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Existence of Trimethylamine N-oxide (TMAO) and trimethylamine (TMA) are well recognized through our multiple human activities. Most of them are derived from quaternary ammoniums widely distributed in natural products, which have N-trimethyl moiety. There could also be some inhibitors to reduce their yield. TMAO is known as a representative component in seafood and is recently gaining large attention. TMAO is formed mostly from choline and carnitine in animal products by mediating gut microbes and host monooxygenase in the human body. Teleost tilapia also has a similar mechanism well mediating choline. In marine habitants, TMAO is utilized as an osmolyte. In human, however, the endogenous TMAO is reported to be associated with a risk of cardiovascular events. During the organic evolution, marine creatures could develop utilizing TMAO while avoiding risks. This article, therefore, reviews and characterize the TMAO/TMA having different profiles, and consider the possible inhibitors preventing undesired metabolisms, to try to find clues of the TMAO subjects and consider possibilities and prospects. [ABSTRACT FROM AUTHOR]

Diet for many years has been considered a general health determinant. Recent research shows a connection between gut microbiota composition that is shaped by our diet and lifestyle diseases. Plasma trimethylamine N-oxide (TMAO) originates from gut bacteria metabolism of dietary l-carnitine, betaine, and choline. A number of studies suggest a positive correlation between elevated plasma trimethylamine N-oxide levels and a risk for cardiovascular diseases, diabetes, and cancer. Recent experimental and clinical evidence shows that TMAO may serve as a diagnostic and prognostic marker of many pathologic conditions. Therefore, rapid determination of serum TMAO concentration is of clinical interest. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile acids, indoles, different gases, neurotransmitters, vitamins, and complex lipids, are discussed in relation to their CVD-promoting or preventing activities. Molecules of mixed microbial and human hepatic origin, such as trimethylamine N-oxide and phenylacetylglutamine, are also presented. Finally, dietary agents with cardioprotective effects, such as probiotics, prebiotics, mono- and poly-unsaturated fatty acids, carotenoids, and polyphenols, are also discussed. A special emphasis is given to their gut microbiota-modulating properties. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a liver disease causing different progressive pathological changes. Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, is a specific agonist of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the endoplasmic reticulum stress (ERS) pathways. TMAO has been associated with the occurrence and development of NAFLD based on the results of previous studies, but whether the simple consumption of TMAO can directly induce NAFLD and its underlying mechanism remain unclear. To investigate this question, we constructed an animal model in which adult male zebrafish were fed a controlled diet containing 1 % or 3 % TMAO for 20 weeks. Eventually, we observed that TMAO caused lipid accumulation, inflammatory infiltration, liver injury and liver fibrosis in zebrafish livers; meanwhile, the PERK signaling pathway was activated in the zebrafish livers. This finding was further confirmed in HepG2 cells and hepatic stellate cells models. In conclusion, this study found that TMAO directly induced different pathological states of NAFLD in zebrafish liver, and the activation of PERK pathway is an important mechanism, which may provide crucial strategies for the diagnosis and treatment of NAFLD. • Hepatic steatosis caused by TMAO mainly occurred at the initial stage of the lesion. • TMAO provoked NASH and promoted liver fibrotic pathological changes in zebrafish. • The activation of PERK pathway was involved in TMAO-induced NAFLD. [ABSTRACT FROM AUTHOR]

The prevalence of pancreatic steatosis has increased and it has been linked to the rising prevalence of metabolic syndrome. Metabolic syndrome is known to have a strong connection with changes in intestinal microbiota. The aim of this study was to explore the relationship between pancreatic steatosis and the levels of trimethylamine N-oxide (TMAO) and butyrate. In this study, 136 individuals were randomly selected from outpatient clinics at Firat University Hospital. The study evaluated their demographic characteristics, anthropometric measurements, and biochemical parameters. The presence of pancreatic steatosis was assessed using abdominal ultrasonography. Additionally, the levels of TMAO and butyrate were measured. The mean age of individuals in the study was 44.5 ± 14.6. 84 of the subjects were females. Using the waist circumference, 61 were considered obese and 34 overweight. The detection rate of pancreatic steatosis was found to be 70.6%. The study found that individuals with steatosis had higher average age, presence of hepatic steatosis, BMI, waist circumference measurements, and presence of metabolic syndrome than those without steatosis. A significantly higher butyrate level was detected in those without steatosis (p = 0.001). TMAO levels were slightly higher in patients without steatosis than in those with steatosis; however, this was insignificant. Pancreatic steatosis is highly associated with alterations in levels of microbiota metabolites, indicating a potential role of these metabolites in the pathogenesis of the disease and subsequent therapeutic targets. Several other factors, such as age, hepatic steatosis, diabetes, and waist circumference, have also been identified as potential predictors of pancreatic steatosis. [ABSTRACT FROM AUTHOR]

Yang Deng,1,* Rui Duan,2,* Ye Hong,2,* Qiang Peng,2 Zhong-Yuan Li,2 Xiang-Liang Chen,2 Ying-Dong Zhang1 1Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, Nanjing, 210006, People’s Republic of China; 2Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang-Liang Chen, Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, Jiangsu, 210006, People’s Republic of China, Email chenxl@njmu.edu.cn Ying-Dong Zhang, Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.68, Changle Road, Nanjing, Jiangsu, 210006, People’s Republic of China, Email zhangyingdong@njmu.edu.cnPurpose: Vascular dementia (VaD) is the second most common dementia in the world. An increasing number of studies have demonstrated the important role of long non-coding RNAs (lncRNAs) in VaD. Our previous investigation demonstrated that Trimethylamine-N-oxide (TMAO) exacerbates cognitive impairment and neuropathological alterations in VaD rats. Thus, we hypothesized that TMAO could play an injury role in VaD by regulating lncRNAs.Materials and Methods: The rats using the bilateral common carotid artery (2VO) model were administered TMAO (120 mg/kg) for 8 consecutive weeks, 4 weeks preoperatively and 4 weeks postoperatively. High-throughput sequencing was conducted to investigate the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was performed to identify potential downstream targets. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of lncRNA fetal-lethal noncoding developmental regulatory RNA (Fendrr), miR-145-5p, and paxillin (PXN). Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. Furthermore, we used the Fendrr loss-of-function assay, miR-145-5p gain-of-function assays and PXN loss-of-function assay to explore the mechanisms by which TMAO acts on VaD.Results: TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr exhibits highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats.Conclusion: The results of this study indicated that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of VaD.Keywords: trimethylamine N-oxide, neuroinflammation, Fendrr, MiR-145-5p, PXN, vascular dementia

Abstract Background Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems. Main body of the manuscript In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis. Conclusion Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions.

