Gut microbes impact stroke severity via the trimethylamine N-oxide pathway.
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ABSTRACT:
SUBMITTER: Zhu W
PROVIDER: S-EPMC8288076 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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 derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.
| S-EPMC8052457 | biostudies-literature
Project description:Trimethylamine N-oxide (TMAO), a metabolite derived from intestine microbial flora, enhances vascular inflammation in a variety of cardiovascular disease, and the bacterial communities associated with trimethylamine N-oxide (TMAO) metabolism is higher in pulmonary hypertension (PH) patients. The effects of TMAO on PH, however, has not been elucidated. In the present study, we found that circulating TMAO is elevated in intermediate to high-risk PH patients when compared to healthy control or low-risk PH patients. In monocrotaline-induced rat PH models, circulating TMAO is elevated; and reduction of TMAO using 3,3-dimethyl-1-butanol (DMB) significantly decreased right ventricle systolic pressure, pulmonary vascular muscularization in both monocrotaline-induced rat PH and hypoxia induced mice PH models. RNA sequencing of rat lungs on DMB revealed significant suppression of pathways involved in cytokine-cytokine receptor interaction, and cytokine and chemokine signaling. Protein-protein interaction analysis of the differentially expressed transcripts regulated by DMB showed 5 hub genes with a strong connectivity of proinflammatory cytokines and chemokines including Kng1, Cxcl1, Cxcl2, CxcL6 and Il6. In vivo, TMAO significantly increased the expression of Kng1, Cxcl1, Cxcl2, CxcL6 and Il6 in bone marrow derived macrophage. And TMAO-treated conditioned medium from macrophage increased the proliferation and migration of pulmonary artery smooth muscle cells; but TMAO treatment did not change the proliferation or migration of pulmonary artery smooth muscle cells. In conclusion, our study demonstrates that TMAO is increased in severe PH, and the reduction of TMAO using DMB reduces pulmonary vascular muscularization and alleviates PH via suppressing the macrophage production of chemokines and cytokines.
2022-06-07 | GSE190203 | GEO
Project description:Background: Acute ischemic stroke (AIS) is an atherothrombotic disease. Trimethylamine-N-oxide (TMAO), a gut microbiota-dependent metabolite, has been shown to be proatherogenic and prothrombotic. However, the involvement of TMAO in AIS remains unclear. This study aimed to observe the dynamic changes of TMAO in AIS patients and identify the prognostic value of TMAO for major ischemic events and unfavorable functional outcomes. Methods: This study included 204 AIS patients and 108 healthy controls. Blood samples for TMAO analyses were drawn at admission, 2 and 7 days of admission. Logistic regression models and receiver operating characteristic curves were established to identify associations between TMAO levels and major ischemic events (ischemic stroke, myocardial infarction, or death from an ischemic vascular event), as well as unfavorable functional outcomes (modified Rankin Scale score ≥3), at 90 days and 12 months. Results: TMAO levels showed no significant changes before and within 24 h of AIS treatment (at admission) but decreased significantly thereafter. Elevated log2-transformed baseline TMAO levels were associated with increased risks of 90-day [odds ratio (OR), 2.62; 95% confidence interval (CI), 1.55-4.45; p < 0.001] and 12-month (OR, 3.59; 95% CI, 2.12-6.09; p < 0.001) major ischemic events, as well as 90-day (OR, 2.89; 95% CI, 1.46-5.71; p = 0.002) and 12-month (OR, 2.58; 95% CI, 1.50-4.46; p = 0.001) unfavorable functional outcomes, after adjustments for confounding factors. The areas under curve of baseline TMAO levels for predicting 90-day and 12-month major ischemic events were 0.72 (95% CI, 0.61-0.83; p < 0.001) and 0.76 (95% CI, 0.66-0.85; p < 0.001). Baseline TMAO levels improved the prognostic accuracy of conventional risk factors, National Institutes of Health Stroke Scale (NIHSS) score and N-terminal B-type natriuretic peptide (NT-proBNP) level. Conclusions: TMAO levels decreased with time since stroke onset. Elevated TMAO levels at an earlier period portended poor stroke outcomes, broadening the potential clinical utility of TMAO as an independent prognostic marker and therapeutic target.
