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Background: The diagnosis of ulcerative colitis (UC) today is limited to a small number of biomarkers. Trimethylamine-N-oxide (TMAO) is the product of reactions resulting from the degradation of dietary-free choline, phosphatidylcholine, and carnitine metabolism by the intestinal microbiota. Earlier studies showed his involvement in the pathogenesis of UC. To study the association of TMAO with clinical, laboratory, and endoscopic indicators of UC activity. Methods: an observational cross-sectional comparative study was conducted based on the NCJSC "KMU" clinic, Karaganda, Kazakhstan. High-performance liquid chromatography measured TMAO concentration in 63 patients with UC (age Me 37 (30-52) and 38 healthy individuals (age Me 38 (28.5-49.5). Results: Median TMAO level in patients with UC-0.286 μmol/l was significantly lower than in the control group Me 0.646 μmol/l (p<0.0001). TMAO had significant differences in groups with clinically active and inactive colitis (P=0.003). TMAO correlated with disease activity by Montreal scale (r=-0.389, P=0.002) and severity of attack by Truelove-Witts (r=-0.301, P=0.027 respectively), patient's age (r=0.377, P=0.003), stool frequency (r=-0.427, P=0.001); laboratory parameters: WBC (r=-0.31, P=0.042), blood albumin (r=0.379, P=0.002) and fecal calprotectin (r=-0.314, P=0.022). TMAO did not differ between groups divided by the extent of the pathological process and endoscopic activity. Conclusion: in patients with UC, TMAO levels decrease compared with healthy individuals and differences in groups depend on the disease activity. These results give reason to consider changes in TMAO levels as a potential marker of UC and the severity of its course. [ABSTRACT FROM AUTHOR]

Background: Cerebral white matter hyperintensity (WMH) is a pivotal imaging feature of cerebral small vessel disease (CSVD), closely correlated with an elevated risk of ischemic stroke (IS). Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is increasingly associated with IS and atherosclerosis. However, the intricate relationship between TMAO and WMH remains ambiguous. This study aimed to study the connection between plasma TMAO and WMH. Furthermore, it assessed the potential of TMAO as a risk evaluation instrument for WMH. Methods: In this cross-sectional study, we categorized WMH into periventricular WMH (P-WMH) and deep WMH (D-WMH), based on its locations. The severity of WMH was assessed and grouped according to the Fazekas scale. Plasma TMAO levels were quantitatively determined. We established the correlation between plasma TMAO levels and WMH severity using a Logistic regression model. Additionally, we employed ROC curves to evaluate the diagnostic efficacy of plasma TMAO concentration in distinguishing the severity of WMH. Results: A higher plasma TMAO tertile was significantly linked to a higher Fazekas score, encompassing the overall score, P-WMH score, and D-WMH score (p < 0.001). A logical regression analysis revealed that plasma TMAO levels were independently associated with overall moderate and severe WMH, compared to overall non-mild WMH, in the unadjusted model (OR = 1.373, 95%CI 1.183–1.594 for moderate; OR = 1.384, 95%CI 1.192–1.607 for severe), the adjusted model a (OR = 1.436, 95%CI 1.214–1.669 for moderate; OR = 1.446, 95%CI 1.222–1.711 for severe) and the adjusted model b (OR = 1.490, 95%CI 1.234–1.800 for moderate; OR = 1.494, 95%CI 1.237–1.805 for severe). The analysis also showed an independent correlation between plasma TMAO levels and WMH severity, irrespective of the unadjusted model, adjusted model a, or adjusted model b, when considering P-WMH and D-WMH severity. The ROC indicated that, in overall WMH and P-WMH, the area under curve (AUC) for non-mild and severe WMH were both>0.5, while the AUC for moderate WMH was<0.5. In contrast, in D-WMH, the AUC for non-mild, moderate, and severe WMH were all>0.5. Conclusion: Plasma TMAO levels exhibited a significant correlation with both overall and region-specific WMH severity. Furthermore, the plasma TMAO levels displayed robust predictive capability for D-WMH. [ABSTRACT FROM AUTHOR]

