Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

Boini, Krishna M.; Hussain, Tahir; Li, Pin-Lan; Koka, Sai S

doi:10.1159/000484623

Cited by 302Inflammasome and immune disordersAtherosclerosis and Cardiovascular DiseasesNitric Oxide and Endothelin Effects

Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

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Boini, Krishna M., Hussain, Tahir, Li, Pin-Lan, Koka, Sai S·2017·Cellular Physiology and Biochemistry

DOI 10.1159/000484623PMC PMC5828122

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Abstract

BACKGROUND/AIM: Plasma trimethylamine-N-oxide (TMAO), a product of intestinal microbial metabolism of dietary phosphatidylcholine has been recently associated with atherosclerosis and increased risk of cardiovascular diseases (CVD) in rodents and humans. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. The present study tested whether TMAO induces NLRP3 inflammasome formation and activation and thereby contributes to endothelial injury initiating atherogenesis. METHODS: Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1β production was measured using ELISA, cell permeability was determined by microplate reader and ZO-1 expression was determined by western blot analysis and confocal microscopy. In in vivo experiments, TMAO was infused by osmotic pump implantation. RESULTS: TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1β production, cell permeability in carotid artery endothelial cells (CAECs) compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD or Nlrp3 siRNA abolished the TMAO-induced inflammasome formation, activation and cell permeability in these cells. In addition, we explored the mechanisms by which TMAO activates NLRP3 inflammasomes. TMAO-induced the activation of NLRP3 inflammasomes was associated with both redox regulation and lysosomal dysfunction. In animal experiments, direct infusion of TMAO in mice with partially ligated carotid artery were found to have increased NLRP3 inflammasome formation and IL-1β production in the intima of wild type mice. CONCLUSION: The formation and activation of NLRP3 inflammasomes by TMAO may be an important initiating mechanism to turn on the endothelial inflammatory response leading to endothelial dysfunction.

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TMAO is primarily produced by the small intestinal microbiota from dietary precursors including choline, betaine, carnitine, and deoxycarnitine.
“Another gut-derived metabolite, Trimethylamine N-oxide (TMAO), is primarily produced by the small intestinal microbiota from dietary precursors, including choline, betaine, carnitine, and deoxycarnitine, which are abundant in meat, eggs, and dairy products.”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [64]
TMAO has been implicated in cardiovascular diseases, contributing to platelet hyperreactivity, increased thrombosis risk, and endothelial dysfunction.
“TMAO has been implicated in cardiovascular diseases, contributing to platelet hyperreactivity, increased thrombosis risk, and endothelial dysfunction [63,64,65].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [64]
In carotid artery endothelial cells, TMAO significantly increases activation and formation of NLRP3, caspase-1 activity, IL-1β production and cell permeability.
“some trials performed in carotid artery endothelial cells (CAEC) revealed that TMAO significantly increases the activation and formation of NLRP3, caspase-1 activity, IL-1β production and cell permeability.”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [89]
TMAO can impact inflammation via priming and activation of the NLRP3 inflammasome in endothelial cells and the arterial vascular wall in mice, involving mitochondrial ROS production, TXNIP, and lysosomal destabilization.
“Recent investigations have suggested TMAO can impact inflammation via priming and activation of the NLRP3 inflammasome in endothelial cells, as well as the arterial vascular wall in mice, involving mitochondrial reactive oxygen species (ROS) production, thioredoxin interacting protein (TXNIP) and lysosomal destabilization87, 130, 131.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [130]

