Gut Microbiota-derived Metabolite Trimethylamine N-oxide Research Articles

Gut microbiota-derived metabolite trimethylamine N-oxide aggravates cognitive dysfunction induced by femoral fracture operation in mice.

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N-oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO-induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ-free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO-related POCD and improving the quality of life for elderly patients.

Trimethyllysine, trimethylamine N-oxide, and long-term risk of stroke: the western norway coronary angiography cohort

Abstract Background Trimethyllysine (TML) is a precursor of the gut-microbiota derived metabolite trimethylamine N-oxide (TMAO), and both biomarkers are associated with adverse cardiovascular outcomes. Whether circulating levels of TML or TMAO predict long-term risk of stroke is uncertain. Purpose To examine prospective associations of plasma TML and TMAO with long-term risk of total and ischemic stroke. Methods By Cox regression analyses, risk-associations were examined among 4132 patients undergoing elective coronary angiography for suspected stable coronary heart disease. Endpoints were obtained from the Cardiovascular Disease in Norway project. Results Median levels of TML and TMAO were 0.67 and 5.7 µmol/L, respectively. Median age was 62 years and 28.1% of the participants were female. During a median follow up of 7.4 years, 240 (5.8%) patients experienced a stroke, of which 193 were ischemic strokes. After multivariable adjustments for cardiovascular risk factors, the hazard ratios (95% confidence intervals) per 1 standard deviation increase in log-transformed plasma TML were 1.05 (0.92-1.19, p=0.49) for total stroke and 0.99 (0.86-1.15, p=0.92) for ischemic stroke. Corresponding risk estimates were 0.99 (0.86-1.13, p=0.83) and 0.95 (0.82-1.12, p=0.55) per 1 standard deviation increase in log-transformed plasma TMAO. Conclusion In this large prospective cohort of patients with suspected coronary heart disease, neither plasma TML nor plasma TMAO predicted long-term (∼7 years) risk of stroke.

Gut microbiota-derived metabolite trimethylamine N-oxide and biomarkers of inflammation are linked to endothelial and coronary microvascular function in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD), which is an umbrella term used for ulcerative colitis (UC) and Crohn's disease (CD), is associated with an increased risk for atherosclerotic cardiovascular disease (CVD). We aimed to investigate the association of local and systemic biomarkers of inflammation and gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) with endothelial and coronary microvascular dysfunction in IBD. A total of 56 patients with IBD (20 with UC and 36 with CD) and 34 age and gender matched controls were included. For all participants, samples were collected to analyze faecal calprotectin, and TMAO concentrations. Ultrasound-based examinations were done to measure flow-mediated vasodilatation (FMD) and coronary flow velocity reserve (CFVR). Patients with IBD had lower CFVR (2.07 (1.82-2.40)) and FMD (8.7±3.7) as compared to controls (2.30 (2.07-2.74), p=0.005 and 11.9±6.8, p=0.03). In patients with IBD, TMAO concentration (r=-0.30, p=0.03), C-reactive protein (r=-0.29, p=0.03) and WBC count (r=-0.37, p=0.006) had a significant negative correlation with CFVR, and TMAO (β=-0.27, 95% CI: -0.23 to -0.02) and WBC count (β=-0.31, 95% CI: -0.56 to -0.06) were significant predictors of CFVR after multivariate adjustment. None of the biomarkers of inflammation or TMAO showed significant correlations with FMD. In patients with UC, TMAO showed a significant correlation with both CFVR (r=-0.55, p=0.01) and FMD (r=-0.60, p=0.005) while only WBC count had a statistically significant correlation with CFVR (r=-0.49, p=0.004) in patients with CD. Gut microbiota-derived metabolite TMAO and biomarkers of systemic inflammation are associated with measures of endothelial/coronary microvascular dysfunction in patients with IBD.

Effect of traditional Chinese medicine in attenuating chronic kidney disease and its complications by regulating gut microbiota-derived metabolite trimethylamine N-oxide: a review

Trimethylamine N-oxide(TMAO), a metabolite of gut microbiota, is closely associated with chronic kidney disease(CKD). It can aggravate the kidney injury and promote the occurrence of complications of CKD mainly by inducing renal fibroblast activation, vascular endothelial inflammation, macrophage foaming, platelet hyperreactivity, and inhibition of reverse cholesterol transport. Thus it is of great significance for clinical treatment of CKD to regulate circulating TMAO and alleviate its induced body damage. Currently, therapeutic strategies for TMAO regulation include dietary structure adjustment, lifestyle intervention, intestinal microflora regulation, and inhibition of intestinal trimethylamine synthesis and liver trimethylamine oxidation. Chinese medicinal herbs have the clinical advantage of multi-component and multi-target effects, and application of traditional Chinese medicine(TCM) to synergistically regulating TMAO and improving CKD via multiple pathways has broad prospects. This study systematically reviewed the clinical relevance and mechanism of TMAO in aggravating CKD renal function deterioration and complication progression. In addition, the effect and mechanism of TCM in improving TMAO-induced kidney injury, cardiovascular disease, hyperlipidemia, thrombosis and osteoporosis were summarized. The results provided a theoretical basis for TCM in attenuating gut microbiota-derived metabolite TMAO and improving CKD, as well as a basis and direction for in-depth clinical development and mechanism research in the future.