The gut microbiota is a complex ecosystem that influences digestion, immune response, metabolism, and has been linked to health and well-being. Choline is essential for neurotransmitters, lipid transport, cell-membrane signaling, methyl-group metabolism and is believed to have neuroprotective properties. It is found in two forms, water-soluble and lipid-soluble, and its metabolism is different. Long-term choline deficiency is associated with many diseases, and supplements are prescribed for improved health. Choline supplements can improve cognitive function in adults but not significantly. Choline is a precursor of phospholipids and an acetylcholine neurotransmitter precursor and can be generated de novo from phosphatidylcholine via phosphatidylethanolamine-N-methyltransferase and choline oxidase. Choline supplementation has been found to have a beneficial effect on patients with neurodegenerative diseases, such as Alzheimer's disease (AD), by increasing amyloid-β, thioflavin S, and tau hyper-phosphorylation. Choline supplementation has been shown to reduce amyloid-plaque load and develop spatial memory in an APP/PS1 mice model of AD. Choline is necessary for normative and improved function of brain pathways and can reduce amyloid-β deposition and microgliosis. Clinical research suggests that early neurodegenerative diseases (NDs) can benefit from a combination of choline supplements and the drugs currently used to treat NDs in order to improve memory performance and synaptic functioning. [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]

This systematic review explores the relationship between the gut microbiota metabolite trimethylamine N-oxide (TMAO) and heart failure (HF), given the significant impact of TMAO on cardiovascular health. A systematic search and meta-analysis of peerreviewed studies published from 2013 to 2024 were conducted, focusing on adult patients with heart failure and healthy controls. The review found that elevated levels of TMAO are associated with atherosclerosis, endothelial dysfunction, and increased cardiovascular disease risk, all of which can exacerbate heart failure. The analysis also highlights that high TMAO levels are linked to reduced left ventricular ejection fraction (LVEF) and glomerular filtration rate (GFR), further supporting TMAO's role as a biomarker in heart failure assessment. The findings suggest that interventions targeting gut microbiota to reduce TMAO could potentially benefit patients with heart failure, although further research is needed to evaluate the effectiveness of such approaches. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is an idiopathic and heterogeneous large intestine disease, characterized by chronic mucosa and submucosa inflammation. Alteration of the intestinal microbiome in UC may be responsible for modifications in metabolite production. Aim: To investigate the microbiota status and trimethylamine-N-oxide (TMAO) metabolite levels in patients with UC according to clinical and endoscopic activity. Methods: As part of a grant project AP14871959 from September 2022 to October 2023, 31 patients with UC and 15 healthy volunteers over 18 years at the Clinic of NCJSC "KMU" were assessed for blood TMAO level and metagenomic sequencing of fecal microbiome. Results: A significant depletion of the main representatives of Bacteroides, Parabacteroides, Prevotella; and an increase in the relative abundance of the genera Actinomyces, Klebsiella, Limosilactobacillus, Streptococcus, Escherichia-Shigella were detected in patients with UC. The number of p_Actinobacteria (g_Collinsella) and p_Eubacterium (g_Xylanophilum) representatives with genes encoding TMA-trimethylamine conversion is significantly reduced in UC patients. TMAO levels were significantly lower in UC patients than in healthy individuals (0.233 µmol/L, p = 0.004). TMAO decreased with disease severity and significantly differed between patients with different activities (p = 0.034). Conclusions: The composition of the intestinal microbiome changes and the level of TMAO decreases in patients with UC at different activities. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come. [ABSTRACT FROM AUTHOR]

Understanding how gut flora interacts with oxidative stress has been the subject of significant research in recent years. There is much evidence demonstrating the existence of the microbiome–oxidative stress interaction. However, the biochemical basis of this interaction is still unclear. In this narrative review, possible pathways of the gut microbiota and oxidative stress interaction are presented, among which genetic underpinnings play an important role. Trimethylamine-N-oxide, mitochondria, short-chain fatty acids, and melatonin also appear to play roles. Moreover, the relationship between oxidative stress and the gut microbiome in obesity, metabolic syndrome, chronic ethanol consumption, dietary supplements, and medications is considered. An investigation of the correlation between bacterial community features and OS parameter changes under normal and pathological conditions might provide information for the determination of new research methods. Furthermore, such research could contribute to establishing a foundation for determining the linkers in the microbiome–OS association. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here. Methods: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing. Results: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (− 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray–Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats. Conclusions: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities. [ABSTRACT FROM AUTHOR]