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Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs
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The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases
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The Gut Microbial Metabolite Trimethylamine N-Oxide and Hypertension Risk: A Systematic Review and Dose–Response Meta-analysis
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Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota
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Trimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease
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Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms
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Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome
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Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways
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Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?
Papandreou, C., Moré, M. I., & Bellamine, A. (2020) · Nutrients · doi:10.3390/nu12051330 · Cited by 150 · see citing works
Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System
Falconi, C. A., Junho, C. V. C., Fogaça-Ruiz, F., Vernier, I. C. S., da Cunha, R. S., Stinghen, A. E. M., & Carneiro‐Ramos, M. S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.686249 · Cited by 144 · see citing works
Trimethylamine N‐oxide promotes apoE−/− mice atherosclerosis by inducing vascular endothelial cell pyroptosis via the SDHB/ROS pathway
Wu, P., Chen, J., Chen, J., Tao, J., Wu, S., Xu, G., Wang, Z., Wei, D., & Yin, W. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29518 · Cited by 140 · see citing works
Trimethylamine N-Oxide, Circulating Endothelial Progenitor Cells, and Endothelial Function in Patients with Stable Angina
Chou, R., Chen, C., Chen, I., Huang, H.-L., Lu, Y., Kuo, C., Chang, C., Huang, P., Chen, J., & Lin, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-40638-y · Cited by 135 · see citing works
Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine
Cheng, H., Liu, J., Tan, Y., Feng, W., & Peng, C. Y. (2021) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2021.10.003 · Cited by 137 · see citing works
Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice
Wang, Q., Shen, Y., Wang, X., Fu, S., Zhang, X., Zhang, Y., & Wang, R. (2020) · Aging · doi:10.18632/aging.102645 · Cited by 129 · see citing works
The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation
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Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer’s disease
Gao, Q., Wang, Y., Wang, X., Fu, S., Zhang, X., Wang, R., & Zhang, X. (2019) · Aging · doi:10.18632/aging.102352 · Cited by 118 · see citing works
Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease
Fang, Q., Zheng, B., Liu, N., Liu, J., Liu, W., Huang, X., Zeng, X., Chen, L., Li, Z., & Ouyang, D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.682482 · Cited by 116 · see citing works
Plasma Trimethylamine N-Oxide as a Novel Biomarker for Plaque Rupture in Patients With ST-Segment–Elevation Myocardial Infarction
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Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis
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The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders
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Coptisine from Coptis chinensis blocks NLRP3 inflammasome activation by inhibiting caspase-1
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Gut Metabolite Trimethylamine-N-Oxide in Atherosclerosis: From Mechanism to Therapy
Wang, B., Qiu, J., Lian, J., Yang, X., & Zhou, J. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.723886 · Cited by 108 · see citing works
High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
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Gut microbiota and microbiota-derived metabolites in cardiovascular diseases
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Intestinal microbiota and diabetic kidney diseases: the Role of microbiota and derived metabolites inmodulation of renal inflammation and disease progression
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Longitudinal Plasma Measures of Trimethylamine N‐Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community‐Based Older Adults
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Bifidobacterium breve and Bifidobacterium longum Attenuate Choline-Induced Plasma Trimethylamine N-Oxide Production by Modulating Gut Microbiota in Mice
Wang, Q., Guo, M., Liu, Y., Xu, M., Shi, L., Li, X., Zhao, J., Zhang, H., Wang, G., & Chen, W. (2022) · Nutrients · doi:10.3390/nu14061222 · Cited by 95 · see citing works
Trimethylamine-N-oxide has prognostic value in coronary heart disease: a meta-analysis and dose-response analysis
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NLRP3 Inflammasome and Its Central Role in the Cardiovascular Diseases
Tong, Y., Wang, Z., Li, C., Lin, L., Liu, J., & Cheng, J. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/4293206 · Cited by 89 · see citing works
Uric acid regulates NLRP3/IL-1β signaling pathway and further induces vascular endothelial cells injury in early CKD through ROS activation and K+ efflux
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Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease
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The gut microbiota derived metabolite trimethylamine N-oxide: Its important role in cancer and other diseases
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The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
Kapetanaki, S., Kumawat, A. K., Persson, K., & Demirel, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111864 · Cited by 80 · see citing works
Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study
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Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health
Caradonna, E., Abate, F., Schiano, E., Paparella, F., Ferrara, F., Vanoli, E., Difruscolo, R., Goffredo, V. M., Amato, B., Setacci, C., et al. (2025) · Metabolites · doi:10.3390/metabo15040220 · Cited by 88 · see citing works
The roles of trimethylamine-N-oxide in atherosclerosis and its potential therapeutic aspect: A literature review
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The role and mechanism of gut-lung axis mediated bidirectional communication in the occurrence and development of chronic obstructive pulmonary disease
Song, X., Dou, X., Chang, J., Zeng, X., Xu, Q., & Xu, C. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2414805 · Cited by 83 · see citing works
Role of the Microbiome in Gut-Heart-Kidney Cross Talk
Glorieux, G., Nigám, S. K., Vanholder, R. C., & Verbeke, F. (2023) · Circulation Research · doi:10.1161/circresaha.123.321763 · Cited by 75 · see citing works
Gut microbiota-associated metabolite trimethylamine N-oxide and the risk of stroke: a systematic review and dose-response meta-analysis
Farhangi, M. A., Vajdi, M., & Asghari-Jafarabadi, M. (2020) · Nutrition Journal · doi:10.1186/s12937-020-00592-2 · Cited by 72 · see citing works
The Microbial Metabolite Trimethylamine N-Oxide Links Vascular Dysfunctions and the Autoimmune Disease Rheumatoid Arthritis
Chan, M. M.-Y., Yang, X., Wang, H., Saaoud, F., Sun, Y., & Fong, D. (2019) · Nutrients · doi:10.3390/nu11081821 · Cited by 68 · see citing works
Implications of trimethylamine N-oxide (TMAO) and Betaine in Human Health: Beyond Being Osmoprotective Compounds