Abstract Trimethylamine-n-oxide (TMAO) is a metabolite of intestinal flora following the consumption of phosphatidylcholine-rich foods. Clinical cohort studies have shown that plasma TMAO may be a risk factor for cancer development, including hepatocellular carcinoma (HCC), but fundamental research data supporting this hypothesis are lacking. In this study, HCC cells were treated with TMAO in vivo and in vitro to evaluate the effect on some indicators related to the malignancy degree of HCC, and the relevant molecular mechanisms were explored. In vitro, TMAO promoted the proliferation and migration of HCC cells and significantly upregulated the expression of proteins related to epithelial–mesenchymal transformation (EMT). In vivo, after HCC cells were inoculated subcutaneously in nude mice given water containing TMAO, the tumors grew faster and larger than those in the mice given ordinary water. The immunohistochemistry analysis showed that proliferation, migration and EMT-related proteins in the tumor tissues were significantly upregulated by TMAO. Furthermore, TMAO obviously enhanced the phosphorylation of MAPK signaling molecules in vivo and in vitro. In conclusion, TMAO promotes the proliferation, migration and EMT of HCC cells by activating the MAPK pathway.

Abstract An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N‐oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO‐induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ‐free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO‐related POCD and improving the quality of life for elderly patients.

Abstract Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia–reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was − 5.44, and the MM-GBSA result of − 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes.

Background: Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems. Main body of the manuscript: In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis. Conclusion: Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions. [ABSTRACT FROM AUTHOR]

Trimethylamine-n-oxide (TMAO) is a metabolite of intestinal flora following the consumption of phosphatidylcholine-rich foods. Clinical cohort studies have shown that plasma TMAO may be a risk factor for cancer development, including hepatocellular carcinoma (HCC), but fundamental research data supporting this hypothesis are lacking. In this study, HCC cells were treated with TMAO in vivo and in vitro to evaluate the effect on some indicators related to the malignancy degree of HCC, and the relevant molecular mechanisms were explored. In vitro, TMAO promoted the proliferation and migration of HCC cells and significantly upregulated the expression of proteins related to epithelial–mesenchymal transformation (EMT). In vivo, after HCC cells were inoculated subcutaneously in nude mice given water containing TMAO, the tumors grew faster and larger than those in the mice given ordinary water. The immunohistochemistry analysis showed that proliferation, migration and EMT-related proteins in the tumor tissues were significantly upregulated by TMAO. Furthermore, TMAO obviously enhanced the phosphorylation of MAPK signaling molecules in vivo and in vitro. In conclusion, TMAO promotes the proliferation, migration and EMT of HCC cells by activating the MAPK pathway. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the associations of choline, betaine, dimethylglycine (DMG), L-carnitine, and Trimethylamine-N-oxide (TMAO) with the risk of Gestational diabetes mellitus (GDM) as well as the markers of glucose homeostasis. Methods: We performed a case-control study including 200 diagnosed GDM cases and 200 controls matched by maternal age (±2 years) and gestational age (±2 weeks). Concentrations of serum metabolites were measured by the high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). Results: Compared to the control group, GDM group had significantly lower serum betaine concentration and betaine/choline ratio, and higher DMG concentration. Furthermore, decreased betaine concentration and betaine/choline ratio, increased DMG concentration showed significant association with the risk of GDM. In addition, serum betaine concentrations were negatively associated with blood glucose levels at 1-h post-glucose load (OGTT-1h), and both betaine and L-carnitine concentrations were positively associated with 1,5-anhydroglucitol levels. Betaine/choline ratio was negatively associated with OGTT-1h and blood glucose levels at 2-h post-glucose load (OGTT-2h) and serum choline concentrations were negatively associated with fasting blood glucose and positively associated with OGTT-2h. Conclusion: Decreased serum betaine concentrations and betaine/choline ratio, and elevated DMG concentrations could be significant risk factors for GDM. Furthermore, betaine may be associated with blood glucose regulation and short-term glycemic fluctuations. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota has significant impact on the cardio-metabolism and inflammation, and is implicated in the pathogenesis and progression of atherosclerosis. However, the long-term prospective association between trimethylamine N-oxide (TMAO) level and major adverse clinical events (MACEs) in patients with coronary artery disease (CAD) with or without diabetes mellitus (DM) habitus remains to be investigated. Methods: This prospective, single-center cohort study enrolled 2090 hospitalized CAD patients confirmed by angiography at Beijing Hospital from 2017-2020. TMAO levels were performed using liquid chromatography-tandem mass spectrometry. The composite outcome of MACEs was identified by clinic visits or interviews annually. Multivariate Cox regression analysis, Kaplan-Meier analysis, and restricted cubic splines were mainly used to explore the relationship between TMAO levels and MACEs based on diabetes mellitus (DM) habitus. Results: During the median follow-up period of 54 (41, 68) months, 266 (12.7%) developed MACEs. Higher TMAO levels, using the tertile cut-off value of 318.28 ng/mL, were significantly found to be positive dose-independent for developing MACEs, especially in patients with DM (HR 1.744, 95%CI 1.084-2.808, p = 0.022). Conclusions: Higher levels of TMAO are significantly associated with long-term MACEs among CAD patients with DM. The combination of TMAO in patients with CAD and DM is beneficial for risk stratification and prognosis. [ABSTRACT FROM AUTHOR]

