High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide.
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ABSTRACT:
SUBMITTER: Yoo W
PROVIDER: S-EPMC8506909 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Trimethylamine N-oxide (TMAO), a metabolite derived from the gut microbiota, is proatherogenic and associated with cardiovascular events. However, the change in TMAO with secondary prevention therapies for ST-segment elevation acute myocardial infarction (STEMI) remains unclear. The purpose of this study was to investigate the sequential change in TMAO levels in response to the current secondary prevention therapies in patients with STEMI and the clinical impact of TMAO levels on cardiovascular events We included 112 STEMI patients and measured plasma TMAO levels at the onset of STEMI and 10 months later (chronic phase). After the chronic-phase assessment, patients were followed up for cardiovascular events. Plasma TMAO levels significantly increased from the acute phase to the chronic phase of STEMI (median: 5.63 to 6.76 μM, P = 0.048). During a median period of 5.4 years, 17 patients experienced events. The chronic-phase TMAO level independently predicted future cardiovascular events (adjusted hazard ratio for 0.1 increase in log chronic-phase TMAO level: 1.343, 95% confidence interval 1.122-1.636, P = 0.001), but the acute-phase TMAO level did not. This study demonstrated the clinical importance of the chronic-phase TMAO levels on future cardiovascular events in patients after STEMI.
| S-EPMC6690996 | biostudies-literature
Project description:Unhealthy diet especially high-fat diet (HFD) is the major cause of hyperlipidemia leading to deterioration of chronic kidney diseases (CKD) in patients. Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin. Our previous clinical study demonstrated that the elevation of TMAO was positively correlated with CKD progression. Finasteride, a competitive and specific inhibitor of type II 5a-reductase, has been reported recently to be able to downregulate plasma TMAO level thus preventing the onset of atherosclerosis by our research group. In this study, we established a protein-overload nephropathy CKD mouse model by bovine serum albumin (BSA) injection to investigate whether hyperlipidemia could accelerate CKD progression and the underlying mechanisms. Finasteride was administrated to explore its potential therapeutic effects. The results of biochemical analyses and pathological examination showed that HFD-induced hyperlipidemia led to aggravated protein-overload nephropathy in mice along with an elevated level of circulating TMAO, which can be alleviated by finasteride treatment possibly through inhibition of Fmo3 in liver. The 16 S rRNA sequencing results indicated that HFD feeding altered the composition and distribution of gut microbiota in CKD mice contributing to the enhanced level of TMAO precursor TMA, while finasteride could exert beneficial effects via promoting the abundance of Alistipes_senegalensis and Akkermansia_muciniphila. Immunofluorescence staining (IF) and qRT-PCR results demonstrated the disruption of intestinal barrier by decreased expression of tight junction proteins including Claudin-1 and Zo-1 in HFD-fed CKD mice, which can be rescued by finasteride treatment. Cytokine arrays and redox status analyses revealed an upregulated inflammatory level and oxidative stress after HFD feeding in CKO mice, and finasteride-treatment could alleviate these lesions. To summarize, our study suggested that finasteride could alleviate HFD-associated deterioration of protein-overload nephropathy in mice by inhibition of TMAO synthesis and regulation of gut microbiota.
| S-EPMC9420981 | biostudies-literature
Project description:BACKGROUND:Trimethylamine 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. METHODS:In 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 ?4 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). RESULTS:CSF 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/A?42) and neuronal degeneration (total tau and neurofilament light chain protein). CONCLUSIONS:These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.
