Search Results (278)

Background/Objectives: Gut microbial metabolism of choline and related quaternary amines to trimethylamine (TMA) is the first step in the production of trimethylamine N-oxide (TMAO), a circulating metabolite that contributes to the development of atherosclerosis and other forms of cardiovascular disease (CVD). No data exist on regional differences in TMA production within the colon due to difficulties studying gut regions in vivo. A better understanding of TMA production by gut microbiota is needed to develop strategies to limit TMA production in the gut and TMAO levels in circulation with the goal of reducing CVD risk. Methods: We employed our novel three-compartment MiGut in vitro model, which establishes three distinct microbial ecologies mimicking the proximal, mid, and distal colon, to study conversion of choline to TMA by human gut microbiota using isotopically labelled substrate. Results: Choline-d₉ was almost completely converted to TMA-d₉ in vessels 2–3 (mimicking the mid and distal colon) within 6–8 h, but little conversion occurred in vessel 1 (mimicking the proximal colon). Abundance of cutC, part of the cutC/D gene cluster responsible for choline conversion to TMA, was highest in vessel 1 vs. 2–3, suggesting that its expression or activity may be suppressed in the proximal colon. Another possibility is that the viability/activity of bacteria expressing cutC could be suppressed in the same region. Conclusions: This novel finding suggests that while bacteria capable of converting choline to TMA exist throughout the colon, their activity may be different in distinct colon regions. The regional specificity of TMA production, if confirmed in vivo, has implications for both basic microbial ecology related to CVD and the development of strategies to control TMA and TMAO production, with the goal of lowering CVD risk. These findings warrant further study in vitro and in vivo. Full article

Cardiovascular diseases (CVDs) pose a significant threat to human life and mortality worldwide, encompassing a variety of conditions that affect the heart and blood vessels. These diseases are influenced by both genetic and environmental factors, which play a critical role in their development. Recent research has highlighted the importance of gut microbes—the diverse community of bacteria in the gastrointestinal tract—that function as a “super organ” within the human body. These microbes have a remarkable impact on metabolic pathways and are increasingly recognized for their role in serious conditions like CVDs. They contribute to metabolic regulation, provide essential nutrients and vitamins, and help protect against diseases. Various internal and external factors influence the dynamic relationship between the human host and gut microbiota, thereby regulating overall metabolism. This review explores the complex connection between gut microbiota and microbial metabolites—such as short-chain fatty acids (SCFAs), bile acids (BAs), and trimethylamine N-oxide (TMAO)—and their potential influence on the development and progression of CVDs. We also examine the interaction between dietary interventions and gut microbes in the context of conditions including atherosclerosis, obesity, type 2 diabetes, heart failure, hypertension, atrial fibrillation, and myocardial infarction. Gaining a deeper understanding of the gut microbiota’s role in maintaining physiological balance creates exciting possibilities for identifying novel diagnostic biomarkers and therapeutic targets for treating CVDs. This knowledge offers hope for early disease prediction, improved clinical management, and innovative treatments. Full article

Gut microbiota-derived trimethylamine N-oxide (TMAO) has been implicated in both intestinal and renal diseases; however, its specific role in modulating gut–kidney interactions remains unclear. This study aimed to investigate the effects of TMAO on gut–kidney crosstalk using a mouse model of diarrhea. Mice were divided into four groups: normal, model, TMAO, and TMAO + model. The normal group received sterile water, while the other groups were administered adenine + Folium sennae, TMAO, or a combination of TMAO and adenine + Folium sennae. Samples were collected to assess morphological changes in the colon and kidney, evaluate the colonic mucosal barrier and renal function, and measure NLRP3 inflammasome activity and inflammatory cytokine levels in colonic and renal tissues. TMAO levels and the gut microbiota composition were analyzed using 16S rRNA sequencing. The model group exhibited altered stool morphology, which was further aggravated by TMAO intervention. Both the model and TMAO + model groups exhibited significant damage to intestinal and renal tissues, along with compromised intestinal mucosal barriers and impaired renal function compared to controls. Inflammatory markers were elevated in these groups, with the TMAO + model group showing the most pronounced increases. Correlation analysis indicated significant relationships among TMAO levels, inflammasome activation, and inflammatory cytokines. The genera Mucispirillum and Anaerotruncus negatively correlated with TMAO, whereas Parabacteroides and Parasutterella genera positively correlated with TMAO. In conclusion, TMAO plays a critical role in modulating gut–kidney crosstalk by promoting inflammation, disrupting mucosal and renal integrity, and altering the gut microbial ecosystem. Full article