The gut‐immune axis is a relatively novel phenomenon that provides mechanistic links between the gut microbiome and the immune system. A growing body of evidence supports it is key in how the gut microbiome contributes to several diseases, including hypertension and cardiovascular diseases (CVDs). Evidence over the past decade supports a causal link of the gut microbiome in hypertension and its complications, including myocardial infarction, atherosclerosis, heart failure, and stroke. Perturbations in gut homeostasis such as dysbiosis (i.e., alterations in gut microbial composition) may trigger immune responses that lead to chronic low‐grade inflammation and, ultimately, the development and progression of these conditions. This is unsurprising, as the gut harbors one of the largest numbers of immune cells in the body, yet is a phenomenon not entirely understood in the context of cardiometabolic disorders. In this review, we discuss the role of the gut microbiome, the immune system, and inflammation in the context of hypertension and CVD, and consolidate current evidence of this complex interplay, whilst highlighting gaps in the literature. We focus on diet as one of the major modulators of the gut microbiota, and explain key microbial‐derived metabolites (e.g., short‐chain fatty acids, trimethylamine N‐oxide) as potential mediators of the communication between the gut and peripheral organs such as the heart, arteries, kidneys, and the brain via the immune system. Finally, we explore the dual role of both the gut microbiome and the immune system, and how they work together to not only contribute, but also mitigate hypertension and CVD. [ABSTRACT FROM AUTHOR]

Understanding how gut flora interacts with oxidative stress has been the subject of significant research in recent years. There is much evidence demonstrating the existence of the microbiome–oxidative stress interaction. However, the biochemical basis of this interaction is still unclear. In this narrative review, possible pathways of the gut microbiota and oxidative stress interaction are presented, among which genetic underpinnings play an important role. Trimethylamine-N-oxide, mitochondria, short-chain fatty acids, and melatonin also appear to play roles. Moreover, the relationship between oxidative stress and the gut microbiome in obesity, metabolic syndrome, chronic ethanol consumption, dietary supplements, and medications is considered. An investigation of the correlation between bacterial community features and OS parameter changes under normal and pathological conditions might provide information for the determination of new research methods. Furthermore, such research could contribute to establishing a foundation for determining the linkers in the microbiome–OS association.

Background: This study aimed to compare and correlate between non-diabetic MetS, newly diagnosed drug naive pre-diabetic MetS patients vs. lean, apparently healthy and normoglycemic controls the plasma levels of cardiometabolic risk biomarkers' of pharmacotherapy (appraised using colorimetric and chromatography assays of gut dysbiosis carnitine, choline, ybutyrobetaine, TMAO, Zonulin, survivin, Leukocyte cell-derived chemotaxin 2 (LECT2) and antioxidative stressors (catalase, superoxide dismutase (SOD) and Trolox total antioxidative capacity), adiposity, and atherogenicity with non-insulin based surrogate insulin resistance (sIR) indices. Methods: ANOVA comparisons and Spearman's rank correlations were conducted in this cross-sectional study of 30 normoglycemic lean subjects (control), 30 nonprediabetic MetS subjects and 30 MetS/pre-diabetic (PreDM) enrolled. Results: MetS-PreDM group presented significantly higher values of FPG (P²<0.001,P³ =0.009) and A1C (P values <0.001) than both normoglycemic MetS and control groups. However, MetS-PreDM and normoglycemic MetS recruits had appreciably higher values of DBP, SBP, TG, and non-HDL-C but significantly lower values of HDL-C (P values <0.001) than the controls. Explicitly no significance in variance was noticeable among any of the study arms (P value < 0.05) for any of the hematological indices. Nevertheless, Both MetS groups (nonprediabetic and PreDM) had substantially higher values for each of adiposity, atherogenecity and surrogate insulin resistance (non insulin based) indices (P²<0.001) vs. controls' respectively. Both Survivin and LECT2 levels were significantly higher in PreDM MetS group (P value < 0.05 vs. nondiabetic MetS participants). Conversely all 5 gut dysbiosis biomarkers (carnitinine, choline, γBB, TMAo and Zonulin) which proved significantly lower vs. those of either controls (nondiabetic lean or MetS). Surprisingly, a significant variation in all tested 7 biomarkers' plasma levels were found between nondiabetic MetS and PreDM-MetS groups (P³ < 0.05). Interestingly all 3 antioxidative stressors were on the decline as anticipated; where catalase, SOD % inhibitions and trolox total antioxidative capacities were significantly lower in both MetS recruits vs. controls. Importantly the discrepancy between normoglycemic nonprediabetic MetS vs. the MetS-PreDM (P³ < 0.05) may have not ranked up to significance in indices, clinical parameters or biomarkers. Notably in pooled MetS (both normoglycemic and pre-diabetics participants (N =60)). Most exquisitely survivin with dysbiosis choline and γBB correlated positively and pronouncedly with carnitine in pooled MetS participants. Also in a striking similarity, cardiometabolic LECT2 has a marked direct relation with each of dysbiosis carnitine and γBB. TMAO, nevertheless, related inversely and significantly with all 3 dysbiosis biomarkers, likewise Zonulin associated disproportionally with both choline and γBB. Exceptionally TMAO- TYG and Zonulin-TYG-WHpR paired in substantial and inverse relations in pooled normoglycemic and preDM MetS participants (n=60). To superbly signify the anticipated deterioration in metabolism via gut microbiota-insulin insensitivity interconnectivity; all dysbiosis biomarkers (carnitine, choline, γBB, TMAO, Zonulin and survivin) correlated highly remarkably and proportionally with all non insulin based surrogate insulin resistance indices in 60 MetS recruits (both normoglycemic and prediabetic; equally). Unequivocally γBB associated directly and pronouncedly with almost all adiposity indices. Surprisingly VAI correlated negatively with Zonulin in the same MetS population. FBG associated exceptionally with carnitine and YButyrobetaine (γBB). Substantially A1c correlated proportionally (P values <0.05) with MetS pooled cases dysbiosis' carnitine, choline, yBB, and cardiometabolic surviving. Outstandingly both SBP and DBP had direct and marked linkage to LECT2 and so did DBP with choline's plasma levels. Remarkably TMAO related negatively and pronouncedly with MetS cases levels of FBG, A1c, TG, LDL-C, and so did also zonulin with both A1c and LDL-C. Conclusions: Given the intergroup discrepancies in dysbiosis and cardiometabolic biomarkers along with their elective correlations with MetS-related indices and clinical parameters; our study cannot rule out any potentiality in molecular crosstalk and interplay of those biomarekers with the pathophysiology of MetS and preDM with their related dysregularities. Carnitine, choline, Ybutyrobetaine, TMAO, Zonulin, survivin, and LECT2 can be putatively surrogate biomarkers to use as prognostic/predictive tools for the diagnosis/prevention and potential targets for MetS treatment. [ABSTRACT FROM AUTHOR]

Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population. Highlights: Exploration of microbiome‐related metabolites (trimethylamine N‐oxide [TMAO], choline, betaine, l‐carnitine, and deoxycarnitine) in 7834 participants from five population cohorts.Cardiovascular risk was associated with elevated choline concentrations, but not with TMAO concentrations.Characterization of the genetic architecture behind metabolite concentration variability.Identification of gut microbial taxonomic abundance associated with metabolite's plasma concentration levels.Fish intake is the major dietary driver of TMAO concentrations, and betaine is related to grains and vegetable intake. [ABSTRACT FROM AUTHOR]

This systematic review explores the relationship between the gut microbiota metabolite trimethylamine N-oxide (TMAO) and heart failure (HF), given the significant impact of TMAO on cardiovascular health. A systematic search and meta-analysis of peer-reviewed studies published from 2013 to 2024 were conducted, focusing on adult patients with heart failure and healthy controls. The review found that elevated levels of TMAO are associated with atherosclerosis, endothelial dysfunction, and increased cardiovascular disease risk, all of which can exacerbate heart failure. The analysis also highlights that high TMAO levels are linked to reduced left ventricular ejection fraction (LVEF) and glomerular filtration rate (GFR), further supporting TMAO’s role as a biomarker in heart failure assessment. The findings suggest that interventions targeting gut microbiota to reduce TMAO could potentially benefit patients with heart failure, although further research is needed to evaluate the effectiveness of such approaches.

