TMAO {60000064} Record Keys Parent:[ ] Definition:TMAO Queue:[ ] Details Initialisation date:2020-09-23 Specification: trimethylamine-N-oxideSource: [ ] LinksInfolink Meta Information Structural Type:[ ] Functional Type:[ ] Function:Pro-inflammatory, Enhancing Fibrosis, Building cholesterol plaques Notes: - trimethylamine N-oxide (TMAO) is risk indicator for cardiovascular diseases, diabetes mellitus, nonalcoholic fatty liver disease, and other metabolic events. As the end-product of dietary choline and L-carnitine, TMAO is converted from trimethylamine (TMA) in the liver by flavin-containing monooxygenases (FMOs), especially FMO3. - TMAO promotes the release of the inflammatory cytokines IL-1β and IL-18 via activation of the NLRP3 inflammasome from foetal human colon cells in a time- and dose-dependent manner TMAO induces inflammation by activating the ROS-TXNIP-NLRP3 inflammasome, thereby contributing to endothelial dysfunction in human umbilical vein endothelial cells - injection of TMAO was shown to significantly increase inflammatory markers, including cyclooxygenase 2, IL-6, E-selectin, and ICAM1, through the MAPK and NF-κB signalling pathways, which then recruit leukocytes and induce vascular inflammation. - TMAO aggravates triglyceride accumulation and lipogenesis in the livers of high-fat diet-fed mice. -TMAO promotes vascular endothelial cell pyroptosis via ROS production, thus resulting in the development of atherosclerosis Shared Reference Notes [1.1] - Gut microbe-dependent metabolite, produced from degradation of choline and L-carnitine [1.2] - TMAO is asociated with platelet hyperactivity, lipid disorders, and oxidative stress [1.3] - Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD [1.4] [#Alzheimer’s disease] - Patients with MCI and AD also show higher levels of gut microbiota-derived trimethylamine N-oxide (TMAO) in the cerebrospinal fluid. - TMAO correlate with AD biomarkers including pTau, total Tau, and Aβ42. - TMAO treatment reduces cognitive function and aging signs in mice, by ameliorating neuronal senescence and mitochondrial dysfunction. - TMAO and its precursors have inflammatory biomarkers, possibly contributing to AD-related leaky gut. [#Alzheimer’s disease] [#Western-style diet] - The Western diet consists of low-fiber, high-fat, and high-protein foods, where it is common to eat fatty red meats and eggs that are rich in TMA and choline, thus increase TMAO production. [1.5] [#Diabetes Type 2] - TMA and subsequent conversion to TMAO by host FMO3 is related to T2DM pathogenesis and comorbidities. - Mice with selective hepatic insulin resistance have elevated levels of circulating TMAO. - Dietary supplementation with TMAO can exacerbate glucose intolerance in high-fat–fed mice. - High concentrations TMAO directly binds to and activates PERK, a key effector of the unfolded protein response in the liver, promoting hyperglycemia and metabolic dysfunction - TMAO was found to contribute to #Thrombotic events by causing platelet hyperactivity [1.6] [#High Fat Diet] - A high-fat diet is associated with the occurrence of microbes that catabolize choline and the accumulation of trimethylamine N-oxide (TMAO) in the bloodstream, a contributing factor for heart disease. [1.7] - Choline > Elevated plasma levels of the gut microbe-dependent metabolite TMAO > predict incident risk for #CVD development independent of traditional risk factors. [1.8] [#Meat-based diet] - Chronic dietary red meat > increases systemic TMAO levels through: (i) enhanced dietary precursors; (ii) increased microbial TMA/TMAO production from carnitine, but not choline; and (iii) reduced renal TMAO excretion. - Discontinuation of dietary red meat reduces plasma TMAO within 4 weeks. [1.9] [#CVD] [#Fish consumption] - Fish > rich in preformed TMAO > greatest impact on circulating TMAO concentrations; however, fish intake is associated with decreased risk of cardiovascular disease [#Exercise training, #High-protein diet] - protein-supplemented group without exercise > increases in trimethylamine-N-oxide (TMAO) and #Phenylacetylglycine (PAG). - In contrast, the addition of exercise decreases TMAO [#Alzheimer’s disease, #Colorectal cancer] - Serum TMAO levels in AD/CRC patients are higher than those in healthy people, and its concentrations may be positively correlated with AD/cancer progression [1.11] [#Atherosclerosis, #Coronary artery disease] - #Bilophila, a genus of gut microbes, can metabolize #TMA, resulting in lower TMAO, suggesting that differences in #TMA-metabolizing gut bacteria in individuals lead to different ultimate effects, and replacement of relevant bacteria may reduce the risk from TMAO. [#Para-cresol] - TMAO is the hepatic oxidation product of the microbial trimethylamine (#TMA). - dietary supplementation with TMAO was shown to promote atherogenesis and