Search Results (10)

Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo^®, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo^®, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas. Full article

Cardiovascular disease (CVD) may be inherited, as recently shown with the identification of single nucleotide polymorphisms (SNPs or “snips”) on a 250 kb DNA fragment that encodes 92 proteins associated with CVD. CVD is also triggered by microbial dysbiosis, microbial metabolites, metabolic disorders, and inflammatory intestinal epithelial cells (IECs). The epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3) peptide keeps the gut wall intact and healthy. Variations in Ep-CAM levels are directly linked to changes in the gut microbiome. Leptin, plasminogen activator inhibitor 1 (PAI1), and alpha-1 acid glycoprotein 1 (AGP1) are associated with obesity and may be used as biomarkers. Although contactin 1 (CNTN1) is also associated with obesity and adiposity, it regulates the bacterial metabolism of tryptophan (Trp) and thus appetite. A decrease in CNTN1 may serve as an early warning of CVD. Short-chain fatty acids (SCFAs) produced by gut microbiota inhibit pro-inflammatory cytokines and damage vascular integrity. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates inflammatory Nod-like receptors (NLRs) such as Nod-like receptor protein 3 (NLRP3), which increase platelet formation. Mutations in the elastin gene (ELN) cause supra valvular aortic stenosis (SVAS), defined as the thickening of the arterial wall. Many of the genes expressed by human cells are regulated by gut microbiota. The identification of new molecular markers is crucial for the prevention of CVD and the development of new therapeutic strategies. This review summarizes the causes of CVD and identifies possible CVD markers. Full article

The human gut microbiota is the community of microorganisms living in the human gut. This microbial ecosystem contains bacteria beneficial to their host and plays important roles in human physiology, participating in energy harvest from indigestible fiber, vitamin synthesis, and regulation of the immune system, among others. Accumulating evidence suggests a possible link between compositional and metabolic aberrations of the gut microbiota and coronary artery disease in humans. Manipulating the gut microbiota through targeted interventions is an emerging field of science, aiming at reducing the risk of disease. Among the interventions with the most promising results are probiotics, prebiotics, synbiotics, and trimethylamine N-oxide (TMAO) inhibitors. Contemporary studies of probiotics have shown an improvement of inflammation and endothelial cell function, paired with attenuated extracellular matrix remodeling and TMAO production. Lactobacilli, Bifidobacteria, and Bacteroides are some of the most well studied probiotics in experimental and clinical settings. Prebiotics may also decrease inflammation and lead to reductions in blood pressure, body weight, and hyperlipidemia. Synbiotics have been associated with an improvement in glucose homeostasis and lipid abnormalities. On the contrary, no evidence yet exists on the possible benefits of postbiotic use, while the use of antibiotics is not warranted, due to potentially deleterious effects. TMAO inhibitors such as 3,3-dimethyl-1-butanol, iodomethylcholine, and fluoromethylcholine, despite still being investigated experimentally, appear to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. Finally, fecal transplantation carries conflicting evidence, mandating the need for further research. In the present review we summarize the links between the gut microbiota and coronary artery disease and elaborate on the varied therapeutic measures that are being explored in this context. Full article

Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100–400 μM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway. Full article

Metabolomic analysis provides a wealth of information that can be predictive of distinctive phenotypes of pathogenic processes and has been applied to better understand disease development. Rheumatoid arthritis (RA) is an autoimmune disease with the establishment of chronic synovial inflammation that affects joints and peripheral tissues such as skeletal muscle and bone. There is a lack of useful disease biomarkers to track disease activity, drug response and follow-up in RA. In this review, we describe potential metabolic biomarkers that might be helpful in the study of RA pathogenesis, drug response and risk of comorbidities. TMAO (choline and trimethylamine oxide) and TCA (tricarboxylic acid) cycle products have been suggested to modulate metabolic profiles during the early stages of RA and are present systemically, which is a relevant characteristic for biomarkers. Moreover, the analysis of lipids such as cholesterol, FFAs and PUFAs may provide important information before disease onset to predict disease activity and treatment response. Regarding therapeutics, TNF inhibitors may increase the levels of tryptophan, valine, lysine, creatinine and alanine, whereas JAK/STAT inhibitors may modulate exclusively fatty acids. These observations indicate that different disease modifying antirheumatic drugs have specific metabolic profiles and can reveal differences between responders and non-responders. In terms of comorbidities, physical impairment represented by higher fatigue scores and muscle wasting has been associated with an increase in urea cycle, FFAs, tocopherols and BCAAs. In conclusion, synovial fluid, blood and urine samples from RA patients seem to provide critical information about the metabolic profile related to drug response, disease activity and comorbidities. Full article

Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). Female BALB/c mice were randomly divided into four groups: untreated control mice, control mice treated with the trimethylamine lyase inhibitor 3,3-dimethyl-1-butanol (DMB), IMQ mice, and IMQ mice treated with DMB. The DMB-treated groups were administered the substance in their drinking water for 8 weeks. Treatment with DMB reduced plasma levels of TMAO in mice with IMQ-induced lupus. DMB prevents the development of hypertension, reduces disease progression (plasma levels of anti-dsDNA autoantibodies, splenomegaly, and proteinuria), reduces polarization of T lymphocytes towards Th17/Th1 in secondary lymph organs, and improves endothelial function in mice with IMQ-induced lupus. The deleterious vascular effects caused by TMAO appear to be associated with an increase in vascular oxidative stress generated by increased NADPH oxidase activity, derived in part from the vascular infiltration of Th17/Th1 lymphocytes, and reduced nrf2-driven antioxidant defense. In conclusion, our findings identified the bacterial-derived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice. Full article