| S-EPMC7005238 | biostudies-literature
Project description:BackgroundIntestinal inflammation and periodontitis influence the development of each other through the bidirectional relationship. As the intestinal microbiome metabolite, trimethylamine-N-oxide (TMAO) could contribute to chronic inflammation in the gut by influencing the gut microbial composition and intestinal immunity. Increased circulating TMAO levels often accompany clinical findings in patients with experimental periodontitis. However, the role of TMAO in the bidirectional relationship between intestinal inflammation and periodontitis remains unclear. Thus, we explored whether TMAO influences the periodontitis process by affecting intestinal immunity and microbial composition in this article.MethodsPeriodontitis was induced by unilateral ligation of the first molar in mice, and 3,3-dimethyl-1-butanol (DMB) was used as an inhibitor to reduce TMAO circulating. Twenty-five BALB/c mice were randomly assigned to five study sets (n = 5/group): no periodontitis with DMB (Control group), periodontitis (P) group, periodontitis with TMAO (P+TMAO) group, periodontitis with TMAO and DMB (P+TMAO+DMB) group, and periodontitis with DMB (P+DMB) group. The effect of TMAO was determined by assessing changes in intestinal histology, intestinal flora composition, periodontal tissue, and periodontal pro-inflammatory factors at ten days.ResultsThe outcomes indicated a marked improvement in the intestinal inflammation severity, and intestinal flora diversity was reduced. Firmicutes number and the ratio of Firmicutes/Bacteroidetes were improved in the P+TMAO group. In addition, the alveolar bone resorption and the degree of periodontal tissue inflammation were more severe in the P+TMAO group than in other groups. Immunohistochemistry showed higher levels of TGF-β and IL-1β expression in the periodontal tissues of P+TMAO.ConclusionsOur data suggest that TMAO could influence periodontal immunity and promote periodontal inflammation by affecting the intestinal microenvironment, revealing TMAO may affect the development of periodontitis through the bidirectional relationship of the oral-gut axis.
| S-EPMC9880481 | biostudies-literature
Project description:BACKGROUND:The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes. RESULTS:A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of Enterobacteriaceae was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (n?=?66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by 1H-NMR. As with the in vitro fermentation experiments, TMAO stimulated the growth of Enterobacteriaceae; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of Escherichia coli produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO but did not produce large amounts of TMA. Clostridia (sensu stricto), bifidobacteria, and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did not produce notable quantities of TMA from TMAO in pure culture. CONCLUSIONS:Reduction of TMAO by the gut microbiota (predominantly Enterobacteriaceae) to TMA followed by host uptake of TMA into the bloodstream from the intestine and its conversion back to TMAO by host hepatic enzymes is an example of metabolic retroconversion. TMAO influences microbial metabolism depending on isolation source and taxon of gut bacterium. Correlation of metabolomic and abundance data from mixed microbiota fermentation systems did not give a true picture of which members of the gut microbiota were responsible for converting TMAO to TMA; only by supplementing the study with pure culture work and additional metabolomics was it possible to increase our understanding of TMAO bioconversions by the human gut microbiota.
