Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide Contributes to Cardiac Dysfunction in Western Diet-Induced Obese Mice
Open accessAbstract
Excessive consumption of diets high in sugars and saturated fat, frequently known as western diet (WD), may lead to obesity and metabolic syndrome. Recent evidence shows that WD-induced obesity impairs cardiac function, but the underlying mechanisms are not fully understood. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of specific dietary nutrients, has emerged as a key contributor to cardiovascular disease pathogenesis. We tested the hypothesis that elevated circulating TMAO levels contribute to cardiac dysfunction in WD-induced obesity. CD1 mice were fed a normal diet (ND) or a WD, without or with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with mice fed a ND, mice fed a WD showed a significant increase in body weight and dyslipidemia, and had markedly higher plasma TMAO levels at the end of the feeding protocol. Echocardiography revealed that cardiac systolic and diastolic function was impaired in mice fed a WD. DMB treatment had no effects on body weight and dyslipidemia, but significantly reduced plasma TMAO levels and prevented cardiac dysfunction in mice fed a WD. In addition, mice fed a WD had elevated expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin IL-1β, decreased expression of anti-inflammatory cytokine IL-10, and increased interstitial fibrosis in the hearts, all of which were prevented by DMB treatment. Notably, DMB treatment also reduced plasma TMAO levels in mice fed a ND but did not alter other parameters. These results suggest that consumption of a WD increases circulating TMAO levels, which lead to cardiac inflammation and fibrosis, contributing to cardiac dysfunction. Interventions that reduce circulating TMAO levels may be a novel therapeutic strategy for prevention and treatment of WD-induced cardiac dysfunction.
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There is convincing evidence suggesting an association between TMAO and inflammation.
“nowadays there is convincing evidence suggesting an association between TMAO and inflammation [8,9,10,11,12]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
Mice fed a Western diet have greater plasma TMAO concentrations and develop cardiac dysfunction and heart fibrosis, with increased expression of pro-inflammatory cytokines TNF-α and IL-1β and decreased anti-inflammatory cytokine IL-10.
“Moreover, mice fed a Western diet, a risk factor for CVD, have greater plasma TMAO concentrations and develop cardiac dysfunction and heart fibrosis. They also show a bigger expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and a decrease in the expression of anti-inflammatory cytokines (IL-10).”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
High fat or Western-like diets increase plasma TMAO levels.
“Furthermore, high fat diets or Western-like diets increase plasma TMAO levels [8,34,35,36,37,38,39]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
Treatment with DMB, which inhibits choline TMA lyase, prevents cardiac dysfunction, heart fibrosis, cytokine changes and lowers plasma TMAO levels in mice fed a Western diet.
“The treatment with 3,3-dimethyl-1-butanol (DMB), that inhibits the choline TMA lyase enzyme, prevented all those outcomes and lowered plasma TMAO levels [8].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
DMB inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
DMB cannot avoid complete TMAO synthesis because it cannot inhibit the conversion of GBB to TMA.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [8]
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- Authors
- Chen, K., Zheng, X., Feng, M., Li, D., & Zhang, H.
- Affiliations
- Jining First People's Hospital (CN)
- Shandong University (CN)
- Corresponding author
- Zhang, Hongqi
- ORCID
- Li, Dongliang
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2017-03-21
- Volume
- 8
- Pages
- 139-139
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC5359299
- OpenAlex
- W2598218405
- Cited by
- 279
- References
- 37
- Citations by year
- 2026: 11 · 2025: 32 · 2024: 35 · 2023: 42 · 2022: 50 · 2021: 40 · 2020: 30 · 2019: 23 · 2018: 10 · 2017: 6
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Major Project of Science and Technology of Shandong Province (2016GSF201070)
- Topics
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- trimethylamine N-oxide, Western diet, diet-induced obesity, cardiac dysfunction, gut microbiota, 3,3-dimethyl-1-butanol, cardiac inflammation, myocardial fibrosis, dyslipidemia, inflammatory cytokines, TNF-α, IL-1β, IL-10, cardiovascular disease
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