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Trimethylamine-N-oxide (TMAO), a microbiome-derived metabolite from the metabolism of choline, betaine, and carnitines, is associated to adverse cardiovascular outcomes. A method suitable for routine quantification of TMAO and its precursors (trimethylamine (TMA), choline, betaine, creatinine, and propionyl-, acetyl-, and l-carnitine) in clinical and food samples has been developed based on LC-MS. TMA was successfully derivatized using iodoacetonitrile, and no cross-reactions with TMAO or the other methylamines were detected. Extraction from clinical samples (plasma and urine) was performed after protein precipitation using acetonitrile:methanol. For food samples (meatballs and eggs), water extraction was shown to be sufficient, but acid hydrolysis was required to release bound choline before extraction. Baseline separation of the methylamines was achieved using a neutral HILIC column and a mobile phase consisting of 25 mmol/L ammonium formate in water:ACN (30:70). Quantification was performed by MS using external calibration and isotopic labelled internal standards. The assay proved suitable for both clinical and food samples and was linear from ≈ 0.1 up to 200 μmol/L for all methylamines except for TMA and TMAO, which were linear up to 100 μmol/L. Recoveries were 91–107% in clinical samples and 76–98% in food samples. The interday (n=8, four duplicate analysis) CVs were below 9% for all metabolites in clinical and food samples. The method was applied successfully to determine the methylamine concentrations in plasma and urine from the subjects participating in an intervention trial (n=10) to determine the effect of animal food ingestion on methylamine concentrations.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.

Previous studies suggested a possible gut microbiota dysbiosis in chronic heart failure (CHF). However, direct evidence was lacking. In this study, we investigated the composition and metabolic patterns of gut microbiota in CHF patients to provide direct evidence and comprehensive understanding of gut microbiota dysbiosis in CHF. We enrolled 53 CHF patients and 41 controls. Metagenomic analyses of faecal samples and metabolomic analyses of faecal and plasma samples were then performed. We found that the composition of gut microbiota in CHF was significantly different from controls. Faecalibacterium prausnitzii decrease and Ruminococcus gnavus increase were the essential characteristics in CHF patients’ gut microbiota. We also observed an imbalance of gut microbes involved in the metabolism of protective metabolites such as butyrate and harmful metabolites such as trimethylamine N-oxide in CHF patients. Metabolic features of both faecal and plasma samples from CHF patients also significantly changed. Moreover, alterations in faecal and plasma metabolic patterns correlated with gut microbiota dysbiosis in CHF. Taken together, we found that CHF was associated with distinct gut microbiota dysbiosis and pinpointed the specific core bacteria imbalance in CHF, along with correlations between changes in certain metabolites and gut microbes.

Gut microbiota has increasingly been shown to exert effects beyond the gastrointestinal tract, some of which are mediated through its metabolites, such as trimethylamine N-oxide (TMAO)—a compound converted by gut bacteria from dietary choline found predominantly in animal products that is associated with cardiovascular disease (CVD). However, a significant gap persists in human clinical trials assessing its potential causal role. This narrative review aims to present the current understanding of the gut microbiome, TMAO, and their relationship with CVD, while proposing future directions that may support the use of TMAO as a biomarker and guide potential interventions to reduce its harmful impact. Both animal and human studies have demonstrated a link between TMAO and CVD, with animal studies also indicating a causal effect—showing increased cardiovascular risk following TMAO administration and reduced risk when TMAO is eliminated. While direct extrapolation from animal models to humans is limited due to biological differences, these findings offer a foundation for the development of well-designed clinical trials in human populations. Although direct approaches to target TMAO—such as trimethylamine (TMA) lyase inhibitors and antisense oligonucleotide (ASO) therapy—have shown promising results in animal studies, they have yet to be investigated in human trials, leaving indirect strategies such as dietary changes and probiotics as the only currently available options.

Trimethylamine (TMA) is a tertiary amine with a characteristic fishy odour. It is synthesised from dietary constituents, including choline, L-carnitine, betaine and lecithin by the action of microbial enzymes during both healthy and diseased conditions in humans. Trimethylaminuria (TMAU) is a disease typified by its association with the characteristic fishy odour because of decreased TMA metabolism and excessive TMA excretion. Besides TMAU, a number of other diseases are associated with abnormal levels of TMA, including renal disorders, cancer, obesity, diabetes, cardiovascular diseases and neuropsychiatric disorders. Aside from its role in pathobiology, TMA is a precursor of trimethylamine-N-oxide that has been associated with an increased risk of athero-thrombogenesis. Additionally, TMA is a major air pollutant originating from vehicular exhaust, food waste and animal husbandry industry. The adverse effects of TMA need to be monitored given its ubiquitous presence in air and easy absorption through human skin. In this review, we highlight multifaceted attributes of TMA with an emphasis on its physiological, pathological and environmental impacts. We propose a clinical surveillance of human TMA levels that can fully assess its role as a potential marker of microbial dysbiosis-based diseases.