Divergent Effects of Glycemic Control and Bariatric Surgery on Circulating Concentrations of TMAO in Newly Diagnosed T2D Patients and Morbidly Obese.

High circulating concentrations of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are significantly associated with the risk of obesity and type 2 diabetes (T2D). We aimed at evaluating the impact of glycemic control and bariatric surgery on circulating concentrations of TMAO and its microbiota-dependent intermediate, γ-butyrobetaine (γBB), in newly diagnosed T2D patients and morbidly obese subjects following a within-subject design. Based on HbA1c concentrations, T2D patients achieved glycemic control. However, the plasma TMAO and γBB concentrations were significantly increased, without changes in estimated glomerular filtration rate. Bariatric surgery was very effective in reducing weight in obese subjects. Nevertheless, the surgery reduced plasma γBB concentrations without affecting TMAO concentrations and the estimated glomerular filtration rate. Considering these results, an additional experiment was carried out in male C57BL/6J mice fed a Western-type diet for twelve weeks. Neither diet-induced obesity nor insulin resistance were associated with circulating TMAO and γBB concentrations in these genetically defined mice strains. Our findings do not support that glycemic control or bariatric surgery improve the circulating concentrations of TMAO in newly diagnosed T2D and morbidly obese patients.

Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain. Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults. Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study. 5019U.S. adults aged ≥65years. Plasma TMAO. Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n=1400). Six hundred sixty-six incident hip fractures occurred during up to 26years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42g/cm2*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P<0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI≥25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight. Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

Oxidative Status in Adult Anorexia Nervosa Patients and Healthy Controls-Results from a Cross-Sectional Pilot Study.

Oxidative stress describes an imbalance of reactive oxygen species (ROS) and antioxidative defence systems. Recently, the consequences of oxidative stress have become a central field of research and have been linked to the genesis of multiple psychiatric diseases. Some oxidative stress parameters have not been investigated before in anorexia nervosa (AN) patients, including the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and polyphenols (PPm). In this cross-sectional pilot study, we evaluated these markers together with total peroxides (TOC), antioxidative capacity (TAC), endogenous peroxidase activity (EPA) and antibodies against oxidized LDL (oLAb) in serum samples of 20 patients with AN compared to 20 healthy controls. The antioxidative capacity was significantly decreased in AN patients, with a mean TAC of 1.57 mmol/L (SD: ±0.62); t (34) = −2.181, p = 0.036) compared to HC (mean = 1.91 mmol/L (SD: ±0.56), while the other investigated parameters were not significantly different between the two groups. In AN patients, TAC correlated with EPA (rsp = −0.630, p = 0.009). This study suggests that there is an antioxidative deficiency in AN patients. In this respect, there is a demand for interventional studies to determine whether antioxidants can be used as add-on therapy in the treatment of AN.

Gut microbiota-derived metabolite trimethylamine N-oxide as a biomarker in early Parkinson's disease

Abstract Objectives This study aimed to investigate the potential of using changes in the plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, as a biomarker in early Parkinson's disease (PD). Methods Plasma TMAO levels were measured in 85 patients with drug-naive early stage PD and 20 healthy controls. A linear mixed model was used to assess longitudinal changes in levodopa-equivalent dose (LED) during follow-up (>2 y) in three tertile PD groups according to plasma TMAO levels. Additionally, a Cox regression analysis was performed to assess the effect of plasma TMAO levels on dementia conversion. Results Plasma TMAO levels of patients with PD were lower than those of healthy controls. A linear mixed model demonstrated that patients with PD and lower levels of TMAO ( Conclusions The results demonstrate that lower baseline plasma TMAO levels are associated with faster increases in LED and tend to increase the risk for PD–dementia conversion, suggesting the prognostic implications of TMAO in early stage PD.

Gut microbiota-dependent trimethylamine N-oxide and all-cause mortality: Findings from an updated systematic review and meta-analysis.

