Holistic Metabolomic Profiling of Chronic versus Acute Drug-induced Liver Injury

Abstract

Background and objectives Drug-induced liver injury (DILI) can present as a chronic phenotype or acute course. However, there is a lack of research on the underlying mechanisms of chronic DILI as well as the definition of cut-off point. We aimed to profile holistic metabolic characteristics of chronic DILI and provide evidence for the cut-off point by serum metabolomics.

Methods The sera of DILI patients were divided into Group I (0-6 months), Group II (6-12 months), and Group III (>12 months) based on the duration of liver injury. In total, 2,105 metabolites associated with the DILI duration were screened out as the holistic metabolomic signature (HMS). By unsupervised principal component analysis on the HMS dataset, the samples spontaneously represented a two-cluster pattern of the three groups, i.e., Group I as the first cluster and Group II/III as the second cluster, which suggested six months as the potential metabolomic cut-off point of DILI chronicity. Then, the differentiation ability of the metabolomic signature was validated in an independent cohort. We further screened out 23 most-associated metabolites as the metabolic fingerprint (MFP) for the DILI duration and constructed an eigenmetabolite by dimension reduction.

Results The eigenmetabolite was significantly different in chronic versus acute DILI and was not related to the severity grade of liver injury. Pathway enrichment analysis underlined the enhanced metabolic pathways of lipids in chronic DILI, which are associated with energy metabolism remodeling and immune regulation balance.

Conclusions MFP was different between chronic and acute DILI. Six months might be the potential metabolomic cut-off point in defining chronicity of DILI.

Keywords

Metabolomics / Characteristics / Chronicity / Mechanism / Cut-off point

Acknowledgments

The authors acknowledged Yan Liu for her support and assistance on the biobank sample collection.

Funding

This work was supported by the National Natural Science Foundation of China (82074112, 81721002, 81630100, U21A20412, 82104702, and 81503350), Beijing Talent Youth Science Foundation (JQ21026), and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202005).

Conflict of interest

JBW and XHX are serving as the Editors-in-Chief, ZFB is serving as the editorial board member, and YG and ZTM are serving as the managing editor of Future Integrative Medicine. All of them were not involved in the editorial evaluation or decision to accept this article for publication. The other authors have no relevant financial or non-financial interests to disclose.

Author contributions

All authors contributed to the study’s conception and design. Study concept and design (JBW, YCY, ZSZ and XHX), analysis and in-terpretation of data (JBW, ZS, LGW, YMG and ZFB), acquisition of data (ZS, LGW, XRZ, MN, YG, ZTM and XZ), execution of ex-periments (ZS, LGW, XRZ, MN, YG, ZTM and XZ), recruitment and diagnosis of the patients (AH, JX, JJ, TTH, JXH and MG), drafting the manuscript (ZS and LGW), critical revision of the manuscript (JBW, YMG, ZFB, YCY, ZSZ and XHX), study super-vision (JBW, YCY, ZSZ and XHX), obtained funding (YCY, ZSZ and XHX). All authors read and approved the final manuscript.

Ethical statement

This study was approved by the medical ethics committees of the Fifth Medical Center of PLA General Hospital (Beijing, China) and the Liver Diseases Center of General Hospital of Eastern Theater Command (Nanjing, China). The consent was obtained from all participants, and the protocols conformed to the ethical guidelines of the Declaration of Helsinki.

Data sharing statement

The dataset used to support the findings of this study is included within the supplementary information file.

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