Objectives Trimethylamine N-oxide (TMAO) has been implicated in systemic inflammatory pathways, emphasizing its potential as a biomarker. Elevated plasma TMAO levels have been associated with increased oxidative stress, leading to higher plasma concentrations of TNF-α, a key pro-inflammatory cytokine. Given this systemic inflammatory linkage, saliva—a non-invasive diagnostic medium—offers a unique opportunity to reflect both local and systemic inflammatory changes. This study aimed to evaluate the alterations in salivary and serum TMAO levels in periodontitis and assess the diagnostic potential of salivary TMAO as an indicator of periodontal inflammation. Materials and methods Twenty-four patients with periodontitis (Stage III Grade B) and 24 healthy controls were included. Clinical parameters (probing depth (PD), plaque index (PI), bleeding on probing (BOP), and clinical attachment loss (CAL)) were recorded. TMAO levels in saliva and serum were measured using liquid chromatography-mass spectrometry (LC–MS/MS), and TNF-α levels were assessed using Enzyme-Linked ImmunoSorbent Assay (ELISA). Results Salivary and serum TMAO levels and salivary TNF-α levels were significantly higher in the periodontitis group ( p  = 0.003, p  = 0.004, and p  = 0.031, respectively). Salivary TMAO showed positive correlations with periodontal parameters ( p  < 0.05) and salivary TNF-α levels. A significant positive correlation was also observed between salivary and serum TMAO levels ( p  < 0.001). Salivary TMAO was the accurate biomarker in differentiating between periodontitis and controls (sensitivity = 0.583, specificity = 0.833, AUC = 0.747). Conclusions Salivary TMAO demonstrates potential as a non-invasive marker for periodontitis, showing correlations with clinical parameters and inflammatory markers. These findings suggest that TMAO may reflect both local and systemic inflammatory states associated with periodontal disease. Clinical relevance Salivary TMAO may serve as a potential non-invasive indicator of periodontitis, as it reflects aspects of both local and systemic inflammation, offering insights into periodontal disease status.

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.

Trimethylamine N-oxide (TMAO), as a gut-derived metabolite, has been found to be associated with enhanced risk for atherosclerosis and cardiovascular disease. We presented a method for targeted profiling of TMAO and betaine in serum and food samples based on a combination of one-step sample pretreatment and proton nuclear magnetic resonance spectroscopy. The key step included a processing of sample preparation using a selective solid-phase extraction column for retention of basic metabolites. Proton signals at δ 3.29 and δ 3.28 were employed to quantify TMAO and betaine, respectively. The developed method was examined with acceptable linear relationship, precision, stability, repeatability, and accuracy. It was successfully applied to detect serum levels of TMAO and betaine in TMAO-fed mice and high-fructose-fed rats and also used to determine the contents of TMAO and betaine in several kinds of food, such as fish, pork, milk, and egg yolk.

AimsTo determine the relationship between plasma levels of trimethylamine-N-oxide (TMAO) and odds of diabetic retinopathy (DR).MethodsA cross-sectional study was conducted. Blood samples were obtained from 122 type 2 diabetes mellitus (T2DM) patients with or without DR. Multivariable logistic regression analyses were performed to identify the association between plasma TMAO and DR. The diagnostic value of plasma TMAO was assessed by the area under the receiver operating characteristic curve (AUROC) and integrated discrimination improvement (IDI).ResultsIn the T2DM patients, plasma levels of TMAO were significantly higher in patients with DR compared with those without DR (P = 0.001). As logarithmic (ln) transformation of TMAO increased per standard deviation (SD), there was higher probability to have DR [odds ratio (OR) = 2.31; P = 0.005]. As ln-transformed TMAO increased per SD, the severity of DR was more likely to get worse (OR = 2.05; P = 0.004). In the diagnostic model, the addition of TMAO contributed to the improvement in AUROC from 0.646 to 0.734 (P = 0.043), and the IDI was 10.7% (P < 0.001).ConclusionElevated levels of plasma TMAO were associated with higher odds and worse severity of DR in T2DM patients, and further investigation is required for the causality of this association.

Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC–MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.