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Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease

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Abstract

Background

Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease.

Aims

(1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease.

Methods

We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC–MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease.

Results

Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality.

Conclusions

Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.

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Abbreviations

AP:

Alkaline phosphatase

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

BMI:

Body mass index

CAP:

Controlled attenuation parameter

INR:

International normalized ratio

MELD:

Model for end-stage liver disease

MELDNa:

Sodium model for end-stage liver disease

PMN:

Polymorphonuclear infiltration

AA:

Arachidonic acid

EPA:

Eicosapentaenoic acid

DHA:

Docosahexaenoic acid

HpETE:

Hydroperoxyeicosatetraenoic acid

HETE:

Hydroxyeicosatetraenoic acid

DiHETE:

Dihydroxyeicosatetraenoic acid

PG:

Prostaglandin

TX:

Thromboxane X

EpETrE:

Epoxyeicosatrienoic acid

DiHETrE:

Dihydroxyeicosatrienoic acid

HpEPE:

Hydroperoxy-eicosapentaenoic acid

HEPE:

Hydroxyeicosapentaenoic acid

DiHEPE:

Dihydroxyeicosapentaenoic acid

EpETE:

Epoxyeicosatetraenoic acid

HpDoHE:

Hydroperoxydocosahexaenoic acid

HDoHE:

Hydroxydocosahexaenoic acid

DiHDoHE:

Dihydroxydocosahexaenoic acid

DiHDPE:

Dihydroxydocosapentaenoic acid

PLS-DA:

Partial least squares discriminant analysis

VIP:

Variable importance in projection

MRM:

Multiple reaction monitoring

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Acknowledgments

This study was supported in part by NIH Grants R01 AA020703, R01 AA24726, U01 AA021856, U01 AA026939 and by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.), and by Fond National de Recherche Scientifique (FNRS) Belgium grants CDR J.0146.17 and PDR T.0217.18 (to P.S.).

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Author notes

  1. Peter Stärkel and Bernd Schnabl have contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Bei Gao, Sonja Lang, Yi Duan, Yanhan Wang, Samuel B. Ho & Bernd Schnabl

  2. Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA

    Yi Duan, Yanhan Wang, Samuel B. Ho & Bernd Schnabl

  3. Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, King’s College Hospital, London, UK

    Debbie L. Shawcross

  4. Service des Maladies de L’appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France

    Alexandre Louvet & Philippe Mathurin

  5. St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Peter Stärkel

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Contributions

B.G. was responsible for data acquisition, analysis, interpretation, and writing of the manuscript; S.L. was responsible for data analysis; Y.D. and Y.W. were responsible for preparation of human samples; D.L.S., A.L., P.M., S.B.H., and P.S. enrolled subjects for bio-specimen collection; and B.S. was responsible for the study concept and design, editing the manuscript, and study supervision.

Corresponding author

Correspondence to Bernd Schnabl.

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Conflict of interest

B.S. is consulting for Ferring Research Institute.

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10620_2019_5638_MOESM1_ESM.jpg

Supplemental Figure S1 Venn diagram of significantly altered oxylipins found in both serum and fecal samples (adjusted p value < 0.05). Ctrl: controls; AUD: alcoholic use disorder; AH: alcoholic hepatitis (JPEG 165 kb)

10620_2019_5638_MOESM2_ESM.jpg

Supplemental Figure S2 Spearman correlation of fecal oxylipins with laboratory parameters in alcoholic hepatitis and alcohol use disorder patients. Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05, ** p < 0.01, *** p < 0.001. INR, international normalized ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; AP, alkaline phosphatase (JPEG 267 kb)

10620_2019_5638_MOESM3_ESM.jpg

Supplemental Figure S3 Spearman correlation of fecal oxylipins with parameters of liver disease stage in alcohol use disorder patients (A). CAP: controlled attenuation parameter. Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05. Number of alcohol use disorder patients N = 30. Spearman correlation of fecal oxylipins with liver histology and clinical scores in alcoholic hepatitis patients (B). Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05, ** p < 0.01, *** p < 0.001. MELD, model for end-stage liver disease; MELDNa, sodium model for end-stage liver disease. Number of alcoholic hepatitis patients N = 7 (JPEG 486 kb)

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Supplementary material 6 (XLSX 22 kb)

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Gao, B., Lang, S., Duan, Y. et al. Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease. Dig Dis Sci 64, 1878–1892 (2019). https://doi.org/10.1007/s10620-019-05638-y

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