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N‐oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO‐induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ‐free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO‐related POCD and improving the quality of life for elderly patients. [ABSTRACT FROM AUTHOR]

• The novelty is that MTHFR genotype may modulate the response to betaine intake. • Betaine concentrations increase more in TT/CT compared to CC. • Betaine supplementation decreases serum homocysteine concentration. • Betaine does not affect amino acid profile in healthy, athletic males. • The effect of betaine was not dose dependent. Betaine supplementation is used by athletes, but its mechanism of action is still not fully understood. We hypothesized that betaine supplementation would increase betaine concentration and alter amino acid profiles in relation to MTHFR genotype and dose in physically active males. The study followed a randomized placebo-controlled cross-over design. Blood samples were collected before and after each supplementation period. Serum was analyzed for amino acid profile, homocysteine, betaine, choline, and trimethylamine N-oxide (TMAO) concentrations. For the washout analysis, only participants starting with betaine were included (n = 20). Statistical analysis revealed no differences in the amino acid profile after betaine supplementation. However, betaine concentration significantly increased after betaine supplementation (from 4.89 ± 1.59 µg/mL to 17.31 ± 9.21 µg/mL, P <.001), with a greater increase observed in MTHFR (C677T, rs180113) T-allele carriers compared to CC (P =.027). Betaine supplementation caused a decrease in homocysteine concentration (from 17.04 ± 4.13 µmol/L to 15.44 ± 3.48 µmol/L, P =.00005) and a non-significant increase in TMAO concentrations (from 0.27 ± 0.20 µg/ml to 0.44 ± 0.70 µg/ml, P =.053), but had no effect on choline concentrations. Serum betaine concentrations were not significantly different after the 21-day washout from the baseline values (baseline: 4.93 ± 1.87 µg/mL and after washout: 4.70 ± 1.70 µg/mL, P = 1.000). In conclusion, betaine supplementation increased betaine and decreased homocysteine concentrations, but did not affect the amino acid profile or choline concentrations in healthy active males. Betaine concentrations may be dependent on MTHFR genotype. This was a randomized cross-over study of betaine supplementation in healthy athletic males. We showed that the increase in serum betaine concentrations was dependent on MTHFR genotype. Specifically, T-allele carriers experienced greater increase in betaine concentrations than CC homozygotes. Homocysteine concentration decreased with betaine supplementation. Abbreviations: BET, betaine; Hcy, homocysteine; MTHFR, methylenetatrahydrofolate; PL, placebo; WO, washout. [Display omitted] [ABSTRACT FROM AUTHOR]

Reductive N‐11C‐methylation using [11C]formaldehyde and amines has been used to prepare N‐11C‐methylated compounds. However, the yields of the N‐11C‐methylated compounds are often insufficient. In this study, we developed an efficient method for base‐free reductive N‐11C‐methylation that is applicable to a wide variety of substrates, including arylamines bearing electron‐withdrawing and electron‐donating substituents. A 2‐picoline borane complex, which is a stable and mild reductant, was used. Dimethyl sulfoxide was used as the primary reaction solvent, and glacial acetic acid or aqueous acetic acid was used as a cosolvent. While reductive N‐11C‐methylation efficiently proceeded under anhydrous conditions in most cases, the addition of water to the reductive N‐11C‐methylation generally increased the yield of the N‐11C‐methylated compounds. Substrates with hydroxy, carboxyl, nitrile, nitro, ester, amide, and phenone moieties and amine salts were applicable to the reaction. This proposed method for reductive N‐11C‐methylation should be applicable to a wide variety of substrates, including thermo‐labile and base‐sensitive compounds because the reaction was performed under relatively mild conditions (70°C) without the need for a base. [ABSTRACT FROM AUTHOR]

Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia–reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was − 5.44, and the MM-GBSA result of − 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes. [ABSTRACT FROM AUTHOR]

It is inconclusive whether trimethylamine N-oxide (TMAO) and choline and related metabolites, namely trimethylamine (TMA), l-carnitine, betaine and dimethylglycine (DMG), are associated with non-alcoholic fatty liver disease (NAFLD). Our objective was to investigate these potential associations. Additionally, we sought to determine the mediating role of TMAO. In this 1:1 age- and sex-matched case–control study, a total of 150 pairs comprising NAFLD cases and healthy controls were identified. According to the fully adjusted model, after the highest tertile was compared with the lowest tertile, the plasma TMAO concentration (OR = 2·02 (95 % CI 1·04, 3·92); P trend = 0·003), l-carnitine concentration (OR = 1·79 (1·01, 3·17); P trend = 0·020) and DMG concentration (OR = 1·81 (1·00, 3·28); P trend = 0·014) were significantly positively associated with NAFLD incidence. However, a significantly negative association was found for plasma betaine (OR = 0. 50 (0·28, 0·88); P trend = 0·001). The restricted cubic splines model consistently indicated positive dose–response relationships between exposure to TMAO, l-carnitine, and DMG and NAFLD risk, with a negative association being observed for betaine. The corresponding AUC increased significantly from 0·685 (0·626, 0·745) in the traditional risk factor model to 0·769 (0·716, 0·822) when TMAO and its precursors were included (l-carnitine, betaine and choline) (P = 0·032). Mediation analyses revealed that 14·7 and 18·6 % of the excess NAFLD risk associated with l-carnitine and DMG, respectively, was mediated by TMAO (the P values for the mediating effects were 0·021 and 0·036, respectively). These results suggest that a higher concentration of TMAO is associated with increased NAFLD risk among Chinese adults and provide evidence of the possible mediating role of TMAO. [ABSTRACT FROM AUTHOR]

