Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2024; 30(18): 2454-2466
Published online May 14, 2024. doi: 10.3748/wjg.v30.i18.2454
Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury
Si-Miao Yu, Hao-Cheng Zheng, Si-Ci Wang, Wen-Ya Rong, Ping Li, Jing Jing, Ting-Ting He, Jia-Hui Li, Xia Ding, Rui-Lin Wang
Si-Miao Yu, Hao-Cheng Zheng, Si-Ci Wang, Ping Li, Xia Ding, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
Wen-Ya Rong, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Jing Jing, Ting-Ting He, Rui-Lin Wang, Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
Jia-Hui Li, The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
Co-first authors: Si-Miao Yu and Si-Ci Wang.
Co-corresponding authors: Xia Ding and Rui-Lin Wang.
Author contributions: Yu SM designed and wrote the manuscript; Wang SC, Zheng HC, and Rong WY analyzed the data; Jing J, He TT, Li P, and Li JH screened the literature and collected the data; Ding X and Wang RL critically revised the manuscript. All authors finally read and approved the version to be published. Yu SM and Wang SC contributed equally to this work as co-first authors. The reasons are the following. First, the research was performed as a collaborative effort, and the designation of co-first authors authorship accurately reflects the distribution of responsibilities and burdens associated with the time and effort required to complete the study and the resultant paper. Second, co-first authors contributed efforts of equal substance throughout the research process. Ding X and Wang RL contributed equally to this work as co-corresponding authors. The reasons are the following. First, they played a key role in coordinating the research team. Second, they made a great contribution to the original innovation of the article. In summary, we believe that designating Yu SM and Wang SC as co-first authors, Ding X and Wang RL as co-corresponding authors is fitting for our manuscript as it accurately reflects our team’s collaborative spirit, equal contributions, and diversity.
Supported by Medical Education Association Foundation of China, No. 2020KTY001; National Natural Science Foundation of China, No. 81673806; and National Natural Science Foundation Youth Fund, No. 82104702.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the Fifth Medical Center of PLA General Hospital (2020050D).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Rui-Lin Wang, M.D, Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, No. 100 Middle Road, West Fourth Ring Road, Beijing 100039, China. WRL7905@163.com.
Received: February 20, 2024
Revised: April 5, 2024
Accepted: April 18, 2024
Published online: May 14, 2024
Processing time: 81 Days and 4.5 Hours
Abstract
BACKGROUND

Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests.

AIM

To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools.

METHODS

Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves.

RESULTS

We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1).

CONCLUSION

Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Keywords: Drug-Induced liver injury, Salivary, Metabolomics, Biomarker, Weighted metabolite Coexpression network analysis, Machine learning, Noninvasive, Diagnostic method, Metabolites

Core Tip: Drug-induced liver injury (DILI) is one of the most common and serious adverse reactions to drugs. Conventional biomarkers are not specific and there is an urgent need for a non-invasive DILI marker. Our study has revealed a significant difference in salivary metabolites between patients with DILI and healthy individuals, and identified five metabolites that can distinguish DILI from healthy control, namely 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine. Our study may provide a potential feasible non-invasive diagnostic method for DILI.