Cardiac surgery, particularly procedures involving cardiopulmonary bypass (CPB), is associated with a high risk of postoperative complications, including systemic inflammatory response syndrome (SIRS), postoperative atrial fibrillation (POAF), and infection. Growing evidence suggests that the gut–heart axis, through mechanisms involving intestinal barrier integrity and gut microbiota homeostasis, may influence these outcomes. This review summarizes the relationship between gut microbiota composition and the inflammatory response in patients undergoing cardiac surgery and the extent to which these alterations impact clinical outcomes. The reviewed studies consistently show that cardiac surgery induces notable alterations in microbial diversity and composition during the perioperative period. These changes, indicative of dysbiosis, are characterized by a reduction in health-associated bacteria such as Blautia, Faecalibacterium, and Bifidobacterium and an increase in opportunistic pathogens. Inflammatory biomarkers were frequently elevated postoperatively, even in patients without evident complications. Key microbial metabolites and biomarkers, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and bile acids (BAs), were implicated in modulating inflammation and clinical outcomes. Additionally, vitamin D deficiency emerged as a contributing factor, correlating with increased systemic inflammation and a higher incidence of POAF. The findings suggest that gut microbiota composition prior to surgery may influence the severity of the postoperative inflammatory response and that perioperative modulation of the gut microbiota could represent a novel approach to improving surgical outcomes. However, the relationship between dysbiosis and acute illness in surgical patients is confounded by factors such as antibiotic use and other perioperative interventions. Large-scale, standardized clinical studies are needed to better define these interactions and guide future therapeutic strategies in cardiac surgery. Full article

Trimethylamine N-oxide (TMAO) is known to increase in human cardiovascular, metabolic, and renal diseases. In human medicine, TMAO has recently been utilized as a diagnostic and prognostic biomarker for renal dysfunction, and research is ongoing regarding its potential as a therapeutic target. This study aimed to evaluate the diagnostic and prognostic potential of TMAO as a supportive biomarker in dogs with chronic kidney disease (CKD). To assess its diagnostic utility, TMAO concentrations were compared between a CKD group (n = 32) and a healthy control group (n = 32). In addition, patients with CKD were subdivided into stages 2 (n = 12), 3 (n = 11), and 4 (n = 9) and compared individually with the healthy controls. For prognostic evaluation, the CKD group was monitored over six months, and the TMAO levels were compared between survivors (n = 18) and non-survivors (n = 14). The TMAO concentrations showed a highly significant difference between patients with CKD and healthy controls (p < 0.0001). Patients with each different CKD stage exhibited statistically significant differences compared with the healthy controls (p < 0.05). Furthermore, the median TMAO levels tended to increase with advancing CKD stage; however, the differences among stages were not statistically significant. In addition, within the CKD group, TMAO concentrations were significantly higher in non-survivors than in survivors at the six-month follow-up (p = 0.0142). This pilot study highlights the potential of TMAO as a supportive renal biomarker for diagnostic and prognostic evaluation in canine CKD. Full article

Autism spectrum disorder (ASD) is increasingly associated with microbial and metabolic disturbances, including the altered production of gut-derived uremic toxins. We investigated urinary concentrations of five representative uremic toxins—indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)—in 161 children with ASD and 71 healthy controls. Toxins were measured using LC-MS/MS and were normalized to creatinine. Subgroup analyses were performed by sex, age group (2–5.9 vs. 6–17 years), and autism severity based on the Childhood Autism Rating Scale (CARS). In addition to individual concentrations, we calculated the total toxin burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, and IS/ADMA). While individual toxin levels did not differ significantly between groups, stratified analyses revealed that PCS was higher in girls and in severe cases of ASD, whereas IS and TMAO were reduced in younger and more severely affected children. The functional ratios shifted consistently with severity—IS/PCS declined from 1.69 in controls to 0.99 in severe cases of ASD, while PCS/TMAO increased from 12.2 to 20.5. These patterns suggest a phenolic-dominant microbial signature and an altered host–microbial metabolic balance in ASD. Functional toxin profiling may offer a more sensitive approach to characterizing metabolic disturbances in ASD than concentration analysis alone. Full article