A notable shift in understanding the human microbiome's influence on cardiovascular disease (CVD) is underway, although the causal association remains elusive. A systematic review and meta-analysis were conducted to synthesise current knowledge on microbial taxonomy and metabolite variations between healthy controls (HCs) and those with CVD. An extensive search encompassing three databases identified 67 relevant studies (2012–2023) covering CVD pathologies from 4707 reports. Metagenomic and metabolomic data, both qualitative and quantitative, were obtained. Analysis revealed substantial variability in microbial alpha and beta diversities. Moreover, specific changes in bacterial populations were shown, including increased Streptococcus and Proteobacteria and decreased Faecalibacterium in patients with CVD compared with HC. Additionally, elevated trimethylamine N-oxide levels were reported in CVD cases. Biochemical parameter analysis indicated increased fasting glucose and triglycerides and decreased total cholesterol and low- and high-density lipoprotein cholesterol levels in diseased individuals. This study revealed a significant relationship between certain bacterial species and CVD. Additionally, it has become clear that there are substantial inconsistencies in the methodologies employed and the reporting standards adhered to in various studies. Undoubtedly, standardising research methodologies and developing extensive guidelines for microbiome studies are crucial for advancing the field. [ABSTRACT FROM AUTHOR]

Background: Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N‐oxide (TMAO) and its precursors, choline, L‐carnitine, and betaine. Methods: Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L‐carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori–selected dietary exposures with the four metabolites were also investigated. Results: TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24–2.92; p =.003] and 1.26 [1.17–1.36; p <.0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76–0.79; p <.001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p =.0003). Conclusions: Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology. In a prospective study among men and women in the United States, we measured circulating trimethylamine N‐oxide (TMAO), choline, betaine, and L‐carnitine and found that TMAO and choline were positively associated with distal colon cancers. Our findings support future studies into underlying mechanisms and potential TMAO‐targeted interventions to mitigate colorectal cancer risk. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study was to investigate the relationship between missed abortion and serum trimethylamine N‐oxide (TMAO) levels. Methods: A total of 129 patients with 56 missed abortions and 73 healthy pregnancies were included in our study. Patients who had more than one pregnancy loss, had systemic disease (hypertension, diabetes, rheumatologic disease, hematologic disease, and so forth) and did not accept to participate in the study were excluded. Pregnant women who did not have a fetal heartbeat in the first 20th week of pregnancy were considered as missed abortion. Demographic characteristics of the patients were recorded. The serum TMAO levels of these patients were compared with the serum TMAO levels of healthy pregnant women with the same gestational week between the two groups. Results: The median (IQR) serum level of TMAO was significantly higher in woman with missed abortus compared to the healthy controls (201.5 [IQR, 129.75–345] vs 150 [IQR, 86.9–273], U = 1534, P = 0.015, rrb = 0.25 [95% CI: 0.05–0.43]). We observed a positive and significant relationship between serum TMAO levels and age of the patients (Spearman's rho = 0.272 [95% CI: 0.01–0.50], P = 0.043). However, no significant relationship was found between serum TMAO levels and BMI (Spearman's rho = 0.093 [95% CI: −0.18 to 0.35], P = 0.496). Conclusion: In our study, we found that the serum TMAO level was higher in patients with missed abortion compared to healthy pregnancies. Serum TMAO levels measured at early gestational weeks can provide information about the course of pregnancy. [ABSTRACT FROM AUTHOR]

Background/Aim: Thoracic traumas cause life-threatening problems ranging from pulmonary contusion to multi-organ injuries. One of the most common complications of these traumas is acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). It is important to establish a biochemical marker to determine the severity of traumatic injuries and to monitor the inflammatory process. In this study, we aimed to measure the serum concentration of trimethylamine N-oxide (TMAO) and to investigate the diagnostic value of this metabolite in a low (3.31 joules), medium (6.62 joules) and high energy (9.93 joules) model of blunt thoracic trauma in rabbits. Material and methods: In this study, 27 New Zealand rabbits were divided into four groups: Control, low energy trauma group, medium energy trauma group, and high energy trauma group. Blood samples were collected at 1st, 12th and 24th hours after thoracic trauma. Results: Statistically significant differences in TMAO levels were found both within and between groups (p<0.0001). Conclusion: TMAO levels increased especially in the first hour following trauma and decreased at 12th and 24th hours compared to the first hour (in moderate and high energy trauma groups). These findings suggest that TMAO levels may be related to the severity and timing of trauma. In ALI resulting from blunt thoracic trauma induced at different energy levels, TMAO levels varied between groups and were associated with the timing and severity of trauma. These findings suggest that TMAO levels may be valuable in evaluating the prognosis of trauma and monitoring the inflammatory process. [ABSTRACT FROM AUTHOR]

There are conflicting animal experiments on the effect of trimethylamine N-oxide (TMAO), the dietary metabolite, on non-alcoholic fatty liver disease (NAFLD). This study aims to determine the effect of TMAO on NAFLD. A diet containing 0.3% TMAO was fed to farnesoid X receptor (Fxr)-null mice, a model of NAFLD, for 13 weeks. Fxr-null mice fed TMAO showed significant reductions in liver damage markers but not wild-type mice. Hepatic bile acid and cholesterol levels were significantly decreased, and triacylglycerol levels tended to decrease in TMAO-fed Fxr-null mice. Changes in mRNA levels of hepatic bile acid and cholesterol transporters and synthetic enzymes were observed, which could explain the decreased hepatic bile acid and cholesterol levels in Fxr-null mice given the TMAO diet but not in the wild-type mice. These results suggest that TMAO intake ameliorates liver damage in Fxr-null mice, further altering bile acid/cholesterol metabolism in an FXR-independent manner. [ABSTRACT FROM AUTHOR]

Background: Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. Methods: In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. Results: The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway- related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. Conclusion: This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. Methods: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. Results: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55–7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41–8.05, p = 0.006) and 4.72 (95%CI: 1.47–15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). Conclusion: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention. [ABSTRACT FROM AUTHOR]

ObjectiveThe 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).MethodsGut 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.ResultsMR 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.ConclusionOur 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.

