Trimethylamine N-oxide Research Articles

Vaginal cleansing soap causes pathological vaginal discharge: a case study

Introduction: Vaginal discharge or another name is flour albus or leukorrhea, which occurs in women who are teenagers or of childbearing age. 75% of women will experience vaginal discharge at least once in their lives. Abnormal vaginal discharge is caused by infection from various microorganisms. In Indonesia alone, 90% of women are at risk of experiencing pathological vaginal discharge due to the tropical climate. Women often do vaginal cleaning or vaginal douching. Usually, this activity uses vaginal cleansing fluid. Objective: This study aims to dig deeper into the relationship between the use of vaginal cleansing soaps and pathological vaginal discharge in women, hoping to provide better insight into the effects of using these products and provide appropriate health recommendations. Method: The research design uses a descriptive case study method which aims to describe the relationship between two things experienced by the patient, namely vaginal discharge and the habit of cleaning the vagina with vaginal cleansing soap. Results: A 30-year-old woman came to the clinic with complaints of vaginal discharge coming out of her vagina. The vaginal discharge also feels thick, smells fishy, ​​and feels very itchy in the vaginal area. On physical examination, mucopurulent vaginal discharge with a fishy odor was found. The labia majora looks swollen and red. By using a speculum, the cervix appears reddish. No abrasions or blood spots were found on the cervical neck. Conclusion: There is a relationship between the use of vaginal cleansing soap and the emergence of pathological vaginal discharge. Changes in the acidity of the vagina influence the emergence of pathological flora. There is a need to increase Knowledge of how to maintain vaginal cleanliness, not just using vaginal cleansing fluids. With this study, it is further proven that the use of vaginal cleansing soap can cause pathological vaginal discharge. It is necessary to have good education for women with pathological vaginal discharge so that there is no recurrence of similar cases. In the case study above, it is essential to carry out additional examinations to find out the cause of the vaginal discharge, whether it is fungus, bacteria, or protozoa so that it can speed up the healing of the patient. With this research, it is also hoped that it can be an example of health care about pathological vaginal discharge and increase women's Knowledge of what kind of good vaginal cleaning behavior.

Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO’s aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe–TMAO pathway.

The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease

Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome’s role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.

Periplaneta americana L. extract exerts neuroprotective effects by inhibiting endoplasmic reticulum stress via AKT-dependent pathway in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that currently has no curable strategies. More and more evidence suggests that endoplasmic reticulum (ER) stress plays an essential role in PD pathogenesis. Periplaneta americana L. (P. americana) is a traditional Chinese medicine with diverse therapeutic properties. This study aims to investigate the neuroprotective effect and underlying mechanism of P. americana in in vitro and in vivo PD models. The exposure of SH-SY5Y cells to 1-methyl-4-phenyl-pyridinium (MPP+) was used as the in vitro PD model. MTT assay, Hoechst staining, Calcein AM-PI staining and flow cytometry were performed to measure the cell viability and apoptosis. DCFH-DA and JC-1 assay were used to measure the intracellular ROS and mitochondrial membrane potential (Δψm), respectively. Western-blot and immunostaining were conducted to detect the expression of key molecules related with ER stress. For the in vivo PD model induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro-pyridine (MPTP), the motor function of mice was assessed by behavioral tests, the level of TH was examined by western-blot and immunostaining, the expression of key molecules related with ER stress was measured by western-blot. Periplaneta americana ethanol extract (PAE) concentration-dependently inhibited MPP+-induced cell loss and increased cell viability. PAE also remarkably attenuated ROS accumulation, the decline of Δψm as well as the excessive ER stress. The neuroprotective effects of PAE could be blocked by ROS inducer trimethylamine N-Oxide or ER stress activator tunicaymycin, while the antioxidant N-Acetyl-L-cysteine or ER stress inhibitor sodium 4-phenylbutyrate mimicked the effects of PAE. Furthermore, we found that PAE could activate AKT/GSK3β/β-catenin pathway. The effect of PAE on ROS production, Δψm and ER stress was blocked by AKT inhibitor MK-2206. In in vivo model, PAE significantly improved motor function, prevented dopaminergic neuronal loss and attenuated ER stress in substantia nigra and striatum of MPTP-treated mice. Similarly, the effects of PAE on MPTP-treated mice were also abolished by MK-2206. Our results suggest that P. americana exerts neuroprotective effects through inhibiting ER stress via AKT-dependent pathway. Periplaneta americana may represent a promising therapeutic agent for PD treatment and is worthy of further being exploited.

