Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity
Abstract
Emerging evidence shows that obesity induces renal injury and is an independent risk factor for the development of chronic kidney disease (CKD), even without diabetes or hyperglycemia. Although multiple metabolic factors have been suggested to account for obesity-associated renal injury, the precious underlying mechanisms are not completely understood. Recent study shows that increased trimethylamine N-Oxide (TMAO), a gut microbiota-generated metabolite, directly contributes to renal interstitial fibrosis and dysfunction. Circulating TMAO is elevated in high-fat diets (HFD)-induced obese animals. Here we tested the hypothesis that elevated TMAO might play a contributory role in the development of renal dysfunction in a mouse model of HFD-induced obesity that mimics human obesity syndrome. Male C57BL/6 mice received either a low-fat diet (LFD) or a HFD, without or with 3,3-Dimethyl-1-butanol (DMB, a trimethylamine formation inhibitor) for 16 weeks. Compared with mice fed a LFD, mice fed a HFD developed obesity and metabolic disorders, and exhibited significantly elevated plasma TMAO levels at the end of the experiment. Molecular and morphological studies revealed that renal interstitial fibrosis, phosphorylation of SMAD3 (a key regulator of renal fibrosis), expression of kidney injury molecule-1 and plasma cystatin C were significantly increased in mice fed a HFD, compared with mice fed a LFD. Additionally, expression of NADPH oxidase-4 and pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1 β was also augmented in mice fed a HFD as compared to mice fed a LFD. These molecular and morphological alterations observed in mice fed a HFD were prevented by concomitant treatment with DMB, which reduced plasma TMAO levels. Furthermore, elevated circulating TMAO levels were positively correlated with increased renal interstitial fibrosis and expression of kidney injury molecule-1. Notable, there was no difference in blood pressure among groups, and DMB treatment had no effects on body weight and metabolic parameters. These data suggest that HFD-induced obesity leads to elevations in gut microbiota-generated metabolite TMAO in the circulation, which contributes to renal interstitial fibrosis and dysfunction by promoting renal oxidative stress and inflammation. These findings may provide new insights into the mechanisms underlying obesity-associated CKD. Targeting TMAO may be a novel strategy for prevention and treatment of CKD in patients with obesity.
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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 [38]
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 [38]
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 [38]
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- Authors
- Sun, G., Yin, Z., Liu, N., Bian, X., Yu, R., Su, X., Zhang, B., & Wang, Y.
- Affiliations
- Sheng Jing Hospital (CN)
- Hospital 463 People's Liberation Army (CN)
- Corresponding author
- Sun, Guangping
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 493
- Issue
- 2
- Pages
- 964-970
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2755113788
- Cited by
- 140
- References
- 36
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 14 · 2023: 17 · 2022: 23 · 2021: 20 · 2020: 14 · 2019: 20 · 2018: 7
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Doctoral Scientific Research Foundation of Liaoning Province (20101143)
- Liaoning Province Science and Technology Agency (Z062)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- trimethylamine N-oxide, tubulointerstitial fibrosis, gut microbiota metabolites, high-fat diet-induced obesity, 3,3-dimethyl-1-butanol, Smad3 phosphorylation, KIM-1, cystatin C, NOX4, oxidative stress, renal inflammation, TNF-α, IL-1β
- MeSH terms
- Gastrointestinal Microbiome, Animals, Disease Models, Animal, Hemodynamics, Inflammation, Kidney, Kidney Diseases, Male, Methylamines, Mice, Inbred C57BL, Obesity, Oxidative Stress, Mice, Diet, High-Fat
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