriminant analysis (PLS-DA), and ANOVA was applied to compare metabolite abundance. Forty-two metabolites were identified and categorized into amino acids, organic acids, sugars, sugar alcohols, and others. PCA and HCA demonstrated clear dis-crimination among BD, PSS, and RAS. Metabolites with VIP\u2009&gt;\u20091 included malonic acid sorbitol, pyroglutamic acid, aspartic acid, decanoic acid, hexadecenoic acid, and L-proline. Notably, malonic acid and aspartic acid were significantly elevated in BD compared to PSS and RAS, suggesting their diagnostic potential. Global salivary metabolite profiling by GC\/MS provides distinct metabolic signatures enabling discrimination among BD, PSS, and RAS. This approach may enhance understanding of oral mucosal manifestations in systemic autoimmune diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0351403","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T17:30:12Z","timestamp":1781026212000},"page":"e0351403","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolite profiling of saliva for the discrimination of Behcet\u2019s disease, Sj\u00f6gren\u2019s syndrome, and recurrent aphthous 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Cui","year":"2024","journal-title":"Biochem Pharmacol"},{"issue":"5","key":"pone.0351403.ref030","doi-asserted-by":"crossref","first-page":"816","DOI":"10.3390\/polym13050816","article-title":"Malonic Acid Isolated from Pinus densiflora Inhibits UVB-Induced Oxidative Stress and Inflammation in HaCaT Keratinocytes","volume":"13","author":"C Park","year":"2021","journal-title":"Polymers (Basel)"},{"issue":"2","key":"pone.0351403.ref031","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.cmet.2020.06.010","article-title":"Amino Assets: How Amino Acids Support Immunity","volume":"32","author":"B Kelly","year":"2020","journal-title":"Cell Metab"},{"issue":"4","key":"pone.0351403.ref032","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1007\/BF01971486","article-title":"Putrescine--a potent endogenous anti-inflammatory substance in inflammatory exudates","volume":"13","author":"J Bird","year":"1983","journal-title":"Agents Actions"},{"issue":"1","key":"pone.0351403.ref033","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1186\/s12964-023-01373-0","article-title":"Polyamines: their significance for maintaining health and contributing to diseases","volume":"21","author":"M Xuan","year":"2023","journal-title":"Cell Commun Signal"},{"key":"pone.0351403.ref034","doi-asserted-by":"crossref","first-page":"977235","DOI":"10.3389\/fimmu.2022.977235","article-title":"Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice","volume":"13","author":"H Li","year":"2022","journal-title":"Front Immunol"},{"issue":"11","key":"pone.0351403.ref035","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.3945\/jn.117.256404","article-title":"Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing","volume":"147","author":"VL Albaugh","year":"2017","journal-title":"J Nutr"},{"issue":"9","key":"pone.0351403.ref036","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nri.2016.70","article-title":"A guide to immunometabolism for immunologists","volume":"16","author":"LAJ O\u2019Neill","year":"2016","journal-title":"Nat Rev Immunol"},{"issue":"8","key":"pone.0351403.ref037","article-title":"A Comparative Metabolomic Evaluation of Behcet\u2019s Disease with Arthritis and Seronegative Arthritis Using Synovial Fluid","volume":"10","author":"JK Ahn","year":"2015","journal-title":"PLoS One"},{"issue":"11","key":"pone.0351403.ref038","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.3390\/ijms18112309","article-title":"Urinary Metabolomic Profiling to Identify Potential Biomarkers for the Diagnosis of Behcet\u2019s Disease by Gas Chromatography\/Time-of-Flight-Mass Spectrometry","volume":"18","author":"JK Ahn","year":"2017","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0351403.ref039","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jbspin.2017.05.019","article-title":"Potential metabolomic biomarkers for reliable diagnosis of Behcet\u2019s disease using gas chromatography\/ time-of-flight-mass spectrometry","volume":"85","author":"JK Ahn","year":"2018","journal-title":"Joint Bone Spine"},{"issue":"6155","key":"pone.0351403.ref040","doi-asserted-by":"crossref","first-page":"1242454","DOI":"10.1126\/science.1242454","article-title":"Fueling immunity: insights into metabolism and lymphocyte function","volume":"342","author":"EL Pearce","year":"2013","journal-title":"Science"},{"key":"pone.0351403.ref041","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1146\/annurev.nutr.22.110801.140547","article-title":"Regulation of enzymes of the urea cycle and arginine metabolism","volume":"22","author":"SM Morris","year":"2002","journal-title":"Annu Rev Nutr"},{"key":"pone.0351403.ref042","doi-asserted-by":"crossref","first-page":"112999","DOI":"10.1016\/j.jpba.2019.112999","article-title":"Discovering new metabolite alterations in primary sj\u00f6gren\u2019s syndrome in urinary and plasma samples using an HPLC-ESI-QTOF-MS methodology","volume":"179","author":"\u00c1 Fern\u00e1ndez-Ochoa","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"pone.0351403.ref043","doi-asserted-by":"crossref","first-page":"100459","DOI":"10.1016\/j.clinsp.2024.100459","article-title":"Targeted saliva metabolomics in Sj\u00f6gren\u2019s syndrome","volume":"79","author":"G Piacenza Florezi","year":"2024","journal-title":"Clinics (Sao Paulo)"},{"issue":"1","key":"pone.0351403.ref044","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005800","article-title":"A Glutathione-Nrf2-Thioredoxin Cross-Talk Ensures Keratinocyte Survival and Efficient Wound Repair","volume":"12","author":"M Telorack","year":"2016","journal-title":"PLoS 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