The renal elimination of uremic toxins (UTs) can be potentially altered by drugs that inhibit organic anion transporters 1/3 (OAT1/OAT3). The objective of the present study was to determine whether the prescription of at least one OAT1/OAT3 inhibitor was associated with the plasma accumulation of certain UTs in kidney transplant recipients. We included 403 kidney transplant recipients. For each patient, we recorded all prescription drugs known to inhibit OAT1/OAT3. Plasma levels of four UTs (trimethylamine N-oxide (TMAO), indole acetic acid (IAA), para-cresylsulfate (pCS), and indoxylsulfate (IxS) were assayed using liquid chromatography-tandem mass spectrometry. Plasma UT levels were significantly higher among patients prescribed at least one OAT inhibitor (n = 311) than among patients not prescribed any OAT inhibitors (n = 92). Multivariate analysis revealed that after adjustment for age, estimated glomerular filtration rate (eGFR), plasma level of albumin and time since transplantation, prescription of an OAT1/OAT3 inhibitor was independently associated with the plasma accumulation of pCS (adjusted odds ratio (95% confidence interval): 2.11 (1.26; 3.61]). Our results emphasize the importance of understanding the interactions between drugs and UTs and those involving UT transporters in particular. Full article

Maternal exposure to environmental pollutants affects fetal development, which can result in hypertension in adulthood. Gut microbiota-derived metabolite trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and short chain fatty acids (SCFAs) have been associated with hypertension. We tested a hypothesis that maternal 3,3-Dimethyl-1-butanol (DMB, a TMA inhibitor) therapy prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure-induced hypertension in adult offspring relevant to alterations of gut microbiota-derived metabolites, the mediation of aryl hydrocarbon receptor (AHR) signaling, and the renin-angiotensin system (RAS). Pregnant Sprague-Dawley rats were given weekly oral dose of TCDD 200 ng/kg for four doses (T), 1% DMB in drinking water (D), TCDD + DMB (TD), or vehicle (C) in pregnancy and lactation periods. Male progeny (n = 8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused hypertension in adult male offspring coinciding with reduced α-diversity, increased the Firmicutes to Bacteroidetes ratio, less abundant beneficial bacteria, impaired SCFA receptors’ expression, the activation of AHR signaling, and the aberrant activation of the RAS. Treatment with DMB during pregnancy and lactation rescued hypertension induced by perinatal TCDD exposure. This was accompanied by reshaping gut microbiota, mediating TMA-TMAO metabolic pathway, increasing acetic acid and its receptors, and restoring the AHR and RAS pathway. Our data provide new insights into the therapeutic potential of DMB, a microbiome-based metabolite treatment, for the prevention of hypertension of developmental origins. Full article

Melatonin, a signaling hormone with pleiotropic biofunctions, has shown health benefits. Trimethylamine-N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) are uremic toxins involved in the development of hypertension. TMAO originates from trimethylamine (TMA), a gut microbial product. ADMA is an endogenous nitric oxide (NO) synthase inhibitor. We examined whether melatonin therapy could prevent hypertension and kidney disease by mediating gut microbiota-derived metabolites and the NO pathway using an adenine-induced chronic kidney disease (CKD) young rat model. Six-week-old young Sprague Dawley rats of both sexes were fed a regular diet (C group), a diet supplemented with 0.5% adenine (CKD group), or adenine plus 0.01% melatonin in their drinking water (CKD + M group) for three weeks (N = 8/group). Adenine-fed rats developed renal dysfunction, hypertension, renal hypertrophy and increased uremic toxin levels of TMAO and ADMA. Melatonin therapy prevented hypertension in both sexes and attenuated kidney injury in males. Melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in both sexes. Besides, the protective effects of melatonin were associated with restoration of gut microbiota alterations, including increased α-diversity, and enhancement of the abundance of the phylum Proteobacteria and the genus Roseburia in male rats. Melatonin therapy also partially prevented the increases in ADMA in male CKD rats. Melatonin sex-specifically protected young rats against hypertension and kidney injury induced by CKD. The results of this study contribute toward a greater understanding of the interaction between melatonin, gut microbiota-derived metabolites, and the NO pathway that is behind CKD, which will help to prevent CKD-related disorders in children. Full article

Choline is metabolized by the gut microbiota into trimethylamine (TMA), the precursor of pro-atherosclerotic molecule trimethylamine N-oxide (TMAO). A reduction in TMA formation has shown cardioprotective effects, and some phytochemicals may reduce TMA formation. This study aimed to develop an optimized, high-throughput anaerobic fermentation methodology to study the inhibition of choline microbial metabolism into TMA by phenolic compounds with healthy human fecal starter. Optimal fermentation conditions were: 20% fecal slurry (1:10 in PBS), 100 µM choline, and 12 h fermentation. Additionally, 10 mM of 3,3-dimethyl-1-butanol (DMB) was defined as a positive TMA production inhibitor, achieving a ~50% reduction in TMA production. Gallic acid and chlorogenic acid reported higher TMA inhibitory potential (maximum of 80–90% TMA production inhibition), with IC₅₀ around 5 mM. Neither DMB nor gallic acid or chlorogenic acid reduced TMA production through cytotoxic effects, indicating mechanisms such as altered TMA-lyase activity or expression. Full article