Comparison of the protective effects of silymarin and thymoquinone in the focal cerebral ischemia–reperfusion rat model

ABSTRACT Silymarin and thymoquinone exert neuroprotective effects, although their combined effects in focal cerebral ischemia/reperfusion (I/R) models are unknown. We compared the effect of silymarin and thymoquinone in an I/R rat model. Wistar rats were divided into five groups: SHAM, REP (I/R), SIR (200 mg/kg silymarin+I/R), TIR (3 mg/kg thymoquinone+I/R), and STIR (200 mg/kg silymarin+3-mg thymoquinone+I/R). The rats underwent bilateral carotid artery occlusion for 30 min and neurological assessments 24 h thereafter. Apoptosis was evaluated using anti-caspase-3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assays. Astrocyte activation was determined using an anti-GFAP antibody. Total antioxidant status (TAS), total oxidant status (TOS), and trimethylamine N-oxide (TMAO) levels were measured. SHAM and REP rats had the lowest and highest neurological scores, respectively (p = 0.001). REP rats showed greater deterioration than SIR, TIR, and STIR rats. SIR, TIR, and STIR rats had fewer TUNEL and caspase-3-positive cells than REP rats (p<0.05). GFAP expression was higher in REP rats (p<0.05) than in SIR, TIR, and STIR rats (p<0.05). SIR and TIR rats showed higher TAS than REP rats (p<0.05). SIR, TIR, and STIR rats had lower TMAO values than REP and SHAM rats (p<0.05). Silymarin/thymoquinone reduces impairment, apoptosis, and astrocyte activation. Combination therapy reduces TMAO levels.

Temperature-Dependent Trimethylamine N-Oxide Induced the Formation of Substance P Dimers.

Interactions of the peptide substance P (SP) (RPKPQQFFGLM-NH2) with trimethylamine N-oxide (TMAO) were investigated by using cryo-ion mobility-mass spectrometry (cryo-IM-MS), variable-temperature (278-358 K) electrospray ionization (vT-ESI) MS, and molecular dynamics (MD) simulations. Cryo-IM-MS provides evidence that cold solutions containing SP and TMAO yield abundant hydrated SP dimer ions, but dimer formation is inhibited in solutions that also contain urea. In addition, we show that SP dimer formation at cold solution temperatures (<298 K) is favored when TMAO interacts with the hydrophobic C-terminus of SP and is subject to reduced entropic penalty when compared to warmer solution conditions (>298 K). MD simulations show that TMAO lowers the free energy barrier for dimerization and that monomers dimerize by forming hydrogen bonds (HBs). Moreover, differences in oligomer abundances for SP mutants (P4A, P2,4A, G9P, and P2,4A/G9P) provide evidence that oligomerization facilitated by TMAO is sensitive to the cis/trans orientation of residues at positions 2, 4, and 9.

Primary Prevention Strategy for Non-Communicable Diseases (NCDs) and Their Risk Factors: The Role of Intestinal Microbiota

Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide. These conditions have numerous health consequences and significantly impact patients’ lifestyles. Effective long-term treatment is essential since NCDs are irreversible. Therefore, primary healthcare must be both exclusive and of the highest quality, ensuring comprehensive care. The primary goal should be to improve quality of life with a focus on patients, families, and communities, as most of these diseases can be prevented and controlled, although not cured. Several factors have been linked to individual health, including social, cultural, and economic aspects, lifestyle, and certain environmental factors, including work, that can have positive or negative effects. More of these variables may contribute to the onset of NCDs, which are defined by their chronic nature, propensity for prolongation, and generally slow rate of progression. Examples of NCDs include hypertension, type 2 diabetes (T2D), dyslipidemia, and fatty liver disease linked to metabolic dysfunction. The onset of these diseases has been associated with an imbalance in certain microbial niches, such as the gut, which hosts billions of microorganisms performing multiple metabolic functions, such as the production of metabolites like bile acids (BAs), short-chain fatty acids (SCFAs), and trimethylamine N-oxide (TMAO). Therefore, lifestyle changes and personal habits can significantly impact the gut microbiota (GM), potentially preventing chronic diseases associated with metabolism. NCDs are highly prevalent worldwide, prompting increased attention to strategies for modifying the intestinal microbiota (IM). Approaches such as probiotics, prebiotics, synbiotics, and fecal transplantation (FMT) have demonstrated improvements in the quality of life for individuals with these conditions. Additionally, lifestyle changes and the adoption of healthy habits can significantly impact IM and may help prevent chronic diseases related to metabolism. Therefore, the main aim of this review is to analyze and understand the importance of microbiota intervention in the prevention of non-communicable diseases. R3:A1

Enhanced lutein and protein production with improved organoleptic properties in a novel yellow strain of Auxenochlorella pyrenoidosa mutant through atmospheric and room temperature plasma mutagenesis and norflurazon-based screening

To achieve the triple purpose of enhancing lutein and protein contents as well as improving organoleptic properties in biomass of Auxenochlorella pyrenoidosa mutant as raw material of future food, a novel yellow mutant, CX41 strain, was successfully selected through atmospheric and room temperature plasma (ARTP) mutagenesis and norflurazon-based screening. CX41 strain exhibited a significantly increased lutein (0.86 mg/g) and protein (49.00 % DW) contents simultaneously, while higher levels of total (33.47 % DW) and essential amino acids (14.78 % DW) were achieved with higher amino acid score (86.49) than that of the original A4-1 strain, a yellow and high protein mutant bred previously. Sensory evaluation showed that CX41 biomass has more comparable to A4-1, while in comparison to the wild type (WT), it has a more inclination towards roasted, with a fainter grassy, woody, rancid and fishy odor, and a significant improvement in taste is reflected by a decrease of 8.40 % in sweetness, a reduction of 14.86 % in bitterness, and an increase of 5.93 % in umami intensity. Metabolome analysis revealed that the superior sensory profile was due to the significantly reduced relative odor activity of β-ionone (herbaceous odor) and substances such as 1-octene, hexanal, 1-octen-3-ol, and heptanal (fishy and rancid odors). The extensive enhancements demonstrated CX41 biomass as a highly promising raw material with high nutrients of lutein and protein as well as excellent taste and flavor for future food application.

Early vascular aging in chronic kidney disease: focus on microvascular maintenance, senescence signature and potential therapeutics

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. In vivo measurement revealed no major difference in endothelial function between ESKD and control group, aside from higher stiffness detected in the microcirculation of ESKD participants. In contrast, ex vivo measurements revealed a notable change in the contribution of endothelium-derived factors and increased stiffness in ESKD patients vs. controls. In support, we demonstrated that ex vivo exposure of arteries to uremic toxins such as Trimethylamine N-oxide, Phenylacetyl glutamine, or extracellular vesicles from CKD patients impaired endothelial function via diminishing the contribution of endothelium-derived relaxing factors such as nitric oxide and endothelium derived hyperpolarizing factor. Uremic arteries displayed elevated expression of senescence markers (p21CIP1, p16INK4a, and SA-β-gal), calcification marker (RUNX2), and reduced expression of Ki67, sirtuin1, Nrf2, and MHY11 markers, indicating the accumulation of senescent cells and EVA phenotype. Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a “senescence signature”, which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.

Role of Gpcpd1 in intestinal alpha-glycerophosphocholine metabolism and trimethylamine N-oxide production

