Microbiome & Chronic Diseases

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TMAO {60000064}

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Functional Type:[  ]
Pro-inflammatory, Enhancing Fibrosis, Building cholesterol plaques


- 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
    - 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.
  • - 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] [#Non alcoholic steatohepatitis, #Non-alcoholic 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] [#Human 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] [#CVD] [#Bile Acids, #Primary bile acids, #Secondary bile acids, #Short Chain Fatty Acid, #TMA
  • [1.18] [#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.
  • [1.19] [#CVD] [#Tomato
  • [#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.
  • [1.21] [#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.
  • [#Elevated 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.
  • [1.22] [#TMA
    - #Hungatella is associated with #Paleolithic diet and is known to produce the precursor molecule for trimethylamine-N-oxide (TMAO).
  • [1.23] [#Atherosclerosis, #CVD] [#Lipopolysaccharide, #TMA
  • [1.24] [#Cannabidiol
    - CBD decreased the levels of TMAO and PAGln in the plasma
  • [1.25
    - 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.

References Notes

  • (1) [1.26
  • (2) [1.27

Common References