| S-EPMC6303862 | biostudies-other
Project description:IntroductionThe relationship between baseline trimethylamine N-oxide (TMAO) levels and stroke outcomes remains unclear. Therefore, this systematic review aimed to summarize the existing relevant research.MethodsWe searched for studies on the association between baseline plasma levels of TMAO and stroke outcomes in the PubMed, EMBASE, Web of Science, and Scopus databases from their inception to 12 October 2022. Two researchers independently reviewed the studies for inclusion and extracted the relevant data.ResultsSeven studies were included in the qualitative analysis. Among them, six studies reported the outcome of acute ischemic stroke (AIS) and one study of intracerebral hemorrhage (ICH), respectively. Furthermore, no study reported the outcome of subarachnoid hemorrhage. Among patients with AIS, high baseline TMAO levels were associated with unfavorable functional outcomes or mortality at 3 months, as well as a high hazard ratio of mortality, recurrence, or major adverse cardiac event. Moreover, TMAO levels showed predictive utility for unfavorable functional outcomes or mortality at 3 months. Among patients with ICH, high TMAO levels were associated with unfavorable functional outcomes at 3 months, regardless of whether the TMAO value was considered a continuous or a categorical variable.ConclusionLimited evidence indicates that high baseline plasma levels of TMAO may be associated with poor stroke outcomes. Further studies are warranted to confirm the relationship between TMAO and stroke outcomes.
| S-EPMC10272813 | biostudies-literature
Project description:Trimethylamine N-oxide (TMAO), a microbiota-derived metabolite has been implicated in human health and disease. Its early detection in body fluids has been presumed to be significant in understanding the pathogenesis and treatment of many diseases. Hence, the development of reliable and rapid technologies for TMAO detection may augment our understanding of pathogenesis and diagnosis of diseases that TMAO has implicated. The present work is the first report on the development of a molecularly imprinted polymer (MIP) based electrochemical sensor for sensitive and selective detection of TMAO in body fluids. The MIP developed was based on the polypyrrole (PPy), which was synthesized via chemical oxidation polymerization method, with and without the presence of TMAO. The MIP, NIP and the non-sonicated polymer (PPy-TMAO) were separately deposited electrophoretically onto the hydrolyzed indium tin oxide (ITO) coated glasses. The chemical, morphological, and electrochemical behavior of MIP, non-imprinted polymer (NIP), and PPy-TMAO were characterized using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and electrochemical techniques. The detection response was recorded using differential pulse voltammetry (DPV), which revealed a decrease in the peak current with the increase in concentration of TMAO. The MIP sensor showed a dynamic detection range of 1-15 ppm with a sensitivity of 2.47 µA mL ppm-1 cm-2. The developed sensor is easy to construct and operate and is also highly selective to detect TMAO in body fluids such as urine. The present research provides a basis for innovative strategies to develop sensors based on MIP to detect other metabolites derived from gut microbiota that are implicated in human health and diseases.
| S-EPMC7809026 | biostudies-literature
Project description:Pre-eclampsia (PE) is the most common complication of pregnancy and seriously threatens the health and safety of the mother and child. Studies have shown that an imbalance in gut microbiota can affect the progression of PE. Trimethylamine N-oxide (TMAO) is an intestinal microbiota-derived metabolite that is thought to be involved in the occurrence of PE; however, its causal relationship and mechanism remain unclear. In this clinical cohort study, including 28 patients with eclampsia and 39 matched healthy controls, fecal samples were collected for 16S rRNA gene sequencing, and serum was collected for targeted metabolomics research. The results showed that the level of TMAO and the abundance of its source bacteria had significantly increased in patients with PE, and were positively correlated with the clinical progression of PE. Fecal microbiota transplantation (FMT) was applied to an antibiotic-depleted-treated mouse model and targeted inhibition of TMAO. The results of the FMT experiment revealed that mice that received fecal microbiota transplantation from patients with PE developed typical PE symptoms and increased oxidative stress and inflammatory damage, both of which were reversed by 3,3-Dimethyl-1-butanol (DMB), a TMAO inhibitor, which also improved pregnancy outcomes in the model mice. Similar results were obtained in the classical NG-Nitroarginine methyl ester (L-NAME) induced PE mouse model. Mechanistically, TMAO promotes the progression of PE by regulating inflammatory and oxidative stress-related signaling pathways, affecting the migration and angiogenesis of vascular endothelial cells, as well as the migration and invasion of trophoblast cells. Our results reveal the role and mechanism of gut microbiota and TMAO in the progression of PE, provides new ideas for exploring the pathogenesis and therapeutic targets of PE, and determines the potential application value of TMAO as a target for PE intervention.
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Project description:Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA) is an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.
