UMMS Affiliation

Department of Population and Quantitative Health Sciences

Publication Date

2022-01-27

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Digestive System | Digestive System Diseases | Hepatology | Substance Abuse and Addiction

Abstract

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.

Keywords

human, liver disease, medicine, metabolism, microbiome, mouse, nutrition

Rights and Permissions

Copyright © 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.

DOI of Published Version

10.7554/eLife.76554

Source

Helsley RN, Miyata T, Kadam A, Varadharajan V, Sangwan N, Huang EC, Banerjee R, Brown AL, Fung KK, Massey WJ, Neumann C, Orabi D, Osborn LJ, Schugar RC, McMullen MR, Bellar A, Poulsen KL, Kim A, Pathak V, Mrdjen M, Anderson JT, Willard B, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Garcia-Garcia JC, Rotroff DM, Allende DS, Wang Z, Hazen SL, Nagy LE, Brown JM. Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice. Elife. 2022 Jan 27;11:e76554. doi: 10.7554/eLife.76554. PMID: 35084335; PMCID: PMC8853661. Link to article on publisher's site

Journal/Book/Conference Title

eLife

PubMed ID

35084335

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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