Background: Quinic acid (QA) and its derivatives have good lipid-lowering and hepatoprotective functions, but their role in atherosclerosis remains unknown. This study attempted to investigate the mechanism of QA on atherogenesis in Apoe−/− mice induced by HFD. Methods: HE staining and oil red O staining were used to observe the pathology. The PCSK9, Mac-3 and SM22a expressions were detected by IHC. Cholesterol, HMGB1, TIMP-1 and CXCL13 levels were measured by biochemical and ELISA. Lipid metabolism and the HMGB1-SREBP2-SR-BI pathway were detected by PCR and WB. 16 S and metabolomics were used to detect gut microbiota and serum metabolites. Results: QA or low-frequency ABX inhibited weight gain and aortic tissue atherogenesis in HFD-induced Apoe−/− mice. QA inhibited the increase of cholesterol, TMA, TMAO, CXCL13, TIMP-1 and HMGB1 levels in peripheral blood of Apoe−/− mice induced by HFD. Meanwhile, QA or low-frequency ABX treatment inhibited the expression of CAV-1, ABCA1, Mac-3 and SM22α, and promoted the expression of SREBP-1 and LXR in the vascular tissues of HFD-induced Apoe−/− mice. QA reduced Streptococcus_danieliae abundance, and promoted Lactobacillus_intestinalis and Ileibacterium_valens abundance in HFD-induced Apoe−/− mice. QA altered serum galactose metabolism, promoted SREBP-2 and LDLR, inhibited IDOL, FMO3 and PCSK9 expression in liver of HFD-induced Apoe−/− mice. The combined treatment of QA and low-frequency ABX regulated microbe-related Glycoursodeoxycholic acid and GLYCOCHENODEOXYCHOLATE metabolism in HFD-induced Apoe−/− mice. QA inhibited TMAO or LDL-induced HCAECs damage and HMGB1/SREBP2 axis dysfunction, which was reversed by HMGB1 overexpression. Conclusions: QA regulated the gut-liver lipid metabolism and chronic vascular inflammation of TMA/TMAO through gut microbiota to inhibit the atherogenesis in Apoe−/− mice, and the mechanism may be related to the HMGB1/SREBP2 pathway. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have indicated that diarrhea with kidney-yang deficiency syndrome leads to a disorder of small intestine contents and mucosal microbiota. However, the relationship of TMA-lyase (CutC) activity and TMAO with diarrhea with kidney-yang deficiency syndrome remains unexplored. Therefore, this study explores the relationship between cecal microbiota and choline TMA-lyase (CutC) activity, as well as the correlation between trimethylamine oxide (TMAO), inflammatory index, and CutC activity. Method: Twenty SPF-grade male KM mice were randomly divided into the normal group (CN) and the diarrhea model group (CD). Diarrhea mouse models were established by adenine combined with Folium sennae administration. CutC activity, TMAO, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were detected, and the cecal content microbiota was sequenced. Result: After 14  days, diarrhea occurred in the CD group. Compared with the CN group, there was no significant change in the activity of CutC in the small intestine of the CD group, while the activity of CutC in the cecum was significantly increased, and the levels of TMAO, IL-6, and TNF-α showed a significant increase. The Chao1 index, Observed_species index, Shannon index, and Simpson index all exhibited a decreasing trend. The main changes at the bacterial genus level were Alistipes, Enterorhabdus, Desulfovibrio, Bacteroides, Candidatus_Saccharimonas, and [Ruminococcus]_torques_group. The results of LEfSe analysis, random forest analysis and ROC curve analysis revealed Paludicola, Blautia, Negativibacillus, Paraprevotella, Harryflintia, Candidatus_ Soleaferrea, Anaerotruncus, Oscillibacter, Colidextribacter, [Ruminococcus]_ torques_group, and Bacteroides as characteristic bacteria in the CD group. Correlation analysis showed a significant negative correlation between cecal CutC activity and Ligilactobacillus, and a significant positive correlation with Negativibacillus and Paludicola. The level of TMAO was significantly positively correlated with CutC activity and IL-6. Conclusion: Diarrhea with kidney-yang deficiency syndrome significantly affects the physiological status, digestive enzyme activity, CutC activity, TMAO levels, and inflammatory response in mice. Additionally, there are changes in the composition and function of cecal microbiota, indicating an important impact of diarrhea with kidney-yang deficiency syndrome on the host intestinal microbiota balance. The occurrence of diarrhea with kidney-yang deficiency syndrome may be associated with dysbiosis of intestinal microbiota, increased CutC activity, elevated TMAO levels, and heightened inflammatory factor levels. [ABSTRACT FROM AUTHOR]

Overall diet, lifestyle choices, genetic predisposition, and other underlying health conditions may contribute to higher trimethylamine N‐oxide (TMAO) levels and increased cardiovascular risk. This review explores the potential therapeutic ability of RSV to protect against cardiovascular diseases (CVD) and affect TMAO levels. This review considers recent studies on the association of TMAO with CVD. It also examines the sources, mechanisms, and metabolism of TMAO along with TMAO‐induced cardiovascular events. Plant polyphenolic compounds, including resveratrol (RSV), and their cardioprotective mechanism of regulating TMAO levels and modifying gut microbiota are also discussed here. RSV's salient features and bioactive properties in reducing CVD have been evaluated. The close relationship between TMAO and CVD is clearly understood from currently available data, making it a potent biomarker for CVD. Precise investigation, including clinical trials, must be performed to understand RSV's mechanism, dose, effects, and derivatives as a cardioprotectant agent. [ABSTRACT FROM AUTHOR]