Glycerophosphocholine (GPC) is an intracellular metabolite in phosphatidylcholine metabolism and has been studied for endogenous choline supply in cells. GPC, as a water-soluble supplement, has been expected to play a role in preventing brain disorders; however, recent studies have shown that intake of high levels of choline-containing compounds is related to trimethylamine N-oxide (TMAO) production in the liver, which is reportedly associated with the progression of atherosclerosis. In this study, we aimed to explore the mechanisms underlying the intestinal absorption and metabolism of GPC. Caco-2 cell monolayer experiments showed that exogenously added GPC was hydrolyzed to choline in the apical medium, and the resulting choline was transported into the Caco-2 cells and further to the basolateral medium. Subsequently, we focused on glycerophosphodiesterase 1 (Gpcpd1/GDE5), which hydrolyzes GPC to choline in vitro and is widely expressed in the gastrointestinal epithelium. Our results revealed that the Gpcpd1 protein was located not only in cells but also in the medium in which Caco-2 cells were cultured. Gpcpd1 siRNA decreased the GPC-hydrolyzing activity both inside Caco-2 cells and in conditioned medium, suggesting the involvement of Gpcpd1 in luminal GPC metabolism. Finally, we generated intestinal epithelial–specific Gpcpd1-deficient mice and found that Gpcpd1 deletion in intestinal epithelial cells affected GPC metabolism in intestinal tissues and partially abolished the increase in blood TMAO levels induced by GPC administration. These observations demonstrate that Gpcpd1 triggers choline production from GPC in the intestinal lumen and is a key endogenous enzyme that regulates TMAO levels following GPC supplementation.

Unveiling the hidden culprit: How the brain-gut axis fuels neuroinflammation in ischemic stroke

Background: The brain-gut axis represents a bidirectional communication network between the gut microbiome and the central nervous system that plays an important role in homeostasis. Compelling evidence now confirms that ischemic stroke disrupts this delicate balance by inducing gut dysbiosis. Methods: A comprehensive literature search was performed in PubMed, Web of Science, and Google Scholar for articles published between January 2000 and January 2023 using relevant keywords. Studies were limited to English and included original studies, literature, and systematic reviewers from peer-reviewed journals which discussed gut microbiota composition in models/subjects with ischemic stroke or assessed stroke impact on gut microbiota. Comments, meeting abstracts, and case reports were excluded. From the 80 relevant articles, we summarized key findings related to gut microbiota changes after stroke and their association with stroke outcomes. Results: Emerging preclinical evidence underscores the pivotal role of the gut microbiome in glial cell development and function. Germ-free models exhibit compromised microglial activation and impaired cellular debris clearance, exacerbating tissue damage following ischemic stroke. Targeted interventions, including prebiotics, probiotics, and fecal microbiota transplantation, have demonstrated efficacy in rescuing glial phenotypes in preclinical stroke models. Beyond its local effects, the gut microbiome significantly influences systemic immunity. Ischemic stroke polarizes pro-inflammatory phenotypes of neutrophils and T cells, amplifying neurovascular inflammation. Microbiota manipulation modulates leukocyte trafficking and metabolic signaling, offering potential avenues to mitigate infarct pathology. Conclusion: Our review demonstrates that in preclinical stroke models, modulating the lipopolysaccharide, short-chain fatty acid, and trimethylamine N-oxide pathways through the gut-brain axis reduces infarct sizes and edema and improves functional recovery after ischemic stroke. Further exploration of this important axis may unveil additional adjunctive stroke therapies by elucidating the complex interplay between the microbiome and the brain. Rigorously controlled clinical studies are now warranted to translate these promising preclinical findings and investigate whether manipulating the microbiome-brain relationship can help improve outcomes for stroke patients. Overall, continued research on the gut-brain axis holds exciting possibilities for developing novel treatment strategies that may enhance recovery after stroke.

Glycation modification of protein hydrolysate from channel catfish (Ictalurus Punetaus) viscera to mitigate undesirable flavor: Unraveling structure and flavor characteristics

To investigate the impacts of glycation modification on the structure and flavor of fish viscera-derived protein hydrolysates, channel catfish viscera was utilized and hydrolyzed by Flavourzyme, followed by glycation with glucosamine, xylose, ribose and glucose, respectively. The structural characteristics, taste and odor of glycated products were evaluated. The results revealed that glycation led to an increase in peptides (<1 kDa) and a decrease in peptide fraction (>5 kDa). UV and fluorescence spectra indicated a gradual rise in absorbance and fluorescence intensity. Glucosamine-induced glycation significantly mitigated bitterness, while enhancing saltiness and umami. GC–MS/MS analysis revealed that glycation led to reduced undesirable odor, and formation of aromatic compounds. LC-MS/MS identified Arg and Lys as the main modification sites. Interestingly, aldehydes were found to modify peptides via carbonyl-amine reaction, leading to decreased fishy odor. The present study contributes to flavor improvement of fish viscera-derived peptides through glycation and high-value utilization of fish viscera.

