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Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease

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Abstract

Background and aim

The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients.

Methods

This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight–mass spectrometry (LC–TOF–MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages.

Results

The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism.

Conclusions

This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression.

Clinical trial

Clinicaltrials.gov, number NCT04339725.

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Availability of data and materials

All data generated or analyzed during this study are included either in this article or in the supplementary information fles.

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Acknowledgements

Ki Tae Suk would like to thank the NRF of Korea, the Ministry of Education, Science, and Technology, and the Ministry of SMEs and Startups (MSS) for the funding support. Raja Ganesan specially thanks Ki Tae Suk for his support.

Funding

This research was supported by Hallym University Research Fund, the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2019R1I1A3A01060447 and NRF-2020R1A6A1A03043026), Korea Institute for Advancement of Technology (P0020622), and Bio Industrial Technology Development Program (20018494) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea).

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Authors and Affiliations

Authors

Contributions

Conceptualization: RG, DJK, KTS. Data curation: all authors. Formal analysis: RG, HG, SS. Funding acquisition: KTS. Investigation: KTS. Methodology: RG, HG. Software: RG, HG, SJY. Project administration: KTS. Supervision: KTS. Writing-original draft: RG, HG, DJK, KTS. Writing—review & editing: RG, HG, YAG, SS, SJY, DJK, KTS. All authors contributed to manuscript revision and read and approved the submitted version.

Corresponding author

Correspondence to Ki Tae Suk.

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Conflict of interest

There are no conflicts to declare (Raja Ganesan, Haripriya Gupta, Jin-Ju Jeong, Satya Priya Sharma, Sung-Min Won, Ki-Kwang Oh, Sang Jun Yoon, Sang Hak Han, Young Joo Yang, Gwang Ho Baik, Chang Seok Bang, Dong Joon Kim, Ki Tae Suk).

Ethical approval statement

This study was conducted in conformance with the ethical guidelines from the 1975 Helsinki Declaration as it is reflected by a priori approval of the institutional review board for human research. Informed consent on enrollment was obtained from each participant.

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Ganesan, R., Gupta, H., Jeong, JJ. et al. Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease. Hepatol Int 18, 486–499 (2024). https://doi.org/10.1007/s12072-023-10518-9

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  • DOI: https://doi.org/10.1007/s12072-023-10518-9

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