Coordinated action of a gut–liver pathway drives alcohol detoxification and consumption

Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal

site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver

only plays a partial role in clearing systemic AcH. Here we show that a liver–gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol

drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is

further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile

flow and secretion are potential therapeutic strategies to treat AUD.

All data from these studies are contained within this paper. Source data are provided with this paper.

We thank D. Lovinger (NIAAA, National Institutes of Health) for critical comments and suggestions during the study. We also thank the National Institute of Allergy and Infectious Diseases

Gnotobiotic Animal Facility for providing GF mice and V. Ling (British Columbia Cancer) for providing Bsep−/− mice. This work was supported by the intramural programme of NIAAA, National

Institutes of Health (B.G., G.K., P.P.). H.Z. is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs (grant no. IK6BX004477). The funders had no role

in study design, data collection and analysis, decision to publish or preparation of the manuscript.

These authors contributed equally: Yaojie Fu, Bryan Mackowiak.

Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

Yaojie Fu, Bryan Mackowiak, Yu-Hong Lin, Luca Maccioni, Taylor Lehner, Hongna Pan, Yukun Guan, Hongkun Lu, Cheng Chen, Dechun Feng & Bin Gao

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

Luca Maccioni, Grzegorz Godlewski, Cheng Chen & George Kunos

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, VA, USA

Y.F. and B.M. were responsible for the conception, experimental design, performing experiments and writing the paper. Y.L. conducted the GC–MS experiments. L.M., T.L., H.P., Y.G., G.G.,

H.L., C.C., S.W., D.F. and J.P. performed the animal experiments and staining. H.Z., P.P., L.Z. and G.K. carried out the conception, data analysis, and reviewing and editing of the paper.

B.G. was responsible for conceptualization, resources and supervision, and writing, reviewing and editing of the paper.

Nature Metabolism thanks Daria Mochly-Rosen, Claudia Fuchs-Steiner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor:

Yanina-Yasmin Pesch, in collaboration with the Nature Metabolism team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

(a) To identify which organ(s) in addition to the liver controls blood AcH clearance, several lines of tissue-specific KO mice were generated and listed in the table. (b) Measurement of AcH

levels in serum from Aldh2f/f mice (n = 6), Aldh2E2a−/− mice (n = 5), and global Aldh2 KO mice (n = 4) 3 h post ethanol oral gavage (5 g/Kg). (c) Western blot analysis or immunofluorescent

staining was performed to confirm the deletion of ALDH2 in tissues (IF staining: upper left panel: smooth muscle tissue; upper right panel: liver tissue; lower left panel: blood vessels of

heart tissue were shown, scale bar: 50 μm) from various organ-specific Aldh2 KO mice listed in Table (a), representative of two independent experiments. Values represent means ± SEM. Two-way

ANOVA and two-sided Student’s t-test was performed for the comparison between indicated two groups. ns: No significance.

(a–d). 2-bottle choice (2-BC) experiments were performed in endothelial cell (Male: n = 8, n = 10; Female: n = 8, n = 10) in Aldh2Tie2−/−, (Male: n = 9, n = 7; Female: n = 6, n = 5) in

Aldh2Tek2−/−, *P = 0.0377, *P = 0.0357), smooth muscle (n = 8, n = 9), and skeletal muscle (n = 8, n = 10) (*P = 0.0321, *P = 0.0345) specific Aldh2 KO mice. Sex of mice were indicated, ‘M’

means ‘male’ and ‘F’ means ‘female’. Values represent means ± SEM. *p