development of #Atherosclerosis in mice. - TMAO levels associate with an increased risk of adverse cardiovascular events. - Carotid #Atherosclerosis was demonstrated to be associated with gut microbial metabolites (especially TMAO and p-cresol sulfate) in >3,000 patients, which could serve as an independent predictor of the disease. - TMAO levels are also associated with #Heart failure and #Coronary artery disease. - TMAO enhances the responsiveness of platelets to multiple agonists, promoting platelet hyperactivity and thus thrombosis and subsequent cardiovascular disease. [1.12] [#Metabolic Dysfunction-associated Steatohepatitis, #Metabolic associated fatty liver disease] [#Lipopolysaccharide, #TMA] - A shift in the metabolic function of intestinal bacteria is predominantly caused by dysbiosis. In the intestine, it leads to an increase in the permeability of intestinal mucosa for LPS and ultimately causes chronic inflammation. Concentration of bacterial metabolites in the blood, such as trimethylamine which is metabolized in the liver to trimethylamine-N-oxide (TMAO) correlates with the severity of #Steatohepatitis [1.13] [#Atherosclerosis, #Hearth attack] [#Carnitine, #Crotonobetaine, #γ-butyrobetaine] [#Meat-based diet] [1.14] [#Atherosclerosis] - Trimethylamine (#TMA) is generated by the gut microbiome and in the host converted by flavin-containing monooxygenase (FMO3) into trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular and metabolic diseases. - Using cell culture systems and patient biopsies > TMAO reprograms skin fibroblasts, vascular endothelial cells, and adipocytic progenitor cells into myofibroblasts via the putative TMAO receptor protein R-like endoplasmic reticulum kinase (PERK). - FMO3 was detected in skin fibroblasts and its expression stimulated by TGF-β1. - FMO3 was elevated in #Systemic sclerosis skin biopsies and in #Systemic sclerosis fibroblasts. [1.15] [#End-stage renal disease] - TMAO is a major risk factor for cardiovascular disease, renal fibrosis and functional impairment, #Atherosclerosis, and #Colorectal cancer. [#Coronary artery disease] - a precursor to TMAO, #trimethyllysine (TML), alone and combined with TAMO, is involved in cardiovascular events for patients with the acute coronary syndrome. [1.16] [#Egg Consumption, #Meat-based diet] - dietary #Choline or L-#Carnitine, which are found in foods such as meat and eggs, are metabolized by the gut microbiota into #TMA in the intestine. - #TMA enters the blood circulation and is transformed into TMAO in the liver. - gut microbe–derived metabolite trimethylamine N-oxide (TMAO), enhanced antitumor immunity to Pancreatic ductal adenocarcinoma (PDAC) - Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. - TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN–dependent manner. - bacteria producing an enzyme that generates #TMA was associated with positive immunotherapy outcomes in people with #Pancreatic Cancer. - #Bacillus and #Paenibacillus species, were present at higher levels in people who survived for a long period of time after #Pancreatic Cancer. [1.17] [#Parkinson’s Disease] - Circulating levels of TMAO, a gut microbiome derived oxidation product of #TMA, are reportedly elevated in PD and correlate with disease progression and severity. Gene families involved in #TMA production were elevated in PD, including cutC (choline lyase) which cleaves choline to produce #TMA , and caiT (L-carnitine/gamma-butyrobetaine antiporter) which exchanges carnitine for gamma-butyrobetaine before #TMA can be produced. [1.18] [#Human gammaherpesvirus 4] - #Tomato > Fruitflow when administered over 4 wk at 2×150 mg Fruitflow per d > Significant changes in relative abundance of microbial taxa with Fruitflow, such as decreases in #Bacteroides, Ruminococccus, and #Hungatella related OTUs, as well as increases in #Alistipes which are all known for the involvement in #TMA/TMAO metabolism. [#CVD] [#Tomato] [#Lipopolysaccharide] - #Tomato > Fruitflow when administered over 4 wk at 2×150 mg Fruitflow per d > significantly reduced fasting plasma and urine TMAO as well as plasma LPS from baseline to the end of intervention. [1.19] [#Alzheimer’s disease] [#Lipopolysaccharide] - methylamine trimethylamine N-oxide (TMAO), enhance BBB integrity by altering expression of annexin A1, a tight junction protein. - TMAO limit LPS-mediated memory impairment by limiting microglial and astrocyte-mediated neuroinflammation. - BBB breakdown is well documented in AD. [#Meat-based diet] - The animal meat-derived metabolites #Carnitine, #Choline, or #Phosphocholine (PC) are degraded by gut bacteria to trimethylamine (#TMA), which is further metabolized in the liver to trimethylamine N-oxide (TMAO) - The microbiota metabolizes phosphatidylcholine, #Choline, and #Carnitine to produce trimethylamine (#TMA), which