AimElevated plasma trimethylamine N-oxide (TMAO) is related to atherosclerosis. Whether the relationship of TMAO and coronary heart disease (CHD) is influenced by sex or age is uncertain. We aim to explore the sex and age differences in the relationship between plasma TMAO and CHD risk and severity.MethodsA case–control study was conducted in patients undergoing elective coronary angiography. Matched by sex, age (±2 years), and operation date (±180 days), a total of 429 CHD case–control pairs were included. Plasma TMAO was quantified using liquid chromatography–tandem mass spectrometry. Logistic regression analyses were performed to evaluate the association between plasma TMAO and CHD risk and severity.ResultsThe overall median (interquartile range) plasma TMAO level was 0.11 (0.06–0.18) μg/ml. After stratification by sex and age, and adjustment for common CHD risk factors, the association between TMAO and CHD risk was significant in the older (≥65 years) male subgroup [odds ratios (OR) = 1.57, 95% confidence interval (CI): 1.09–2.28, P = 0.016], but not in other sex–age subgroups (all P > 0.05). The relationship of plasma TMAO and CHD risk was modified by age (adjusted Pinteraction = 0.001) in male individuals. Plasma TMAO was also associated with a higher risk of multi-vessel disease in male patients with CHD (OR = 1.65, 95% CI: 1.18–2.32, P = 0.004), but not in females.ConclusionsPlasma TMAO is significantly positively associated with the risk and severity of CHD in Chinese men. Age has an interactive effect on the relationship between plasma TMAO and CHD risk in men. Our findings warrant further investigation.

Abstract Background Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. Methods Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. Results Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100–4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019–2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358–0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245–0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367–0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231–0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. Conclusions Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

Xiaoxiao Zhao,1 Hanjun Zhao,1 Runzhen Chen,1 Jiannan Li,1 Jinying Zhou,1 Nan Li,1 Shaodi Yan,2 Chen Liu,1 Peng Zhou,1 Yi Chen,1 Li Song,1 Hongbing Yan2 1Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, BeiJing, People’s Republic of China; 2Department of Cardiology, Fuwai Hospital Chinese Academy of Medical Sciences, ShenZhen, People’s Republic of ChinaCorrespondence: Hanjun Zhao, Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, No. 167, Beijing, 100037, People’s Republic of China, Tel +86-15210020808, Email 15210020808@163.com Hongbing Yan, Fuwai Hospital, Chinese Academy of Medical Sciences, 12 Langshan Road, Shenzhen, 518000, People’s Republic of China, Tel +86-1301339287, Email hbyanfuwai2018@163.comBackground and Aim: An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown.Methods: We studied 274 consecutive aged ≥ 18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019.Outcomes: There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723– 0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p= 0.033). A similar tendency was found in the cohort with hyperlipidemia (p= 0.016) and diabetes mellitus (p= 0.036).Conclusion: This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics.Trial Registration: This study was registered at ClinicalTrials.gov as NCT03593928.Keywords: optical coherence tomography, triglyceride glucose index, trimethylamine N-oxide, high risk plaque feature, major adverse cardiovascular events, prospective study

Abstract Background Cervical cancer (CC) is a danger to women’s health, especially in many developing countries. Metabolomics can make the connection between genotypes and phenotypes. It provides a wide spectrum profile of biological processes under pathological or physiological conditions. Method In this study, we conducted plasma metabolomics of healthy volunteers and CC patients and integratively analyzed them with public CC tissue transcriptomics from Gene Expression Omnibus (GEO). Result Here, we screened out a panel of 5 metabolites to precisely distinguish CC patients from healthy volunteers. Furthermore, we utilized multi-omics approaches to explore patients with stage I-IIA1 and IIA2-IV4 CC and comprehensively analyzed the dysregulation of genes and metabolites in CC progression. We identified that plasma levels of trimethylamine N-oxide (TMAO) were associated with tumor size and regarded as a risk factor for CC. Moreover, we demonstrated that TMAO could promote HeLa cell proliferation in vitro. In this study, we delineated metabolic profiling in healthy volunteers and CC patients and revealed that TMAO was a potential biomarker to discriminate between I-IIA1 and IIA2-IV patients to indicate CC deterioration. Conclusion Our study identified a diagnostic model consisting of five metabolites in plasma that can effectively distinguish CC from healthy volunteers. Furthermore, we proposed that TMAO was associated with CC progression and might serve as a potential non-invasive biomarker to predict CC substage. Impact These findings provided evidence of the important role of metabolic molecules in the progression of cervical cancer disease, as well as their ability as potential biomarkers.

The Mediterranean diet (MD), rich in minimally processed plant foods and in monounsaturated fats but low in saturated fats, meat, and dairy products, represents one of the most studied diets for cardiovascular health. It has been shown, from both observational and randomized controlled trials, that MD reduces body weight, improves cardiovascular disease surrogates such as waist-to-hip ratios, lipids, and inflammation markers, and even prevents the development of fatal and nonfatal cardiovascular disease, diabetes, obesity, and other diseases. However, it is unclear whether it offers cardiovascular benefits from its individual components or as a whole. Furthermore, limitations in the methodology of studies and meta-analyses have raised some concerns over its potential cardiovascular benefits. MD is also associated with characteristic changes in the intestinal microbiota, mediated through its constituents. These include increased growth of species producing short-chain fatty acids, such as Clostridium leptum and Eubacterium rectale, increased growth of Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii species, and reduced growth of Firmicutes and Blautia species. Such changes are known to be favorably associated with inflammation, oxidative status, and overall metabolic health. This review will focus on the effects of MD on cardiovascular health through its action on gut microbiota. [ABSTRACT FROM AUTHOR]