Volatile flavor characteristics of scallops (Chlamys farreri) with different drying methods were analyzed based on GC-IMS and GC-O-QTOF

To investigate the effects of different drying methods on the flavor of scallops, headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS) combined with gas chromatography-olfactometry-quadrupole time-of-flight (GC-O-QTOF) was used to analyze the flavor of scallops processed by five drying methods. A total of 62 volatile organic compounds (VOCs) were identified by GC-IMS. 27 characteristic aroma compounds were identified by GC-O-QTOF, and the highest content was trimethylamine. 17 aroma compounds with GC-O ≥ 6 were screened by the time-intensity method, and the maximum aroma intensity value of 2-acetyl-1-pyrroline was 9.9 aroma compounds with relative odor activity value (ROAV) ≥ 1 were identified. Using GC-O ≥ 6 and ROAV ≥1 as the criteria, 6 differential aroma compounds were further screened, and the results proved that naturally dried scallops had a heavier fishy odor. These findings will provide deeper insights into the processing of scallops.

α-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice

Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson’s disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.

Atomistic Simulations of Hydration and Antibiofouling Behavior of Amphiphilic Polymer Brush Surfaces Functionalized with TMAO and Short Fluorocarbon.

Developing fouling-resistant materials is of paramount interest in marine industries and biomedical applications. In this work, we studied the interfacial hydration and surface-protein interactions of the amphiphilic brush surface functionalized with hybrid hydrophilic trimethylamine N-oxide (TMAO) and hydrophobic pentafluoroethyl groups using a combination of atomistic molecular dynamics simulations and free-energy computations. Our results show that while the interfacial hydration density of the amphiphilic surface slightly decreases with the introduction of small fluorocarbons compared to that of the pure TMAO-functionalized surface, the amphiphilic surface remains relatively strong in resisting protein adsorption. The nanosized clustering of hydrophobic fluorine atoms on the top of the amphiphilic brush surface introduces weak protein adsorption; however, due to the strong interfacial hydration and weak hydrophobic interaction, the amphiphilic surface exhibits sufficient antibiofouling activities. Our fundamental studies will be critical for the discovery of marine fouling-resistant coating surfaces.

Exploring trimethylamine n-oxide's role in coronary microvascular dysfunction and prognostic outcomes in ST-elevation myocardial infarction patients

Abstract Background Coronary microvascular dysfunction (CMD) subsequent to ST-elevation myocardial infarction (STEMI) is increasingly recognized as a determinant of adverse clinical prognoses. Despite its significance, CMD diagnosis is rare in clinical settings, mainly due to its complexity and technical challenges. Considering these challenges, this study endeavors to explore the diagnostic potential of Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbiota. TMAO has been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis, suggesting its utility as a novel biomarker for CMD and determining prognosis. Purpose To investigate the association between TMAO levels and CMD in STEMI patients, evaluating TMAO's utility as a biomarker for CMD and prognosis predictor. Methods In this prospective, observational study, 210 STEMI patients were enrolled. At the 3-month follow-up, these patients were subjected to comprehensive coronary physiology assessments, including measurements of coronary flow reserve (CFR), fractional flow reserve (FFR), and the index of microcirculatory resistance (IMR) via utilization of pressure-temperature sensor-tipped wires. CMD was diagnosed in patients presenting with an IMR ≥ 25 or a CFR &amp;lt; 2.0, alongside an FFR &amp;gt; 0.80. Levels of TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP), along with other traditional biomarkers were measured at baseline, 3 and 12-month follow-up. Using the Delong test and Youden index to find optimal TMAO cutoffs for CMD detection, due to no predefined TMAO threshold. The primary endpoint was the incidence of CMD at 3 months, with the secondary endpoint being major adverse cardiovascular and cerebrovascular events (MACCE) at 12 months. Results Among enrolled patients, 85 (40.5%) were female, with a median age of 65 (IQR: 58-76). TMAO's baseline receiver operating characteristic (ROC) curve area was 0.55 (95% CI: 0.46-0.64; p=0.426), improving to 0.80 (95% CI: 0.73-0.87; P&amp;lt;0.001) at 3-month follow-up. An optimal TMAO cutoff of 3.91 μM achieved 75% sensitivity (95% CI: 0.63-0.86) and 82% specificity (95% CI: 0.76-0.88), outperforming BNP and CRP with ROC areas of 0.62 and 0.67, respectively. Patients were divided into low (n=140) and high (n=70) TMAO groups at the 3.91 μM threshold. A higher percentage of females was noted in the high TMAO group (55.7% vs. 32.9%; p&amp;lt;0.001). Clinical characteristics and risk factors like stroke and CAD history showed no significant differences across TMAO groups. Multivariable logistic regression revealed TMAO levels at 3 months as an independent predictor for CMD. A cubic spline curve indicated a marked increase in CMD odds with TMAO between 3 and 6 μM.The Incidence of MACCE was significantly higher in patients with a TMAO≥3.91 (41.4% vs 10.7%; p &amp;lt; 0.001). Conclusion Elevated TMAO levels 3 months post-STEMI are significantly associated with increased CMD risk, and significantly predict MACCE.TMAO as a Biomarker for CMD and MACCETMAO Cubic Spline Analysis for CMD Odds