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Genetic Deficiency of Flavin-Containing Monooxygenase 3 ( Fmo3 ) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels—Brief Report
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Blood–brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins
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MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway
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Uremic Toxins and Cardiovascular Risk in Chronic Kidney Disease: What Have We Learned Recently beyond the Past Findings?
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Novel findings of the association between gut microbiota–derived metabolite trimethylamine N-oxide and inflammation: results from a systematic review and dose-response meta-analysis
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The role of trimethylamine‐N‐Oxide in the development of Alzheimer's disease
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The dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison
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TMA/TMAO in Hypertension: Novel Horizons and Potential Therapies
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Inflammatory Mediators in Atherosclerotic Vascular Remodeling
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Association of moderately elevated trimethylamine N-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance
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Dynamic Changes and Prognostic Value of Gut Microbiota-Dependent Trimethylamine-N-Oxide in Acute Ischemic Stroke
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Targeting NLRP3 Inflammasome in the Treatment Of Diabetes and Diabetic Complications: Role of Natural Compounds from Herbal Medicine
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Salvianolic Acid B Suppresses ER Stress‐Induced NLRP3 Inflammasome and Pyroptosis via the AMPK/FoxO4 and Syndecan‐4/Rac1 Signaling Pathways in Human Endothelial Progenitor Cells
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Gut microbial metabolites in Parkinson's disease: Association with lifestyle, disease characteristics, and treatment status
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Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways
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The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis
Wang, Z., Hazen, J. E., Jia, X., Org, E., Zhao, Y., Osborn, L. J., Nimer, N. A., Buffa, J. A., Culley, M. K., Krajcik, D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413477 · Cited by 52 · see citing works
Gut microbiota-derived trimethylamine N-oxide is associated with the risk of all-cause and cardiovascular mortality in patients with chronic kidney disease: a systematic review and dose-response meta-analysis
Li, Y., Lü, H., Guo, J., Zhang, M., Zheng, H., Liu, Y., & Liu, W. (2023) · Annals of Medicine · doi:10.1080/07853890.2023.2215542 · Cited by 53 · see citing works
Prognostic Value of Plasma Trimethylamine N-Oxide Levels in Patients with Acute Ischemic Stroke
Zhai, Q., Wang, X., Chen, C., Tang, Y., Wang, Y., Tian, J., Zhao, Y., & Liu, X. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00714-3 · Cited by 51 · see citing works
Gut microbiota dependant trimethylamine N-oxide and hypertension
Mutengo, K. H., Masenga, S. K., Mweemba, A., Mutale, W., & Kirabo, A. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1075641 · Cited by 52 · see citing works
Antiobesity Effect of Prebiotic Polyphenol-Rich Grape Seed Flour Supplemented with Probiotic Kefir-Derived Lactic Acid Bacteria
Cho, Y.-J., Lee, H. G., Seo, K., YOKOYAMA, W. H., & Kim, H. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b03720 · Cited by 50 · see citing works
The interplay between microbiota‐dependent metabolite trimethylamine N ‐oxide, Transforming growth factor β /SMAD signaling and inflammasome activation in chronic kidney disease patients: A new mechanistic perspective
El‐Deeb, O. S., Atef, M. M., & Hafez, Y. M. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28707 · Cited by 50 · see citing works
Higher Circulating Trimethylamine N-Oxide Aggravates Cognitive Impairment Probably via Downregulating Hippocampal SIRT1 in Vascular Dementia Rats
Deng, Y., Zou, J., Hong, Y., Peng, Q., Fu, X., Duan, R., Chen, J., & Chen, X. (2022) · Cells · doi:10.3390/cells11223650 · Cited by 48 · see citing works
Hawthorn fruit extract reduced trimethylamine-N-oxide (TMAO)-exacerbated atherogenesis in mice via anti-inflammation and anti-oxidation
He, Z., Kwek, E., Hao, W., Zhu, H., Liu, J., Ma, K. Y., & Chen, Z. (2021) · Nutrition & Metabolism · doi:10.1186/s12986-020-00535-y · Cited by 51 · see citing works
Dysbiotic Gut Microbiota-Derived Metabolites and Their Role in Non-Communicable Diseases
Tan, J., Taitz, J., Nanan, R. K. H., Grau, G. E., & Macia, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015256 · Cited by 56 · see citing works
The Association between Plasma Levels of Trimethylamine N-Oxide and the Risk of Coronary Heart Disease in Chinese Patients with or without Type 2 Diabetes Mellitus
Dong, Z., Liang, Z., Guo, M., Hu, S., Shen, Z., & Hai, X. (2018) · Disease Markers · doi:10.1155/2018/1578320 · Cited by 49 · see citing works
Small Molecule Metabolites at the Host–Microbiota Interface
Bishai, J. D., & Palm, N. W. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100528 · Cited by 47 · see citing works
Stroke and Vascular Cognitive Impairment: The Role of Intestinal Microbiota Metabolite TMAO
Tu, R., & Xia, J. (2024) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230203140805 · Cited by 47 · see citing works
Gut microbiota–associated trimethylamine N -oxide and increased cardiometabolic risk in adults: a systematic review and dose-response meta-analysis
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Trimethylamine/Trimethylamine-N-Oxide as a Key Between Diet and Cardiovascular Diseases
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The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders
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Fish Oil Is More Potent than Flaxseed Oil in Modulating Gut Microbiota and Reducing Trimethylamine-N-oxide-Exacerbated Atherogenesis
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Trimethylamine N-oxide: a meta-organismal axis linking the gut and fibrosis
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Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation
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Citrus reticulatae pericarpium Extract Decreases the Susceptibility to HFD-Induced Glycolipid Metabolism Disorder in Mice Exposed to Azithromycin in Early Life
Lu, H., You, Y., Zhou, X., He, Q., Wang, M., Chen, L., Zhou, L., Sun, X., Liu, Y., Jiang, P., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.774433 · Cited by 43 · see citing works
Integrated Analysis Reveals the Gut Microbial Metabolite TMAO Promotes Inflammatory Hepatocellular Carcinoma by Upregulating POSTN
Wu, Y., Rong, X., Pan, M., Wang, T., Yang, H., Chen, X., Xiao, Z., & Zhao, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.840171 · Cited by 42 · see citing works
The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad
Krueger, E. S., Lloyd, T. S., & Tessem, J. S. (2021) · Nutrients · doi:10.3390/nu13082873 · Cited by 40 · see citing works
Advances in the Progression and Prognosis Biomarkers of Chronic Kidney Disease
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Trimethylamine-N-oxide and cerebral stroke risk: A review
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Trimethylamine‐N‐Oxide, an Intestinal Microbial Metabolite Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
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Self-citation

