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Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential
Open accessAbstract
Rationale: Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)—the precursor to TMAO—is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals. Objective: Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported. Methods and Results: Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC -dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC ). Conclusions: Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
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“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 [14]
In the citing paper
“While only present at a very low abundance (only ~ 0.1%) within the large intestine gut microbial community, the gain-of-function C. sporogenes mutant elevated circulating TMA and TMAO levels within the host, and both enhanced rate of thrombus formation and reduced time to cessation of blood flow following arterial injury in vivo14.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [14]
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“Importantly, studies using germ-free mice colonized with synthetic microbial communities +/- a genetically engineered gain or loss of function cutC mutant human commensal confirmed that a functional microbial cutC gene is sufficient to transmit TMA and TMAO generation, as well as in vivo thrombosis potential.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [14]
In the citing paper
“Zhu et al. found that TMAO alters human platelet calcium signaling, heightening their responsiveness to sub-maximal stimulation by agonists (e.g. thrombin, ADP, collagen).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [14]
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“Notably, however, TMAO levels appear to be driven more so by the gut microbial community composition than by the dietary intervention, and significant variation in TMAO production among individuals on a given diet is observed14, 111.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [14]
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Metadata
- Authors
- Skye, S. M., Zhu, W., Romano, K. A., Guo, C.-J., Wang, Z., Jia, X., Kirsop, J., Haag, B., Lang, J. M., DiDonato, J. A., Tang, W. H. W., Lusis, A. J., Rey, F. E., Fischbach, M. A., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- University of Wisconsin–Madison (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2018-10-26
- Volume
- 123
- Issue
- 10
- Pages
- 1164-1176
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6223262
- OpenAlex
- W2898598580
- Cited by
- 189
- References
- 48
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 24 · 2023: 27 · 2022: 31 · 2021: 28 · 2020: 21 · 2019: 11 · 2018: 2
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od016346-01a1, 5t32dk007470-35)
- National Heart, Lung, and Blood Institute (P01HL030568, R01HL126827, T32HL134622, R01HL103866)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110174, DP1DK113598, R01DK106000, R01DK108259, T32-DK 007470, R01DK101674)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- gut microbiota, trimethylamine N-oxide, trimethylamine, platelet reactivity, thrombosis, Clostridium sporogenes, gnotobiotic mice, microbial colonization, cardiovascular risk
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Adult, Animals, Bacterial Proteins, Choline, Clostridium, Female, Humans, Lyases, Male, Methylamines, Mice, Inbred C57BL, Middle Aged, Thrombosis, Platelet Activation, Mice
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