is further metabolized in the liver to trimethylamine-N-oxide (TMAO). [#Colorectal cancer] - Plasma #Choline and TMAO levels correlate with an increased risk for CRC and serum TMAO levels are significantly increased in CRC patients. [#Serum CRP] - TMAO activates NLRP3 and increases reactive oxygen species formation. - The level of circulating TMAO correlates with that of C-reactive protein, an inflammation indicator. [1.21] [#TMA] - #Hungatella is associated with #Paleolithic diet and is known to produce the precursor molecule for trimethylamine-N-oxide (TMAO). [1.22] [#Atherosclerosis, #CVD] [#Lipopolysaccharide, #TMA] [1.23] - TMAO can reduce the production of #Cholesterol 7α-hydroxylase, thereby reducing the production of #Bile Acids, causing #Cholesterol to accumulate in cells. - At the same time, up-regulating the expression of the vascular cellular adhesion molecule-1 (VCAM-1) can promote monocyte adhesion, activate protein kinase C (PKC) and p-NF-κB, and further lead to the formation of atherosclerotic plaque. - elevation in inflammation-associated monocytes caused by elevated TMAO levels can raise the risk of #Stroke and compromise the severity of #Stroke. [1.24] [#CVD] [#Exercise training, #Western-style diet] - voluntary exercise curbs TMAO elevation and decreases myocardial inflammation and #Fibrosis, leading to the prevention of cardiac dysfunction in western diet-induced #Obesity [1.25] - certain bacteria-related metabolites, such as trimethylamine-N-oxide (TMAO), #5-aminovaleric acid (5-AVA), #5-AVA Betaine (5-AVAB), #Imidazolepropionic acid, and #Hippuric acid have been reported to promote early-life axonogenesis both in vitro and in vivo. [#Blood Brain Barrier Integrity] - physiologically appropriate doses of the oxidized form of trimethylamine, TMAO, improved the BBB integrity. [1.26] - #Choline, #Carnitine and #Betaine present in fish, egg, and red meats are metabolized to TMAO by gut bacteria. - Responsible Bacteria are #Anaerococcus hydrogenalis, #Clostridium asparagiforme, #Clostridium hathewayi, #Clostridium sporogenes, #Escherichia fergusonii, #Proteus penneri, #Providencia rettgeri etc. [#Diabetes Type 2] - Chronic T2DM patients show a markedly high plasma level of TMAO. It increases the risk of cardiovascular disease and mortality among the patients. - TMAO promotes metabolic dysfunction, insulin resistance, adipose tissue inflammation, and hepatic gluconeogenesis. [1.27] - trimethylamine-N-oxide (TMAO) from #Choline metabolism can cross the blood–brain barrier to influence brain pathology and the development of neuropsychiatric disorders. - A positive association between serum TMAO levels and #Depression severity has been reported in individuals. [1.28] - Bacterial enzymes in the gut digest #Choline into trimethylamine, which is then transported to the liver where it undergoes an oxidation step to form trimethylamine N-oxide (TMAO) [1.29] [#Parkinson’s Disease] - plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, are associated with faster increases in levodopa-equivalent dose and tend to increase the risk for PD-#Dementia conversion, and can therefore be considered as a biomarker in early PD [#Pancreatic Cancer] - TMAO is associated with increased risk of several #Cancer types including pancreatic #Cancer. - TMAO induces activation of inflammatory pathways, including the nuclear factor κB (NF-κB) pathway and the thioredoxin-interactive protein (TXNIP)-NLRP3 inflammasome, resulting in increased #Oxidative stress, DNA damage, and release of inflammatory cytokines that may potentiate #Cancer development [#Pancreatic Cancer] - The microbial-related metabolite panel includes indoleacyrlic acid, an #Indole-derivative, and TMAO. - TMAO- and indoleacrylic-acid-producing #Bacteria include those in the phyla of #Bacillota, #Bacteroidota, #Actinomycetota, and Pseudomonadota. - #Bacillota species such as Cs and Er and Bacteriodota species including Bt and Pd have been shown to be increased in fecal samples of patients with PDAC compared with control subjects. - Relative abundances of fecal #Collinsella aeofaciens, a species of #Actinomycetota, is associated with poor prognosis in PDAC. - levels of TMAO in cystic fluid were positively correlated with bacterial clusters corresponding to Enterobacteriacea, #Granulicatella, #Klebsiella, #Stenotrophomonas, #Streptococcus, #Haemophilus, and #Fusobacterium > associated with #Pancreatic Cancer. - TMAO is elevated in pancreatic cystic fluid of individuals presenting with high-risk intraductal papillary mucinous neoplasms or #Pancreatic Cancer compared with those harboring non-cancerous cysts [1.31] - TMAO has been shown to promote the formation of #Atherosclerosis in murine macrophages by upregulating the scavenger receptor (SR), increasing the expression of #Heat shock proteins (HSPs), proinflammatory