PMID- 37156409 OWN - NLM STAT- MEDLINE DCOM- 20230620 LR - 20230622 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 144 DP - 2023 Jul TI - Serum metabolomic profiling reveals potential biomarkers in systemic sclerosis. PG - 155587 LID - S0026-0495(23)00190-7 [pii] LID - 10.1016/j.metabol.2023.155587 [doi] AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored. METHODS: High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis. RESULTS: The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis. CONCLUSIONS: Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Guo, Muyao AU - Guo M AD - Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Liu, Di AU - Liu D AD - Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. FAU - Jiang, Yu AU - Jiang Y AD - Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Institute of Emergency Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China. FAU - Chen, Weilin AU - Chen W AD - Department of Nephrology and Rheumatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Zhao, Lijuan AU - Zhao L AD - Department of Nephrology and Rheumatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Bao, Ding AU - Bao D AD - Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Li, Yisha AU - Li Y AD - Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Distler, Jorg H W AU - Distler JHW AD - Clinic for Rheumatology, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University, 40225 Dusseldorf, Germany; Hiller Research Center, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University, 40225 Dusseldorf, Germany. FAU - Zhu, Honglin AU - Zhu H AD - Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: honglinzhu@csu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230506 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Glucuronides) RN - 0 (Biomarkers) RN - 5688UTC01R (Tretinoin) SB - IM MH - Humans MH - Mice MH - Animals MH - Glucuronides/adverse effects MH - *Lung Diseases, Interstitial/complications/metabolism MH - *Scleroderma, Systemic/metabolism MH - Fibrosis MH - Biomarkers MH - Tretinoin/adverse effects OTO - NOTNLM OT - Biomarkers OT - Machine learning algorithm OT - Metabolic reprogramming OT - Metabolomics OT - Systemic sclerosis COIS- Declaration of competing interest The authors have declared no conflicts of interest. EDAT- 2023/05/09 00:42 MHDA- 2023/06/20 06:41 CRDT- 2023/05/08 19:22 PHST- 2023/02/13 00:00 [received] PHST- 2023/04/24 00:00 [revised] PHST- 2023/05/02 00:00 [accepted] PHST- 2023/06/20 06:41 [medline] PHST- 2023/05/09 00:42 [pubmed] PHST- 2023/05/08 19:22 [entrez] AID - S0026-0495(23)00190-7 [pii] AID - 10.1016/j.metabol.2023.155587 [doi] PST - ppublish SO - Metabolism. 2023 Jul;144:155587. doi: 10.1016/j.metabol.2023.155587. Epub 2023 May 6.