A comprehensive bibliometric analysis of literature is imperative to elucidate current research landscapes and hotspots in the interplay between gut microbiota and hypertension, identify knowledge gaps, and establish theoretical foundations for the future. We used publications retrieved from the Web of Science Core Collection (WoSCC) and SCOPUS databases (January 2001–December 2024) to analyze the annual publication trends with GraphPad Prism 9.5.1, to evaluate co-authorship, keywords clusters, and co-citation patterns with VOSviewer 1.6.20, and conducted keyword burst detection and keyword co-occurrence utilizing CiteSpace v6.4.1. We have retrieved 2485 relevant publications published over the past 24 years. A 481-fold increase in global annual publications in this field was observed. China was identified as the most productive country, while the United States demonstrated the highest research impact. For the contributor, Yang Tao (University of Toledo, USA) and the University of Florida (USA) have emerged as the most influential contributors. Among journals, the highest number of articles was published in Nutrients (n = 135), which also achieved the highest citation count (n = 5397). The emergence of novel research hotspots was indicated by high-frequency keywords, mainly “hypertensive disorders of pregnancy”, “mendelian randomization”, “gut-heart axis”, and “hepatitis B virus”. “Trimethylamine N-oxide (TMAO)” and “receptor” may represent promising new research frontiers in the gut microbiota–hypertension nexus. The current research trends are shifting from exploring the factors influencing gut microbiota and hypertension to understanding the underlying mechanisms of these factors and the potential therapeutic applications of microbial modulation for hypertension management. Full article

Background/Objectives: Trimethylamine N-oxide (TMAO) is implicated in the development of atherosclerosis and cardiovascular diseases. Preventive strategies must recognize the excessive consumption of products rich in choline, carnitine, and betaine, which are substrates essential for TMAO synthesis. The aim of this study was to develop and validate a dietary questionnaire to assess the consumption of these compounds and investigate the correlation with serum TMAO levels in a Central European population. Methods: A dietary questionnaire was designed based on a literature review identifying foods high in TMAO precursors. The tool was validated in a prospective study with 94 participants. The theoretical relevance and reliability of the tool were assessed using factor analysis and statistical indices. Reproducibility was evaluated in a subgroup of 10 participants who completed the questionnaire a second time 24 h later. The results of the questionnaire helped us to determine factors contributing to serum TMAO levels. Results: The final questionnaire consisted of 15 questions, providing acceptable data quality (KMO = 0.654). Three main dietary factors were detected: (1) the consumption of fish products and legumes (SS loadings = 1.72; 10.78% variance), (2) the consumption of cereal products and root vegetables (SS loadings = 1.61; 10.05% variance), and (3) the consumption of meat (SS loadings = 1.47; 9.22% variance). Conclusions: The validated questionnaire is a useful tool for assessing the intake of TMAO-promoting foods in post-myocardial infarction patients from Central Europe. It may support dietary risk assessment and nutritional counseling in clinical practice, particularly for secondary cardiovascular prevention. Full article

Background/Objectives: Trimethylamine (TMA), produced by gut microbiota, and its derivative trimethylamine N-oxide (TMAO) are both associated with cardiometabolic diseases. While the effects of high-fat diets (HFDs) and high-disaccharide diets (HDDs) on gut microbiota in the context of obesity have been well studied, their impact on TMA/TMAO production, particularly alongside physiological caloric intake, remains obscure. This study investigates how standard HFDs and HDDs alongside physiological caloric intake influence gut microbiota composition and TMA/TMAO production in rats. Methods: Sprague Dawley rats were fed one of three diets a standard diet, an HFD, or an HDD for 12 weeks, with chow availability adjusted by age to maintain physiological caloric intake. Gut bacterial diversity was analyzed using 16S rRNA gene sequencing, and metabolites were quantified via High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) in urine and plasma. Results: The HFD group had significantly higher urinary levels of TMA and TMAO compared to the control and HDD groups. Gut bacterial diversity in the HFD group was markedly reduced, displaying the lowest species richness and phylogenetic diversity among all the groups. Notably, Pasteurellaceae (within the order Pasteurellales) and S24-7 (within the order Bacteroidales) were positively correlated with TMAO levels. The demonstrated HDD group increased microbial diversity compared to both the control and HFD groups. Conclusions: A high-fat diet during controlled and physiological caloric intake increases TMA/TMAO production and reduces gut microbial diversity. This underscores the role of diet composition, beyond caloric excess, in shaping gut microbiota and the related cardiometabolic biomarkers. Full article