cytokines, and plasma #Cholesterol levels [#Thrombotic events] - TMAO has a direct effect on platelets, increasing platelet reactivity and thrombosis through altered intracellular calcium signals elicited by a variety of agonists. [1.32] [#Clostridium asparagiforme, #Clostridium citroniae, #Clostridium hathewayi, #Clostridium sporogenes] [#TMA] - #Clostridium sp (C asparagiforme, C citroniae, C hathewayi, and C sporogenes), #Desulfovibrio, and #Enterobacteriaceae (#Escherichia coli and #Acinetobacter sp), can respond to a diet rich in #Choline, an essential nutrient for omnivores, and convert it to trimethylamine, which is then metabolised in the liver to trimethylamine N-oxide, a microbiome derived proatherogenic metabolite. [1.33] [#Preeclamsia] - the methanogenesis pathway mediated by #Methanobrevibacter has been shown to reduce serum TMAO levels, thereby reducing the risk of PE [#Preeclamsia] - Trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, has been found to be significantly enriched in PE patients [1.34] [#Chronic kidney disease] - In CKD patients, the concentrations of microbiota-derived trimethylamine N-oxide (TMAO), indoxyl #Sulfate and p-cresyl #Sulfate in the blood are increased. Because of poor renal function in CKD patients, these #Uremic toxins remain in the circulation, promote inflammation, thereby contributing to progressive kidney injury. [1.35] - The types of samples analyzed for TMAO quantification include plasma or urine. - A key consideration when quantifying TMAO is that levels differ between males and females, with males generally having lower TMAO levels than females [ [1.36] [1.37] [#Chronic kidney disease] - TMAO causes kidney injury and tubulointerstitial #Fibrosis. - Higher TMAO levels associated with higher risk of incident CKD and greater annualized eGFR decline, and with monotonic dose-response relationships. [1.38] [#Anxiety] - Elevated levels of TMAO have been detected in patients with #Autism spectrum disorders and have also been linked to acute stress levels. [#Meat-based diet] - #TMA is synthesized from #Choline found in eggs, red meat or fish and is subsequently transformed in the liver into its active metabolite trimethylamine Noxide (TMAO), which eventually acts as a neuronal protein stabilizer. [1.39] [#Quinolinic acid] [#High Fat Diet] - QA inhibits the increase of #Cholesterol, #TMA, TMAO, CXCL13, TIMP-1 and HMGB1 levels in peripheral blood of Apoe−/− mice induced by HFD, suggesting that QA can effectively inhibit HFD-induced #Atherosclerosis. [#High temperature and humidity] HTH > elevated plasma TMAO, which are transformed from #Choline by specific bacterial genera, and associated with high #Atherosclerosis burden [#Lithocholic acid] - #Lachnoclostridium is described with higher microbial capacity for bile acid conversion through a 7α-dehydratase process38, explained the robust increase in LCA abundance. - #Lachnoclostridium produces trimethylamine (#TMA), which was turned into trimethylamine-N-oxide (TMAO) in liver [1.41] - Elevated TMAO was associated with increased abdominal #Aortic aneurysm (AAA) incidence and growth in both patient cohorts studied. - Dietary #Choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. - Treatment with fluoromethylcholine ablated TMAO production, attenuated #Choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. [1.42] [#Chronic kidney disease] - TMAO was also able to significantly induce #IL-6 release alone from renal fibroblast, strengthening the link to renal #Fibrosis. [#Chronic kidney disease] [#TNF-alfa] - combined exposure of TMAO and TNF-α can increase fibronectin release from renal fibroblasts. - Several studies indicate that TMAO exacerbates tubulointerstitial #Fibrosis and renal inflammation in CKD. - neither TMAO nor TNF-α alone increased fibronectin release from renal fibroblasts. - TMAO and TNF-α alone or in combination increased total collagen production. - the combination of TMAO and TNF-α can increase fibronectin release compared to TNF-α alone. - Fibronectin, a high molecular weight glycoprotein with adhesive properties, holds a pivotal function in both wound-healing processes and the formation of extracellular matrix - TNF-α and TMAO induced increased fibroblast proliferation and that the combination of TNF-α 1 ng/ml and TMAO induced increased cell proliferation compared to TNF-α alone. - both TMAO and TNF-α mediate their proliferative and collagen inducing effects on renal fibroblast via Akt, mTOR and ERK, but not PI3K. [#Chronic kidney disease] - TMAO can reduce megalin expression in proximal tubular cells via PI3K and ERK - TMAO induced increased renal fibroblast proliferation and #Collagen production via Akt and mTOR, but not via PI3K [#CVD] - TMAO has been linked to promote vascular inflammation via ERK activationReferences Notes (2) [1.43]