Background and Aims: Emerging evidence suggests a detrimental impact of high red meat intake on hepatic steatosis. We investigated the potential interplay between red meat intake and gut microbiome on circulating levels of trimethylamine N‐oxide (TMAO) and hepatic steatosis risk. Methods: This cross‐sectional study was conducted in a representative sample of 754 community‐dwelling adults in Huoshan, China. Diet was collected using 4 quarterly 3 consecutive 24‐h dietary (12‐day) recalls. We profiled faecal microbiome using 16S ribosomal RNA sequencing and quantified serum TMAO and its precursors using LC‐tandem MS (n = 333). We detected hepatic steatosis by FibroScan. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Results: TMAO levels but not its precursors were positively associated with the likelihood of hepatic steatosis (aOR per 1‐SD increment 1.86, 95% CI 1.04–3.32). We identified 14 bacterial genera whose abundance was associated with TMAO concentration (pFDR <.05) belonging to the phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria families. Per 10 g/day increase in red meat intake was positively associated with TMAO levels among participants who had higher red meat intake (>70 g/day) and higher TMAO‐predicting microbial scores (TMS, β =.045, p =.034), but not among others (pinteraction =.030). TMS significantly modified the positive association between red meat and steatosis (pinteraction =.032), with a stronger association being observed among participants with higher TMS (aOR 1.30, 95% CI 1.07–1.57). Conclusions: The bacterial genera that predicted TMAO levels may jointly modify the association between red meat intake and TMAO levels and the subsequent risk of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Trimethylamine-N-oxide (TMAO) is a common intestinal metabolite. The Choline in the nutrient forms TMA under the action of the gut microbiota, which passes through the liver and eventually forms TMAO. Initial studies of TMAO focused on cardiovascular disease, but as research progressed, TAMO's effects were found to be multisystem and closely related to the development of neurological diseases. Intestinal tract is the organ with the largest concentration of bacteria in human body, and the composition and metabolism of gut microbiota affect human health. As a two-way communication axis connecting the central nervous system and the gastrointestinal tract, the brain-gut axis provides the structural basis for TMAO to play its role. This article will review the correlation between TMA/TMAO and neurological diseases in order to find new directions and new targets for the treatment of neurological diseases. [ABSTRACT FROM AUTHOR]

Background: Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. Methods: Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. Results: Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100–4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019–2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358–0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245–0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367–0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231–0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. Conclusions: Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically. [ABSTRACT FROM AUTHOR]

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 μM vs. 1.85, IQR: 1.40 to 3.35 μM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or β-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management. [Display omitted] • Plasma levels of TMAO were significantly higher in AD patients compared with those in healthy subjects. • TMAO aggravates the development of AD. • TMAO induces EC dysfunction and activates the NF-κB signaling pathway. • Gut microbiota may be a new therapeutic target in AD. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer (CC) is a danger to women's health, especially in many developing countries. Metabolomics can make the connection between genotypes and phenotypes. It provides a wide spectrum profile of biological processes under pathological or physiological conditions. Method: In this study, we conducted plasma metabolomics of healthy volunteers and CC patients and integratively analyzed them with public CC tissue transcriptomics from Gene Expression Omnibus (GEO). Result: Here, we screened out a panel of 5 metabolites to precisely distinguish CC patients from healthy volunteers. Furthermore, we utilized multi-omics approaches to explore patients with stage I-IIA1 and IIA2-IV4 CC and comprehensively analyzed the dysregulation of genes and metabolites in CC progression. We identified that plasma levels of trimethylamine N-oxide (TMAO) were associated with tumor size and regarded as a risk factor for CC. Moreover, we demonstrated that TMAO could promote HeLa cell proliferation in vitro. In this study, we delineated metabolic profiling in healthy volunteers and CC patients and revealed that TMAO was a potential biomarker to discriminate between I-IIA1 and IIA2-IV patients to indicate CC deterioration. Conclusion: Our study identified a diagnostic model consisting of five metabolites in plasma that can effectively distinguish CC from healthy volunteers. Furthermore, we proposed that TMAO was associated with CC progression and might serve as a potential non-invasive biomarker to predict CC substage. Impact: These findings provided evidence of the important role of metabolic molecules in the progression of cervical cancer disease, as well as their ability as potential biomarkers. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhagic stroke, characterized by acute hemorrhage in the brain, has a significant clinical prevalence and poses a substantial threat to individuals' well-being and productivity. Recent research has elucidated the role of gut microorganisms and their metabolites in influencing brain function through the microbiota-gut-brain axis (MGBA). This article provides a comprehensive review of the current literature on the common metabolites, short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), produced by gut microbiota. These metabolites have demonstrated the potential to traverse the blood-brain barrier (BBB) and directly impact brain tissue. Additionally, these compounds have the potential to modulate the parasympathetic nervous system, thereby facilitating the release of pertinent substances, impeding the buildup of inflammatory agents within the brain, and manifesting anti-inflammatory properties. Furthermore, this scholarly analysis delves into the existing dearth of investigations concerning the influence of gut microorganisms and their metabolites on cerebral functions, while also highlighting prospective avenues for future research. [ABSTRACT FROM AUTHOR]

