Choline Diet and Its Gut Microbe–Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload–Induced Heart Failure
Open accessAbstract
BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. METHODS AND RESULTS: C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. CONCLUSIONS: Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility.
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In a transverse aortic constriction mouse model, a choline (1.2%)/TMAO (0.12%)-enriched diet significantly increased plasma TMAO and worsened pulmonary edema, cardiac enlargement, myocardial fibrosis, and left ventricular ejection fraction.
“In the transverse aortic constriction surgical mouse model for pressure overload-induced heart failure, a choline (1.2%)/TMAO (0.12%)-enriched diet significantly increased plasma TMAO concentrations and worsened pulmonary edema, cardiac enlargement, myocardial fibrosis, and left ventricular ejection fraction (90).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [90]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [14]
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 [91]
The UDCA effects on peripheral blood flow appeared to occur independently from inflammation, as TNF and IL-6 were unchanged.
“However, these effects appeared to occur independently from inflammation, as markers such as tumor necrosis factor (TNF) and IL-6 were unchanged.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [154]
UDCA supplementation in chronic heart failure patients resulted in limited but positive improvements in peripheral blood flow.
“The results showed limited but positive improvements in peripheral blood flow.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [154]
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- Authors
- Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., & Lefer, D. J.
- Affiliations
- Cleveland State University (US)
- Corresponding author
- Organ, Chelsea L.
- Otsuka, Hiroyuki
- ORCID
- Venue
- Circulation: Heart Failure
- Published
- 2016-01
- Volume
- 9
- Issue
- 1
- Pages
- e002314-e002314
- ISSN
- 1941-3289 (ISSN-L)
- 1941-3297
- PMC
- PMC4943035
- OpenAlex
- W2548611371
- Cited by
- 382
- References
- 22
- Citations by year
- 2026: 25 · 2025: 42 · 2024: 33 · 2023: 47 · 2022: 49 · 2021: 42 · 2020: 46 · 2019: 37 · 2018: 25 · 2017: 26 · 2016: 10
- FWCI
- 14.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- Funders
- Agency for Healthcare Research and Quality (R01 HS011657)
- National Heart, Lung, and Blood Institute (1R01 HL11657, R01HL093579, U24HL094373, P20HL113452, R01HL092141, R01HL116571, R01HL103866, R01HL060849)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- trimethylamine N-oxide, dietary choline, heart failure, pressure overload, transverse aortic constriction, gut microbiota, myocardial fibrosis, cardiac function, pulmonary edema, gut-heart axis
- MeSH terms
- Animals, Bacteria, Choline, Diet, Disease Models, Animal, Fibrosis, Cardiomegaly, Heart Failure, Intestines, Male, Methylamines, Mice, Inbred C57BL, Myocardium, Pulmonary Edema, Risk Factors, Severity of Illness Index, Stroke Volume, Time Factors, Ventricular Function, Left, Disease Progression, Ventricular Dysfunction, Left
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