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p&amp;lt;0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p &amp;lt; 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Plasma trimethylamine-n-oxide associates with reduced hippocampal volume and cognitive impairment in atrial fibrillation

Abstract Background/Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in modern society and affected patients appear particularly vulnerable to cognitive dysfunction. Yet, the pathomechanism of this association other than thromboembolism (TE) is not fully understood. We have shown earlier an association of cognitive dysfunction with the gut microbiome derivate trimethylamine-N-oxide (TMAO), which predominantly results from the consumption of red meat. We therefore hypothesized that TMAO may affect hippocampal volume (HV) as a brain structure relevant for cognition. Purpose To demonstrate the structure-function correlation of high TMAO levels with reduced cognitive function and lower HV in a large cohort of patients with atrial fibrillation. Methods We included 1’736 patients with confirmed AF from the Swiss-AF-cohort with both, available blood samples for TMAO measurement and with brain magnetic resonance imaging (bMRI) for the determination of HV at baseline. TMAO levels were measured by liquid chromatography-mass spectrometry (LC-MS). bMRI were obtained by 1.5 or 3 Tesla scanners. HV was assessed by the FreeSurfer software (v 7.4.0) subregion segmentation module and normalized by using Sequence Adaptive Multimodal SEGmentation (SAMSEG) to determine the segmentation based intracranial volume. Patients were divided into TMAO quartiles (Q1: 0.6-3.8, Q2: 3.8-5.5, Q3: 5.5-8.5, Q4: 8.5-164.3μmol/l). Their TMAO levels were compared with their HV (unit = mm3) in linear mixed effect models adjusted for multiple covariates (model 1: age, sex, total intracranial volume (ICV), education level; model 2 = model 1 + smoking status, body mass index (BMI), alcohol consumption, physical activity; model 3 = model 2 + hypertension, coronary artery disease, previous stroke, geriatric depression scale). We assessed both unilateral HV (right = RHV, left = LHV) and bilateral HV standardized by the individual total ICV. Results Overall mean age was 72.5 years (+/-8.4 SD), 27.2% were female. Most of the patients were well educated (39.4% advanced, 48.8% middle education) and 44% never smoked. After multivariable adjustments, patients in the highest TMAO quartile showed a significant reduction of bilateral HV volume of 93.4mm3 (95% CI -179.0 to -7.8, p = 0.03). The RHV appeared more affected and was significantly reduced by 48.2mm3 (CI -93.4, -3.0, p=0.04), whereas LHV was decreased by 44.2mm3 (-89.4, 1.0, p=0.06) in the highest TMAO quartile. Conclusion(s) TMAO negatively associates with bilateral HV in patients with AF. Our results suggest a structure-function-correlation between high TMAO levels and cognitive dysfunction. The findings may be relevant for the high TMAO-exposed patients and advocates for the importance of (possible dietary) prevention in AF.