The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has been regarded as one of the potent risk factors for cardiovascular events and diabetes. In the current meta-analysis we quantitatively summarized and updated the results of studies regarding the association between TMAO and mortality. A systematic search was performed from PubMed, ProQuest, Scopus, and Embase. All of the studies that evaluated the association between TMAO and mortality were included in the systematic review and meta-analysis. Subgroup analysis and meta-regression were performed to identify the source of heterogeneity. There were 31 230 participants included and the results showed that being in the highest category of TMAO increased the hazard ratio (HR) of mortality by 47%. Moreover, there was a non-linear association between increased TMAO concentrations and HR of mortality. In the current dose-response meta-analysis, we revealed a positive association between TMAO and mortality risk among an adult population.

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose-response meta- analysis.

It has been suggested that trimethylamine N-oxide (TMAO) is associated with increased risk of diabetes and cardiovascular disease (CVD) morbidity and mortality. However, it is not known whether increased TMAO concentrations is associated with obesity. In the current study, we summarized the evidence related to the association of circulating TMAO with the risk of obesity measurements, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in a two-class and dose-response meta-analysis of observational studies. A systematic search carried out in PubMed, SCOPUS, Cochrane, and ProQuest through September 30, 2019 resulted in 12 eligible studies which were included in the current meta-synthesis. In these studies, BMI was reported but there were no reports of WC or WHR. Meta-analysis of two-class variables and dose-response meta-analysis of continuous variables were performed. Subgroup analysis and meta-regression were also performed to identify the source of heterogeneity. There was a dose-response association between circulating TMAO concentration and increased BMI in studies involving healthy individuals (P nonlinearity = .007), while no evidence of departure from linearity was observed according to study design or among patients with CVD. Results showed the highest category of TMAO was associated with 0.56 kg/m2 increase in BMI (weighted mean difference [WMD], 0.563; CI, 0.026-1.100; P = .04). The results of the current meta-analysis revealed a positive association between circulating TMAO and obesity as presented by increased BMI. Moreover, a dose-dependent association between circulating TMAO and obesity was also identified in apparently healthy individuals. This is the first meta-analysis to reveal positive dose-dependent associations between circulating TMAO concentration and obesity.

The Presence of High Levels of Circulating Trimethylamine N-Oxide Exacerbates Central and Peripheral Inflammation and Inflammatory Hyperalgesia in Rats Following Carrageenan Injection.

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote inflammation in peripheral tissues and the central nervous system (CNS), contributing to the pathogenesis of various human diseases. Here, we examined whether the presence of high levels of circulating TMAO would influence central and peripheral inflammation and inflammatory hyperalgesia in a carrageenan (CG)-induced rat model of inflammation. Rats were treated with vehicle or TMAO in drinking water. After 2weeks of treatment, rats received intraplantar injection of saline or CG into the hind paw. Acute nociception was unaltered in TMAO-treated rats that had elevated plasma TMAO. Following CG injection, TMAO-treated rats were significantly more sensitive to thermal and mechanical stimulation of the inflamed paw and displayed greater paw edema. Molecular studies revealed that CG injection induced increases in recruitment of neutrophils/macrophages in the paw and activation of microglia in the spinal cord, along with increased activation of nuclear factor (NF)-kB and production of proinflammatory mediators in both vehicle-treated rats and TMAO-treated rats. However, the increases in the above parameters were more pronounced in TMAO-treated rats. Moreover, TMAO treatment decreased protein levels of anti-inflammatory mediator regulator of G protein signaling (RGS)-10 in both saline-injected rats and CG-injected rats. These findings suggest that the presence of high levels of circulating TMAO downregulates anti-inflammatory mediator RGS10 in both peripheral tissues and the CNS, which may increase the susceptibility to inflammatory challenge-induced NF-kB activity, leading to greater increase in production of inflammatory mediators and consequent exacerbation of peripheral inflammation and inflammatory hyperalgesia.

Higher Circulating Trimethylamine N-oxide Sensitizes Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Probably by Downregulating Hippocampal Methionine Sulfoxide Reductase A.