Trimethylamine N-oxide (TMAO), a gut microbiome metabolite linked to cardiovascular health, can be influenced by dietary factors like choline intake and diet quality. This study compared the effects of mixed tree nuts (MTNs) and pretzels, as part of a 12-week hypocaloric weight loss diet, on TMAO levels and identified dietary predictors. Methods: Plasma samples from 95 overweight individuals consuming either 1.5 oz. of mixed tree nuts (MTNs, n = 56) or isocaloric pretzels (n = 39) daily for 12 weeks were analyzed. Nutritional data were collected at baseline and week 12 through dietary recall using the Automated Self-Administered 24 h Dietary Assessment Tool (ASA24), and the overall diet quality was assessed via the Healthy Eating Index (HEI) score. TMAO levels were determined and analyzed using linear mixed-effect models, adjusting for covariates. Wilcoxon signed-rank tests compared baseline and week 12 TMAO and weight. Multiple linear regression identified baseline predictors of TMAO. Results: Baseline demographics, anthropometric measures, HEI scores, and dietary choline intake were similar between the MTN and pretzel groups. A significant positive association was observed between baseline dietary choline and plasma TMAO levels (p = 0.012). The 12-week hypocaloric diet led to significant weight reduction in both groups (p < 0.01), but the magnitude of weight loss did not differ significantly between the MTN (−3.47 lbs) and pretzel (−4.25 lbs) groups (p = 0.18). Plasma TMAO levels decreased significantly in both groups (p < 0.01), but the between-group difference in reduction was not significant. (MTNs: −0.34 vs. pretzels: −0.37; p = 0.43). HEI scores and dietary choline intake remained unchanged, with no significant time–intervention interaction. Participants with low baseline HEI scores (≤53.72) had a more pronounced reduction in TMAO levels in the MTN group compared to the pretzel group (MTN: −0.54 vs. pretzel: −0.23; p = 0.045) over 12 weeks, despite similar weight loss. This difference was not observed in participants with higher HEI scores. Conclusions: The 12-week hypocaloric diet reduced body weight and plasma TMAO levels similarly in both MTN and pretzel groups. Participants with lower dietary quality saw a greater reduction in TMAO levels in the MTN group, suggesting MTNs may better modulate TMAO levels, especially for those with poorer baseline diets. Full article

Objective: Eggs are a valuable source of nutrients and bioactive compounds that may influence the gastrointestinal tract by modulating the microbiome, promoting the production of gastrointestinal-related metabolites, and mediating inflammation. Limited human studies have explored the effects of whole egg intake on indices of gastrointestinal health. This systematic literature review aimed to synthesise research investigating the impact of whole egg consumption on markers of gastrointestinal health. Methods: Five databases were searched from inception until July 2024. Studies were included if they examined the link between whole egg consumption and gastrointestinal markers, including symptoms, gut microbiome composition, inflammation, colonic fermentation, and egg-derived metabolites such as trimethylamine N-oxide (TMAO) in healthy adults. Two reviewers independently conducted title and abstract and full-text screening, with conflicts resolved by a third reviewer. Similarly, two authors conducted data extraction, which was verified by a third. A risk of bias assessment was conducted using validated tools. Random effects meta-analyses were performed to summarise the effect of egg consumption on TMAO, choline, and C-reactive protein (CRP). Results: Twenty-two studies were included in a narrative synthesis and ten in the meta-analyses. Nine were randomised controlled trials (RCTs), three were non-randomised intervention trials, eight were cross-sectional, and two were prospective cohort studies. Meta-analyses indicated that egg consumption did not impact plasma TMAO (n = 6, p = 0.22) or CRP (n = 3, p = 0.45) concentrations but did increase plasma choline (n = 5, p < 0.001) in the short term (≤4 weeks). Four studies found correlations between habitual egg consumption and specific gut bacteria, although results varied as egg consumption was both positively and negatively associated with butyrate-producing genera. Conclusions: This review found conflicting results regarding egg consumption and most gastrointestinal outcomes, highlighting that future studies are needed to explore links between habitual egg intake and plasma TMAO, microbial diversity, and inflammation (PROSPERO registration: 408532). Full article

Insulin resistance (IR) is a risk factor for various diseases. Diet plays a crucial role in the development of IR. The high-protein diet (HPD) is gaining popularity for its weight control benefit. However, some types of protein can be metabolized by gut microbiota into trimethylamine (TMA), subsequently oxidized into trimethylamine N-oxide (TMAO) in the liver. However, the underlying mechanism of HPD-induced IR remains unclear. In this study, we firstly investigated whether the HPD can induce IR. Next, we examined liver function and the signaling pathways involved in IR. At last, we detected changes in the composition and function of gut microbiota, particularly concerning TMA production. Our results demonstrated that the HPD induces IR and liver injury, 41% higher TMA concentration than in the control group. Transcriptome results confirmed that insulin-related pathways were enriched in the HPD group, especially the Insrr gene, which regulates insulin action through its receptor, was downregulated. Disrupted gut microbiota, dominated by 65.0% of Firmicutes, which have high potential in TMA production. Moreover, several amino acid metabolism pathways closely linked to IR were enriched in the HPD group. These findings highlight the need for careful dietary management, as the HPD can induce IR and liver injury, with gut microbiota playing a key role in TMA production. Full article