Gut microbes play a pivotal role in host physiology by producing beneficial or detrimental metabolites. Gut bacteria metabolize dietary choline and L‐carnitine to trimethylamine (TMA) which is then converted to trimethylamine‐N‐oxide (TMAO). An elevated circulating TMAO is associated with diabetes, obesity, cardiovascular disease, and cancer in humans. In the present study, we investigated the effect of dietary blueberries and strawberries at a nutritional dosage on TMA/TMAO production and the possible role of gut microbes. Blueberry cohort mice received a control (C) or freeze‐dried blueberry supplemented (CB) diet for 12 weeks and subgroups received an antibiotics cocktail (CA and CBA). Strawberry cohort mice received a control (N) or strawberry‐supplemented (NS) diet and subgroups received antibiotics (NA and NSA). Metabolic parameters, choline, TMA, and TMAO were assessed in addition to microbial profiling and characterization of berry powders. Blueberry supplementation (equivalent to 1.5 human servings) reduced circulating TMAO in CB versus C mice (~48%) without changing choline or TMA. This effect was not mediated through alterations in metabolic parameters. Dietary strawberries did not reduce choline, TMA, or TMAO. Depleting gut microbes with antibiotics in these cohorts drastically reduced TMA and TMAO to not‐quantified levels. Further, dietary blueberries increased the abundance of bacterial taxa that are negatively associated with circulating TMA/TMAO suggesting the role of gut microbes. Our phenolic profiling indicates that this effect could be due to chlorogenic acid and increased phenolic contents in blueberries. Our study provides evidence for considering dietary blueberries to reduce TMAO and prevent TMAO‐induced complications. [ABSTRACT FROM AUTHOR]

Trimethylamine N-oxide, Me3N(+)O(−), is an important molecule in biology and medicine. Herein, a survey of the interactions involving the oxide-O atom in crystals containing derivatives of Me3N(+)O(−), namely RR′R″N(+)O(−), is presented; R,R′, R″ = alkyl and/or aryl. A total of 119 RR′R″N(+)O(−) molecules were analysed for the supramolecular interactions involving the oxide-O atom. Hydrates form the largest class of crystals, comprising over 40 % of the 91 crystals investigated, a value slightly higher than expectation. Over 80 % of molecules had at least one O–H⋯O(−)(oxide) hydrogen bond: 3, 45 and 33 % of all molecules had three, two or one O–H⋯O(−)(oxide) hydrogen bonds, respectively. Further, nearly 15 % of molecules formed at least one N–H⋯O(−)(oxide) hydrogen bond, sometimes operating in concert with O–H⋯O(−)(oxide) hydrogen bonds. The overwhelming majority of molecules featured inter- and/or intra-molecular supporting C–H⋯O(−)(oxide) contacts so that a diverse range of supramolecular interaction patterns is apparent, a situation made more complicated by the appearance of different supramolecular association patterns often observed for independent molecules in crystals with more than one molecule in the crystallographic asymmetric-unit. Of the 6 % of molecules devoid of conventional A–H⋯O(−)(oxide) hydrogen bonds, all formed three or four inter-/intra-molecular C–H⋯O(−)(oxide) contacts usually characterised by at least one short H⋯O(−)(oxide) distance. [ABSTRACT FROM AUTHOR]

This study compares two diets, Dietary Approaches to Stop Hypertension (DASH) and a Low-Calorie Diet on Trimethylamine N-oxide (TMAO) levels and gut microbiota. 120 obese adults were randomly allocated to these three groups: a low-calorie DASH diet, a Low-Calorie diet, or a control group for 12 weeks. Outcomes included plasma TMAO, lipopolysaccharides (LPS), and gut microbiota profiles. After the intervention, the low-calorie DASH diet group demonstrated a greater decrease in TMAO levels (-20 ± 8.1 vs. −10.63 ± 4.6 μM) and a significant decrease in LPS concentration (-19.76 ± 4.2 vs. −5.68 ± 2.3) compared to the low-calorie diet group. Furthermore, the low-calorie DASH diet showed a higher decrease in the Firmicutes and Bactericides (F/B) ratio, which influenced TMAO levels, compared to the Low-Calorie diet (p = 0.028). The current study found the low-calorie DASH diet improves TMAO and LPS in comparison to a Low-Calorie diet. [ABSTRACT FROM AUTHOR]

Trimethylamine N-oxide, Me3N(+)O(−), is an important molecule in biology and medicine. Herein, a survey of the interactions involving the oxide-O atom in crystals containing derivatives of Me3N(+)O(−), namely RR′R″N(+)O(−), is presented; R,R′, R″ = alkyl and/or aryl. A total of 119 RR′R″N(+)O(−) molecules were analysed for the supramolecular interactions involving the oxide-O atom. Hydrates form the largest class of crystals, comprising over 40 % of the 91 crystals investigated, a value slightly higher than expectation. Over 80 % of molecules had at least one O–H⋯O(−)(oxide) hydrogen bond: 3, 45 and 33 % of all molecules had three, two or one O–H⋯O(−)(oxide) hydrogen bonds, respectively. Further, nearly 15 % of molecules formed at least one N–H⋯O(−)(oxide) hydrogen bond, sometimes operating in concert with O–H⋯O(−)(oxide) hydrogen bonds. The overwhelming majority of molecules featured inter- and/or intra-molecular supporting C–H⋯O(−)(oxide) contacts so that a diverse range of supramolecular interaction patterns is apparent, a situation made more complicated by the appearance of different supramolecular association patterns often observed for independent molecules in crystals with more than one molecule in the crystallographic asymmetric-unit. Of the 6 % of molecules devoid of conventional A–H⋯O(−)(oxide) hydrogen bonds, all formed three or four inter-/intra-molecular C–H⋯O(−)(oxide) contacts usually characterised by at least one short H⋯O(−)(oxide) distance. [ABSTRACT FROM AUTHOR]

An expanding body of research indicates a correlation between the gut microbiota and various diseases. Metabolites produced by the gut microbiota act as mediators between the gut microbiota and the host, interacting with multiple systems in the human body to regulate physiological or pathological functions. However, further investigation is still required to elucidate the underlying mechanisms. One such metabolite involved in choline metabolism by gut microbes is trimethylamine (TMA), which can traverse the intestinal epithelial barrier and enter the bloodstream, ultimately reaching the liver where it undergoes oxidation catalyzed by flavin-containing monooxygenase 3 (FMO3) to form trimethylamine N-oxide (TMAO). While some TMAO is eliminated through renal excretion, remaining amounts circulate in the bloodstream, leading to systemic inflammation, endoplasmic reticulum (ER) stress, mitochondrial stress, and disruption of normal physiological functions in humans. As a representative microbial metabolite originating from the gut, TMAO has significant potential both as a biomarker for monitoring disease occurrence and progression and for tailoring personalized treatment strategies for patients. This review provides an extensive overview of TMAO sources and its metabolism in human blood, as well as its impact on several major human diseases. Additionally, we explore the latest research areas related to TMAO along with future directions.