Influence of chronic dietary nitrate on downstream atherogenic metabolites and the enteral microbiome

Abstract Background Inorganic nitrate, which is abundant in leefy green vegetables and mediates cardioprotective effects through nitric oxide related pathways. The enteral microbiome is an emerging key player in cardiovascular diseases and depends on dietary habits. Whether dietary inorganic nitrate influences atherosclerosis-associated microbiome dependent metabolites like short chain fatty acids (SCFA) and trimethylamine N-oxide (TMAO) has not been elucidated so far. Purpose Aim of this study was to investigate the influence of dietary anorganic nitrate intake on atherosclerosis-associated metabolites and the enteral microbiome composition in a healthy trial cohort. Methods In this double-blind randomized controlled trial, we included 30 healthy volunteers, who either received dietary nitrate (0,12 mmol/kg bodyweight) or placebo (equimolar amounts of sodium nitrate) for 30 days. The microbiome metabolites TMAO and SCFA were analysed. Furthermore, upstream enteral microbiome composition was analysed by 16S-rRNA sequencing at baseline and follow-up. Results Systolic blood pressure significantly decreased after nitrate supplementation (baseline 124,73 mmHg vs follow up 120 mmHg, p &amp;lt; 0.05) with no change in controls. Dietary nitrate supplementation significantly increased TMAO levels (control follow-up 343,88 µg/L vs nitrate follow-up 481,15 µg/L, p &amp;lt; 0.05), while SCFA levels remained unchanged. Mechanistically a change in enteral microbiome composition after dietary nitrate supplementation with decreased abundance of the gram-negative bacteria Akkermansia muciniphila was detected, while overall Shannon diversity, richness and evenness did not differ. Conclusions In conclusion, our results indicate that dietary nitrate supplementation alters the enteral microbiome with impact on proatherogenic metabolites. Further work is warranted to investigate the causal relationship between dietary nitrate, the microbiome, downstream metabolites, and the clinical relevance of those findings in a cardiovascular diseased cohort.

Unveiling the causal effects of gut microbiome on trimethylamine N-oxide: evidence from Mendelian randomization.

The relationship between gut microbiome and trimethylamine oxide (TMAO) has not been fully elucidated. We aimed to assess the causal effects of different gut microbes on TMAO using Mendelian randomization (MR). Gut microbiome and TMAO datasets were acquired from genome-wide association studies and screened for single nucleotide polymorphisms according to the basic assumptions of MR. Inverse variance weighted was used as the main method in MR analysis to assess the causal relationship between the gut microbiome and TMAO. Finally, the MR-Egger intercept, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess the horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. MR analysis revealed that the species Bacteroides finegoldii (odds ratio [OR] 1.064, 95% confidence interval [CI] 1.003 to 1.128, p = 0.039), family Sutterellaceae (OR 1.188, 95% CI 1.003 to 1.407, p = 0.047), and phylum Pseudomonadota (OR 1.205, 95% CI 1.036 to 1.401, p = 0.016), as well as the species Bacteroides uniformis (OR 1.263, 95% CI 1.039 to 1.535, p = 0.019), were positively associated with increased genetic susceptibility to TMAO. In contrast, the species Bacteroides thetaiotaomicron (OR 0.813, 95% CI 0.696 to 0.950, p = 0.009) and Bilophila wadsworthia (OR 0.828, 95% CI 0.690 to 0.995, p = 0.044) were associated with reduced genetic susceptibility to TMAO. Additionally, the MR-Egger intercept indicated no horizontal pleiotropy (p ≥ 0.05), and Cochran's Q test and sensitivity analysis demonstrated that the results were not heterogeneous (p ≥ 0.05) and were robust. Our findings revealed the role of the phylum Pseudomonadota, family Sutterellaceae, species Bacteroides finegoldii, and Bacteroides uniformis in increasing TMAO, as well as the species Bacteroides thetaiotaomicron and Bilophila wadsworthia in decreasing TMAO. This study provides new insights into the relationship between the gut microbiome and TMAO levels.