Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice

Author:

Helsley Robert N123ORCID,Miyata Tatsunori4,Kadam Anagha12,Varadharajan Venkateshwari12,Sangwan Naseer12,Huang Emily C4,Banerjee Rakhee12,Brown Amanda L12,Fung Kevin K12,Massey William J12ORCID,Neumann Chase12,Orabi Danny12,Osborn Lucas J12,Schugar Rebecca C12,McMullen Megan R4,Bellar Annette4,Poulsen Kyle L4,Kim Adam4,Pathak Vai5,Mrdjen Marko124,Anderson James T12,Willard Belinda12,McClain Craig J6,Mitchell Mack7,McCullough Arthur J24,Radaeva Svetlana8,Barton Bruce9ORCID,Szabo Gyongyi10,Dasarathy Srinivasan24ORCID,Garcia-Garcia Jose Carlos11,Rotroff Daniel M5,Allende Daniela S12,Wang Zeneng12,Hazen Stanley L1213,Nagy Laura E24,Brown Jonathan Mark12ORCID

Affiliation:

1. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic

2. Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic

3. Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, College of Medicine, University of Kentucky

4. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic

5. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic

6. Department of Medicine, University of Louisville

7. Department of Internal Medicine, University of Texas Southwestern Medical Center

8. National Institute on Alcohol Abuse and Alcoholism

9. Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School

10. Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School

11. Life Sciences Transformative Platform Technologies, Procter & Gamble

12. Department of Anatomical Pathology, Cleveland Clinic

13. Department of Cardiovascular Medicine, Heart and Vascular and Thoracic Institute, Cleveland Clinic

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.

Funder

National Institutes of Health

JSPS Overseas Research Fellowship

American Heart Association

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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