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote oxidative stress and inflammation in the peripheral tissues, contributing to the pathogenesis of many diseases. Here we examined whether pre-existing higher circulating TMAO would influence cognitive function in aged rats after anesthetic sevoflurane exposure. Aged rats received vehicle or TMAO treatment for 3weeks. After 2weeks of treatment, these animals were exposed to either control or 2.6% sevoflurane for 4h. Oneweek after exposure, freezing as measured by fear conditioning test, microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent reactive oxygen species (ROS) production in the hippocampus (a key brain structure involved in learning and memory) were comparable between vehicle-treated rats exposed to control and vehicle-treated rats exposed to sevoflurane. TMAO treatment, which increased plasma TMAO before and 1week after control or sevoflurane exposure, significantly reduced freezing to contextual fear conditioning, which was associated with increases in microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent ROS production in the hippocampus in rats exposed to sevoflurane but not in rats exposed to control. Moreover, hippocampal expression of antioxidant enzyme methionine sulfoxide reductase A (MsrA) was reduced by TMAO treatment in both groups, and TMAO-induced reduction in MsrA expression was negatively correlated with increased proinflammatory cytokine expression in rats exposed to SEV. These findings suggest that pre-existing higher circulating TMAO downregulates antioxidant enzyme MsrA in the hippocampus, which may sensitize the hippocampus to oxidative stress, resulting in microglia-mediated neuroinflammation and cognitive impairment in aged rats after sevoflurane exposure.

Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes.

Trimethyllysine (TML) serves as a nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and is associated with incident cardiovascular (CV) events in stable subjects. We examined the relationship between plasma TML levels and incident CV events in patients presenting with acute coronary syndromes (ACS). Plasma levels of TML were quantified in two independent cohorts using mass spectrometry, and its relationship with CV events was investigated. In a Cleveland Cohort (N = 530), comprised of patients presenting to the emergency department with chest pain and suspected ACS, TML was associated with major adverse cardiac events (MACE, myocardial infarction, stroke, need for revascularization, or all-cause mortality) over both 30 days [3rd tertile (T3), adjusted odds ratio (OR) 1.77, 95% confidence interval (CI) 1.04-3.01; P < 0.05] and 6 months (T3, adjusted OR 1.95, 95% CI 1.15-3.32; P < 0.05) of follow-up independent of traditional CV risk factors and indices of renal function. Elevated TML levels were also associated with incident long-term (7-year) all-cause mortality [T3, adjusted hazard ratio (HR) 2.52, 95% CI 1.50-4.24; P < 0.001], and MACE even amongst patients persistently negative for cardiac Troponin T at presentation (e.g. 30-day MACE, T3, adjusted OR 4.49, 95% CI 2.06-9.79; P < 0.001). Trimethyllysine in combination with TMAO showed additive significance for near- and long-term CV events, including patients with 'negative' high-sensitivity Troponin T levels. In a multicentre Swiss Cohort (N = 1683) comprised of ACS patients, similar associations between TML and incident 1-year adverse cardiac risks were observed (e.g. mortality, adjusted T3 HR 2.74, 95% CI 1.28-5.85; P < 0.05; and MACE, adjusted T3 HR 1.55, 95% CI 1.04-2.31; P < 0.05). Plasma TML levels, alone and together with TMAO, are associated with both near- and long-term CV events in patients with chest pain and ACS.

The presence of elevated circulating trimethylamine N-oxide exaggerates postoperative cognitive dysfunction in aged rats

Surgical trauma can cause brain oxidative stress and neuroinflammation, leading to postoperative cognitive dysfunction (POCD), especially in the elderly. Additionally, the pre-existing risk factors may enhance POCD. Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to contribute to the pathogenesis of many diseases by increasing oxidative stress and inflammation in the peripheral tissues. Here we examined whether the presence of elevated circulating TMAO would influence surgery-induced cognitive decline. Aged rats were treated with vehicle or TMAO for 3 weeks. After two weeks of treatment, these rats underwent sham-operation or laparotomy. One week after surgery, rats underwent laparotomy exhibited hippocampal-dependent cognitive dysfunction as evidenced by reduced contextual freezing time, which was associated with elevated plasma proinflammatory cytokine levels, increased microglia-mediated neuroinflammation and reactive oxygen species (ROS) production in the hippocampus. Treatment with TMAO, which elevated plasma TMAO before and 1 week after surgery, further increased microglia-mediated neuroinflammation and ROS production in the hippocampus, resulting in exaggerated cognitive dysfunction in laparotomy group but not in sham-operation group. Moreover, TMAO treatment decreased expression of antioxidant enzyme methionine sulfoxide reductase (Msr) A in both groups. The results suggest that the presence of elevated circulating TMAO downregulates antioxidant enzyme MsrA in the hippocampus, which may increase the susceptibility to surgery-induced oxidative stress, contributing to exaggerations of neuroinflammation and cognitive decline in aged rats following surgery. Interventions to reduce circulating TMAO in the perioperative period may be a novel strategy to prevent the exaggeration of cognitive decline in elderly patients with high circulating TMAO.

The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer\u2019s disease

BackgroundTrimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease.MethodsIn this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer’s clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein).ResultsCSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein).ConclusionsThese findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut–brain axis.