The gutmicrobiome is a heterogeneous population ofmicrobes comprising viruses, bacteria, fungi, and protozoa. Such a microbiome is essential for sustaining host equilibrium, and its impact on human health can be altered by a variety of factors such as external variables, social behavior, age, nutrition, and genetics. Gut microbes' imbalances are related to a variety of chronic diseases including cancer, obesity, and digestive disorders. Globally, recent findings show that intestinal microbes have a significant role in the formation of cardiovascular disease (CVD), which is still the primary cause of fatalities. Atherosclerosis, hypertension, diabetes, inflammation, and some inherited variables are all cardiovascular risk variables. However, studies found correlations betweenmetabolism, intestinal flora, and dietary intake. Variations in the diversity of gut microbes and changes in their activity are thought to influence CVD etiology. Furthermore, the gut microbiota acts as an endocrine organ, producing bioactive metabolites such as TMA (trimethylamine)/TMAO (trimethylamine Noxide), SCFA (short-chain fatty acids), and bile acids, which have a substantial impact on host wellness and disease by multiple mechanisms. The purpose of this overview is to compile current evidence highlighting the intricate links between gut microbiota, metabolites, and the development of CVD. It focuses on how intestinal dysbiosis promotes CVD risk factors such as heart failure, hypertension, and atherosclerosis. This review explores the normal physiology of intestinal microbes and potential techniques for targeting gut bacteria for CVD treatment using various microbial metabolites. It also examines the significance of gut bacteria in disease treatment, including supplements, prebiotics, probiotics, antibiotic therapies, and fecal transplantation, which is an innovative approach to the management of CVD. As a result, gut bacteria and metabolic pathways become increasingly attractive as potential targets for CVD intervention. [ABSTRACT FROM AUTHOR]

Abstract Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Trimethylamine N-oxide (TMAO), the oxidized form of trimethylamine (TMA), was previously thought to be a waste product but is now considered an important risk factor for cardiovascular disease (CVD) and its comorbidities. Foods or supplements containing choline and carnitine are major precursors of TMA in the diet and are metabolized by gut microbiota. Trimethylamine N-oxide is produced through the oxidation of this compound by flavin-containing monooxygenase (FMO) in the liver. The organ responsible for the removal of TMAO from body fluids is the kidneys. Therefore, plasma TMAO levels are influenced by multiple complex factors, especially the amount of TMA precursors and dietary TMAO sources in the diet, the dominant genera in the gut microbiota, FMO3 enzyme activity, and kidney functions. Among these, the quantity of TMAO and its precursors in the diet and microbiota can be considered modifiable risk factors. However, discussions continue regarding how plasma TMAO levels reach pathological levels and their role (consequence or cause) in CVD. This review presents the current scientific evidence on the relationship and underlying mechanisms between CVD and TMAO and provides an overview of the association of plasma TMAO levels with modifiable risk factors, such as dietary TMAO precursors, dietary TMAO sources, and microbiota. [ABSTRACT FROM AUTHOR]

Despite major recent therapeutic advances, stroke remains a leading cause of disability and death. Consequently, new therapeutic targets need to be found to improve stroke outcome. The deleterious role of gut microbiota alteration (often mentioned as "dysbiosis") on cardiovascular diseases, including stroke and its risk factors, has been increasingly recognized. Gut microbiota metabolites, such as trimethylamine‐N‐oxide, short chain fatty acids and tryptophan, play a key role. Evidence of a link between alteration of the gut microbiota and cardiovascular risk factors exists, with a possible causality link supported by several preclinical studies. Gut microbiota alteration also seems to be implicated at the acute phase of stroke, with observational studies showing more non‐neurological complications, higher infarct size and worse clinical outcome in stroke patients with altered microbiota. Microbiota targeted strategies have been developed, including prebiotics/probiotics, fecal microbiota transplantation, short chain fatty acid and trimethylamine‐N‐oxide inhibitors. Research teams have been using different time windows and end‐points for their studies, with various results. Considering the available evidence, it is believed that studies focusing on microbiota‐targeted strategies in association with conventional stroke care should be conducted. Such strategies should be considered according to three therapeutic time windows: first, at the pre‐stroke (primary prevention) or post‐stroke (secondary prevention) phases, to enhance the control of cardiovascular risk factors; secondly, at the acute phase of stroke, to limit the infarct size and the systemic complications and enhance the overall clinical outcome; thirdly, at the subacute phase of stroke, to prevent stroke recurrence and promote neurological recovery. [ABSTRACT FROM AUTHOR]