Yue Yue,1,&ast; Han-Bo Cui,2,&ast; Yue-Jie Chu,2 Gui-Ling Zheng1 1Department of Endocrinology, The 983 Hospital of the Joint Logistics Force of the Chinese People’s Liberation Army, Tianjin, People’s Republic of China; 2Department of Diabetes, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yue-Jie Chu, Department of Diabetes, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, 354 North Road, Hongqiao District, Tianjin, 300120, People’s Republic of China, Tel +8613920513352, Email chuyuejie0710@126.comObjective: We aimed to analyze the mechanisms underlying spleen-and-stomach-tonifying, yin-fire-purging, and yang-raising decoction derived from the trimethylamine N-oxide (TMAO) metabolic pathway of intestinal microbiota in the treatment of macrovascular lesions caused by type 2 diabetes mellitus (T2DM).Methods: Hartley-guinea pigs were randomly divided into 3 groups—the blank, model, and intervention groups. The T2DM combined with atherosclerosis guinea pig models were established in the model and intervention groups. After successful modeling, spleen-and-stomach-tonifying, yin-fire-purging, and yang-raising decoction were administered intragastrically to the intervention group, while the same volume of normal saline was administered via gavage to the blank and model groups. After 6 weeks of continuous gavage, guinea pigs were sacrificed in all groups, the colon contents were obtained, and the diversity and structural differences of intestinal microbiota were analyzed via bioinformatics. Serum was collected to detect differences in lipids, TMAO, oxidative stress, and inflammation markers between groups.Results: Compared to the blank group, the species diversity of the intestinal microbiota in the model and intervention groups was significantly reduced. Based on the results of Analysis of Similarities and Multiple Response Permutation Procedure, the microbiota structure of the intervention group was closer to that of the blank group. After modeling, the blood lipid levels of guinea pigs increased significantly, and drug intervention significantly reduced the levels of TC, TG, and LDL-C (P < 0.05). TMAO expression was significantly increased after modeling (P < 0.05), while drug intervention reduced TMAO expression (P < 0.05). Compared to the model group, drug intervention significantly increased the concentrations of SOD while decreasing the concentrations of MDA, ICAM-1, VCAM-1, IL-6, and hs-CRP.Conclusion: Spleen-and-stomach-tonifying, yin-fire-purging, and yang-raising decoction can reduce the risk of macrovascular lesions in T2DM, and its mechanism may be associated with its ability to regulate the TMAO metabolic pathway of intestinal microbiota.Keywords: intestinal microbiota, macrovascular lesions, spleen-and-stomach-tonifying, yin-fire-purging, and yang-raising decoction, trimethylamine N-oxide, type 2 diabetes mellitus

AIM: To provide the direct evidence for the crucial role of trimethylamine N-oxide (TMAO) in vascular permeability and endothelial cell dysfunction under diabetic condition. METHODS: The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells (HRMEC) under high glucose conditions was tested by a cell counting kit, wound healing, a transwell and a tube formation assay. The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction (RT-PCR). The expression of the cell junction was measured by Western blotting (WB) and immunofluorescence staining. In addition, two groups of rat models, diabetic and non-diabetic, were fed with normal or 0.1% TMAO for 16wk, and their plasma levels of TMAO, vascular endothelial growth factor (VEGF), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were tested. The vascular permeability of rat retinas was measured using FITC-Dextran, and the expression of zonula occludens (ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining. RESULTS: TMAO administration significantly increased the cell proliferation, migration, and tube formation of primary HRMEC either in normal or high-glucose conditions. RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation, while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment. Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage, which were even higher in TMAO-feeding diabetic rats. Furthermore, TMAO administration increased the rat plasma levels of VEGF, IL-6 and TNF-α while decreasing the retinal expression levels of ZO-1 and claudin-5. CONCLUSION: TMAO enhances the proliferation, migration, and tube formation of HRMEC, as well as destroys their vascular integrity and tight connection. It also regulates the expression of VEGF, IL-6, and TNF-α.

Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile acids, indoles, different gases, neurotransmitters, vitamins, and complex lipids, are discussed in relation to their CVD-promoting or preventing activities. Molecules of mixed microbial and human hepatic origin, such as trimethylamine N-oxide and phenylacetylglutamine, are also presented. Finally, dietary agents with cardioprotective effects, such as probiotics, prebiotics, mono- and poly-unsaturated fatty acids, carotenoids, and polyphenols, are also discussed. A special emphasis is given to their gut microbiota-modulating properties.

Aim: Phenylacetylglutamine (PAGln) is a phenylalanine‐derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)‐relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Methods and results: Fasting plasma PAGln levels were measured by stable‐isotope‐dilution liquid chromatography–tandem mass spectrometry (LC‐MS/MS) in patients with stable HF from two large cohorts. All‐cause mortality was assessed at 5‐year follow‐up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3‐year follow‐up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4–6.9) μM. Highest quartile of PAGln was associated with 3.09‐fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5‐year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07–2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0–4.8] μM), and PAGln levels were associated with a 1.92‐fold increase in 3‐year HF hospitalization or all‐cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02‐3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N‐oxide levels. Conclusion: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio‐renal risk markers. [ABSTRACT FROM AUTHOR]