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Project description:Changes in gut microbiota (GM) are closely associated with metabolic syndrome, obesity, type 2 diabetes and so on. Several medicinal herbs, including Ephedra sinica (Es), have anti-obesity effects that ameliorate metabolic disorders. Therefore, in this study we evaluated whether Es maintains its anti-obesity effect through Es-altered gut microbiota (EsM) transplantation. GM was isolated from cecal contents of Es treated and untreated rats following repeated transplants into obese rats via oral gavage over three weeks. High-fat-diet (HFD)-induced obese rats transplanted with EsM lost significant body weight, epididymal fat, and perirenal fat weight, but no remarkable changes were observed in abdominal fat, liver, cecum weight and food efficiency ratio. In addition, treatment with EsM also significantly lowered the fasting blood glucose, serum insulin level, and insulin resistance index. Meanwhile, EsM transplantation significantly reduced gene expression of proinflammatory cytokines interleukin-1 and monocyte chemotactic protein-1. Rats treated with EsM also showed changed GM composition, especially blautia, roseburia and clostridium, significantly reduced the level of endotoxin and markedly increased the acetic acid in feces. Overall, our results demonstrated that EsM ameliorates HFD-induced obesity and related metabolic disorders, like hyperglycemia and insulin resistance, and is strongly associated with modulating the distribution of GM, enterogenous endotoxin and enteral acetic acid.
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Project description:Graphene oxide (GO) suspensions can act as a good dispersant and drug delivery system for effective dispersion and drug sustained release. In this study, we investigated the impact of GO on blood/liver lipids and gut microbiota structure in high-fat diet (HFD)-induced hyperlipidemic mice. Oral administration of GO for 28 days remarkably decreased the lipid levels in blood and liver. GO did not decrease the total number of gut bacteria but increased the relative abundance of short-chain fatty acid (SCFA)-producing bacteria such as Clostridium clusters IV and Allobaculum spp. GO also enhanced the copying of bacterial butyryl coenzyme A transferase (BcoA), a key butyrate-producing gene. Although further pharmacological studies are still needed, these results provided an interesting hint that GO may exert beneficial effects on the host's metabolism via selective modulation of SCFA-producing gut microbes.
| S-EPMC9085910 | biostudies-literature
Project description:Elevated circulating trimethylamine N-oxide (TMAO) concentrations have been observed in patients with chronic kidney disease (CKD). We aimed to systematically estimate and quantify the association between TMAO concentrations and kidney function. The PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science databases were systematically searched from 1995 to 1 June, 2020, for clinical studies on circulating TMAO concentrations and kidney function indicators. We used R software to conduct meta-analyses of the extracted data. A cumulative meta-analysis was applied to test whether health status affected the pooled effect value. Meta-regression and subgroup analyses were performed to identify possible sources of heterogeneity. Ultimately, we included a total of 32 eligible clinical studies involving 42,062 participants. In meta-analyses of continuous-outcome variables, advanced CKD was associated with a 67.9 μmol/L (95% CI: 52.7, 83.2; P < 0.01) increase in TMAO concentration, and subjects with high concentrations of TMAO had a 12.9 mL/(min·1.73 m2) (95% CI: -16.6, -9.14; P < 0.01) decrease in glomerular filtration rate (GFR). In meta-analyses of the correlations, TMAO was strongly inversely correlated with GFR [Fisher's z-transformed correlation coefficient (ZCOR): -0.45; 95% CI: -0.58, -0.32; P < 0.01] and positively associated with the urine albumin-to-creatinine ratio (UACR; ZCOR: 0.26; 95% CI: 0.08, 0.43; P < 0.01), serum creatinine (sCr; ZCOR: 0.43; 95% CI: 0.28, 0.58; P < 0.01), urine albumin excretion rate (UAER; ZCOR: 0.06; 95% CI: 0.04, 0.09; P < 0.01), blood urea (ZCOR: 0.50; 95% CI: 0.29, 0.72; P < 0.01), blood uric acid (ZCOR: 0.32; 95% CI: 0.25, 0.38; P < 0.01), and serum cystatin C (CysC; ZCOR: 0.47, 95% CI: 0.44, 0.51; P < 0.01). This is the first systematic review and meta-analysis to reveal a negative association between circulating TMAO concentrations and kidney function.
| S-EPMC8321840 | biostudies-literature