| S-EPMC5909246 | biostudies-literature
Project description:Atherosclerosis is associated with various pathological manifestations, such as ischemic heart disease, ischemic stroke, and peripheral arterial disease, and remains a leading cause of public health concern. Atherosclerosis is an inflammatory disease characterized by endothelial dysfunction; vascular inflammation; and the deposition of lipids, cholesterol, calcium, and cellular debris within the vessel wall intima. In-depth studies of gut flora in recent years have shown that bacterial translocation and the existence of bacterial active products in blood circulation can affect the inflammatory state of the whole blood vessel. The gut flora is considered to be a large "secretory organ," which produces trimethylamine-N-oxide (TMAO), short-chain fatty acids and secondary bile acids by breaking down the ingested food. Studies have shown that TMAO is an independent risk factor for the occurrence of malignant adverse cardiovascular events, but whether it is harmful or beneficial to patients with cardiovascular diseases with mild or no clinical manifestations remains controversial. We review the relationship between TMAO and its precursor (L-carnitine) and coronary atherosclerosis and summarize the potential molecular mechanism and therapeutic measures of TMAO on coronary atherosclerosis.
| S-EPMC8650703 | biostudies-literature
Project description:Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg-1min-1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.
| S-EPMC8408632 | biostudies-literature
Project description:AimsSeveral epidemiological studies have examined the association between trimethylamine N-Oxide (TMAO) and stroke risk; however, the results are still inconclusive. The purpose of this meta-analysis was to evaluate the relationship between TMAO concentrations and stroke risk.MethodsPubMed, Scopus, Cochrane and ProQuest search engines were systematically searched up to 18 June 2019. All of the studies that evaluated the relationship between TMAO and stroke were included in the systematic review and eligible studies were included into the meta-analysis. Meta-regression and subgroup analysis were also employed to find the source of heterogeneity.ResultsEight studies (two cross-sectional studies, two cohort studies, three case-control studies and one nested case-control study) with a total of 6150 participants were included in the meta-analysis. The overall result showed that being in the highest category of TMAO increased the odds of stroke by 68% (OR: 1.675; CI: 0.866-3.243; P = 0.047) and mean TMAO concentrations was 2.201 μmol/L higher in patients with stroke rather than non-stroke controls (weighted mean difference (WMD): 2.20; CI: 1.213-3.188; P < 0.001). Furthermore, we observed revealed a non-linear association between increased TMAO levels and increased odds of stroke (P- for nonlinearity < 0.001). In addition, visual inspection of the funnel plot revealed a significant asymmetry among studies examining the differences in TMAO in patients with stroke versus control group.ConclusionThis is the first meta-analysis to show positive dose-dependent relations between circulating TMAO concentration and stroke risk. However, further interventional studies and long-term studies are needed to better explain causality.
| S-EPMC7393891 | biostudies-literature
Project description:Gut microbiota has been suggested to play a role in almost all major diseases including cardio- and cerebrovascular diseases. A possible mechanism is the transformation of dietary choline and l-carnitine into trimethylamine by gut bacteria. This metabolite is further oxidized into trimethylamine-N-oxide (TMAO) in liver and promotes atherogenesis. Nevertheless, little is known about gut microbial diversity and blood TMAO levels in stroke patients. We performed a case-control study of patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack. TMAO was determined with liquid chromatography tandem mass spectrometry. Gut microbiome was profiled using Illumina sequencing of the 16S rRNA V4 tag. Within the asymptomatic control group, participants with and without carotid atherosclerotic plaques showed similar levels of TMAO without a significant difference in gut microbiota; however, the gut microbiome of stroke and transient ischemic attack patients was clearly different from that of the asymptomatic group. Stroke and transient ischemic attack patients had more opportunistic pathogens, such as Enterobacter, Megasphaera, Oscillibacter, and Desulfovibrio, and fewer commensal or beneficial genera including Bacteroides, Prevotella, and Faecalibacterium. This dysbiosis was correlated with the severity of the disease. The TMAO level in the stroke and transient ischemic attack patients was significantly lower, rather than higher, than that of the asymptomatic group. Participants with asymptomatic atherosclerosis did not exhibit an obvious change in gut microbiota and blood TMAO levels; however, stroke and transient ischemic attack patients showed significant dysbiosis of the gut microbiota, and their blood TMAO levels were decreased.
| S-EPMC4845212 | biostudies-literature