Authors: Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S.
Affiliations: University of Houston (US)
Virginia Commonwealth University (US)
ORCID: Boini, Krishna M.
Hussain, Tahir
Li, Pin-Lan
Venue: Cellular Physiology and Biochemistry
Publisher: S. Karger AG
Published: 2017
Volume: 44
Issue: 1
Pages: 152-162
ISSN: 1015-8987 (ISSN-L)
1421-9778
DOI: 10.1159/000484623
PMC: PMC5828122
OpenAlex: W2767806634
Semantic Scholar: de8ac468d4e798c06de304d9dfc8cf3df3a51462
Cited by: 302
References: 60
Citations by year: 2026: 38 · 2025: 38 · 2024: 38 · 2023: 46 · 2022: 38 · 2021: 39 · 2020: 26 · 2019: 25 · 2018: 13 · 2017: 1
FWCI: 7.26
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
creativecommons.org/licenses/by-nc-nd/4.0/ (tdm)
Locations: Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (R01HL075316, R01HL057244)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104031)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords: trimethylamine N-oxide, NLRP3 inflammasome, endothelial dysfunction, atherosclerosis, caspase-1, IL-1β, endothelial permeability, redox regulation, lysosomal dysfunction, cardiovascular disease, gut microbiota
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Amino Acid Chloromethyl Ketones, Animals, Carotid Arteries, Cells, Cultured, Male, Methylamines, Mice, Inbred C57BL, Microscopy, Fluorescence, Permeability, Signal Transduction, Caspase 1, RNA Interference, RNA, Small Interfering, Endothelial Cells, Mice, Interleukin-1beta, Inflammasomes, Caspase Inhibitors

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Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

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