Background/Objectives: The number of chronic kidney disease (CKD) patients is increasing in Japan, and this population is at high risk of death from cardiovascular and cerebrovascular diseases. Therefore, prevention of arteriosclerosis as a common underlying cause of these diseases is required. In this study, we examined whether 11/19-B1 yogurt, which has been proven to reduce serum low-density lipoprotein (LDL) levels, can decrease the serum levels of indoxylsulfate and trimethylamine-N-oxide (TMAO), which are produced by intestinal microbiota and known to cause arteriosclerosis, through improving dysbiosis in hemodialysis patients. Methods: Nineteen dialysis patients consumed 50 g of 11/19-B1 yogurt daily for 8 weeks, and changes in serum lipid profile and uremic toxin levels, intestinal microbiome, as well as the frequency of bowel movement and stool characteristics were observed. Results: The results demonstrated that an intake of yogurt decreased serum LDL 99.3 to 88.5 (p = 0.049) and indoxylsulfate in seven of nine subjects with previously high concentrations, and improved stool characteristics as estimated by the Bristle stool score, although decreased HDL and no beneficial effect on serum TMAO was observed. Conclusions: These results may suggest that the ingestion of 11/19-B1 yogurt provides a preventative effect against the progression of atherosclerosis and renal dysfunction. Full article

Background/Objectives: Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite considered as a risk metabolite for various non-communicable diseases. This study aims to identify differences in the gut microbiota composition and concentrations of TMAO and related metabolites in subjects with and without metabolic syndrome (MetS). Methods: Plasma samples were collected following an overnight fast on two occasions from subjects with (n = 12) and without (n = 21) MetS. Feces samples were collected on the day before the first blood sampling. The gut microbiota was profiled using 16S rRNA full-gene amplification sequencing. TMAO and related methylamines were quantified using UPLC-MSMS. The fasted plasma glucose, plasma lipid profile, and HbA1c were determined, and blood pressure, circumference, height, and weight were measured. Results: A divergent gut microbiota composition was observed in feces samples from both groups. In contrast to subjects without MetS, subjects with MetS had a reduced microbial diversity, with lower Blautia glucerasea and higher Ruminococcus torques—a pattern associated with (increased) inflammation. Trimethylamine (TMA)-producing bacteria were low in abundance across both groups. While plasma TMAO and related methylamines displayed no significant differences between both groups, L-carnitine was elevated (p = 0.0191) in subjects with MetS. A strong positive correlation was detected between TMAO and TMA (r = 0.439, p = 0.003), with a tendency to correlate with carnitine (r = 0.212, p = 0.087). Conclusions: Subjects with MetS were characterized by gut microbiota favoring inflammation-associated species but not TMA producers. This suggests that TMAO may not play a role in MetS subjects without overt comorbidities, e.g., CVD or T2D. The influence of the gut microbiota on early MetS is likely mediated through inflammatory mechanisms driven by specific bacterial shifts rather than TMAO production. Full article

Trimethylamine N-oxide (TMAO) is a gut microbial metabolite of dietary precursors, including choline and carnitine. Elevated levels of TMAO in human plasma have been associated with several diseases such as cardiovascular, diabetes mellitus, chronic kidney disease, neurological disorders, and cancer. This has led to an increased interest in the accurate determination of TMAO in human blood, for which a reliable, cost-effective and sensitive analytical method should be established. LC-MS/MS has emerged as a powerful tool for the determination of TMAO due to its high sensitivity, specificity, and ability to handle complex matrices. Herein, we describe the development and validation of an LC-MS/MS method for the determination of TMAO in human blood plasma. Our method involves a simple sample preparation protocol, involving a protein precipitation step along with a non-deuterated IS, followed by a Liquid Chromatography-Mass Spectrometry (LC-MS/MS) analysis using a triple quadrupole mass spectrometer. Additionally, the method was adapted and implemented on an UPLC-QTOF/MS. The method was validated using the guidelines set by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for assay performance and robustness in human plasma and successfully applied to plasma derived from healthy and hyperlipidemic volunteers. The developed method was found to be specific, sensitive, and accurate for the determination of TMAO in human plasma, with a lower limit of quantification of 0.25 µM. The intra- and inter-assay precision and trueness were within acceptable limits. Full article