Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N‐oxide‐generating pathway, modulates platelet responsiveness and thrombosis risk
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Essentials Microbe-dependent production of trimethylamine N-oxide (TMAO) contributes to thrombosis risk. The impact of host flavin monooxygenase 3 (FMO3) modulation on platelet function is unknown. Genetic manipulation of FMO3 in mice alters systemic TMAO levels and thrombosis potential. Genetic manipulation of FMO3 is associated with alteration of gut microbial community structure.Summary Background Gut microbes play a critical role in the production of trimethylamine N-oxide (TMAO), an atherogenic metabolite that impacts platelet responsiveness and thrombosis potential. Involving both microbe and host enzymatic machinery, TMAO generation utilizes a metaorganismal pathway, beginning with ingestion of trimethylamine (TMA)-containing dietary nutrients such as choline, phosphatidylcholine and carnitine, which are abundant in a Western diet. Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs). Gut microbial production of TMA is rate limiting in the metaorganismal TMAO pathway because hepatic FMO activity is typically in excess. Objectives FMO3 is the major FMO responsible for host generation of TMAO; however, a role for FMO3 in altering platelet responsiveness and thrombosis potential in vivo has not yet been explored. Methods The impact of FMO3 suppression (antisense oligonucleotide-targeting) and overexpression (as transgene) on plasma TMAO levels, platelet responsiveness and thrombosis potential was examined using a murine FeCl 3 -induced carotid artery injury model. Cecal microbial composition was examined using 16S analyses. Results Modulation of FMO3 directly impacts systemic TMAO levels, platelet responsiveness and rate of thrombus formation in vivo. Microbial composition analyses reveal taxa whose proportions are associated with both plasma TMAO levels and in vivo thrombosis potential. Conclusions The present studies demonstrate that host hepatic FMO3, the terminal step in the metaorganismal TMAO pathway, participates in diet-dependent and gut microbiota-dependent changes in both platelet responsiveness and thrombosis potential in vivo.
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Trimethylamine N-oxide has been shown to promote platelet reactivity and thrombosis potential, vascular inflammation and inflammasome activation, and heightened heart failure and chronic kidney disease related phenotypes in animal models.
“It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [84]
Multiple studies have confirmed through genetic gain and loss of function studies in mice that manipulation of trimethylamine and trimethylamine N-oxide levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential.
“Multiple studies have confirmed through both genetic gain (as global FMO3 transgene) and loss (via anti-sense oligonucleotide to FMO3, and via global FMO3 knock out) of function studies in mice that manipulation of TMA and TMAO levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential83, 84, 119.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [84]
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- Authors
- Zhu, W., Buffa, J. A., Wang, Z., Warrier, M., Schugar, R., Shih, D. M., Gupta, N., Gregory, J. C., Org, E., Fu, X., Li, L., DiDonato, J. A., Lusis, A. J., Brown, J. M., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Corresponding author
- Hazen, S.L.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 16
- Issue
- 9
- Pages
- 1857-1872
- ISSN
- 1538-7836 (ISSN-L)
- PMC
- PMC6156942
- OpenAlex
- W2829671626
- Cited by
- 161
- References
- 50
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 22 · 2023: 22 · 2022: 18 · 2021: 26 · 2020: 20 · 2019: 9 · 2018: 5
- FWCI
- 10.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (2P01HL030568-31A1, DK106000, HL103866, HL122283, HL126827, HL130819, HL28481, HL30568)
- American Heart Association
- FP7 (330381)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- trimethylamine N-oxide, flavin monooxygenase 3, FMO3, platelet response, thrombosis risk, gut microbiota, trimethylamine, hepatic metabolism, choline, L-carnitine, phosphatidylcholine, atherogenesis, host-microbe interactions, platelet activation
- MeSH terms
- Gastrointestinal Microbiome, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Ferric Compounds, Humans, Liver, Methylamines, Mice, Inbred C57BL, Oxygenases, Risk, Oligonucleotides, Antisense, Carotid Artery, Common, Transgenes, Thrombophilia, Ribotyping, Mice, Platelet-Rich Plasma, Gene Knockdown Techniques
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