There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite TMA is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

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Published in eLife, v. 11, e76554.

© 2022, Helsley et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

The first 20 authors (including the one from the University of Kentucky) are shown on the author list above. Please refer to the downloaded document for the complete author list.

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This work was supported in part by National Institutes of Health grants P50 AA024333 (AJM, SD, DSA, LEN, JMB), R01 DK120679 (JMB), P01 HL147823 (JMB, SLH), U01 AA026938 (LEN, JMB), P50 CA150964 (JMB), U01 AA021890 (LEN, SD), U01 AA021893 (SD, BB, CJM, MM, GS, and AJM), R01 HL103866 (SLH), R01 HL144651 (ZW), R01 HL130819 (ZW), U01 AA026980 (CJM), P50 AA 024337 (CJM), R21 AR 071046 (SD), R01 GM119174 (SD), R01 DK113196 (SD), R56 HL141744 (SD), U01 DK061732 (SD), U01 AA026977 (GS), UH3 AA026970 (GS), K99 AA028048 (AK), a Leducq Transatlantic Networks of Excellence Award (SLH), a JSPS Overseas Research Fellowship 201960331 (TM), and the American Heart Association (Postdoctoral Fellowships 17POST3285000 to RNH and 15POST2535000 to RCS). The Orbitrap Elite instrument used for proteomics was purchased via an NIH shared instrument grant 1S10RR031537 (BW).

Related Content

Sequencing data have been deposited in GEO under accession code GSE157681.

The following data sets were generated:

Brown JM, Helsley R, Kadam A, Neumann C (2021) NCBI Gene Expression Omnibus ID GSE157681. The Gut Microbe-Derived Metabolite Trimethylamine is a Biomarker of and Therapeutic Target in Alcohol-Associated Liver Disease. http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE157681

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