The gut microbiome was first termed as 'Animalcules' by Antonie van Leeuwenhoek in the 17th century. The diverse composition and complex interactions of gut microbes are essential for good human health. They play a crucial role in inflammation, which by itself leads to the development of cardiovascular diseases. Although the mechanisms are not fully understood, it has been studied that the gut microbiota produce several bioactive metabolites impacting cardiovascular health mainly through TMAO pathway, SCFA pathway and bile acid pathway. Moreover, studies have found that using dietary interventions like high fiber diet and probiotics to re-establish a healthy equilibrium show promising results on improving cardiovascular health and thus, could be potentially used for prevention and management of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

In recent years, the increasing number of studies on the relationship between the gut microbiota and atherosclerosis have led to significant interest in this subject. The gut microbiota, its metabolites (metabolome), such as TMAO, and gut dysbiosis play an important role in the development of atherosclerosis. Furthermore, inflammation, originating from the intestinal tract, adds yet another mechanism by which the human ecosystem is disrupted, resulting in the manifestation of metabolic diseases and, by extension, cardiovascular diseases. The scientific community must understand and elucidate these mechanisms in depth, to gain a better understanding of the relationship between atherosclerosis and the gut microbiome and to promote the development of new therapeutic targets in the coming years. This review aims to present the knowledge acquired so far, to trigger others to further investigate this intriguing topic. [ABSTRACT FROM AUTHOR]

As a crucial part of the symbiotic system, the gut microbiome is metabolically connected to many diseases and conditions, including cardiovascular diseases (CVD). Trimethylamine (TMA) is produced by gut bacteria from dietary choline, betaine, or L-carnitine, and is then converted in the liver to Trimethylamine N-oxide (TMAO), which in turn affects hepatic and intestinal lipid metabolism. Circulating TMAO is positively associated with CVD risk. Because eggs are rich in choline, it has been speculated that their consumption may increase plasma TMAO. In this study, we hypothesized that 2 eggs per day increases plasma TMAO level by altering gut microbiome composition in mildly hypercholesterolemic postmenopausal women. In this randomized, cross-over study, 20 overweight, postmenopausal women were given 2 whole eggs and the equivalent amount of yolk-free substitute as breakfast for 4 weeks, in randomized order, with a 4-week washout in between. Fasting blood draws and stool were collected at the beginning and end of each treatment period. Plasma TMAO, choline, betaine and other metabolites were analyzed using LC/MS, while gut microbiome composition was analyzed using 16S amplicon sequencing. Plasma choline and betaine were significantly increased after whole egg but not yolk-free substitute, however TMAO level was not significantly affected by treatments. Gut microbiome composition showed large inter-individual variability at baseline and in response to the treatments. The consumption of 2 eggs per day in overweight, postmenopausal mildly hypercholesterolemic women significantly increased plasma choline and betaine, but did not increase plasma TMAO or alter gut microbiome composition.

A growing body of evidence suggests that the gut microbiota affects the cardiovascular system directly and indirectly via biologically active molecules. TMAO, a key metabolite produced by gut bacteria is implicated in atherosclerosis and chronic endothelial dysfunction, but with an unclear effect on vascular tone, oxidative stress, and inflammation. Our study aimed to evaluate the acute effects of TMAO on vascular contractility in relation with oxidative stress markers and inflammation. Aortic rings were harvested from laboratory rats and placed in a tissue bath system containing TMAO in concentrations of 300, 100, 10 µM, and control. Vascular tone under the influence of vasoconstrictor phenylephrine and non-endothelial-dependent vasodilator sodium nitroprusside was assessed using force transducers connected to a computer-based acquisition system. Oxidative stress and inflammation were quantified by vascular assessment of the activity of NF-κB, NRF2, SOD1, and iNOS by western-blotting and MDA by spectrofluorimetry. After the incubation of the aortic rings in TMAO solutions for 1 h, there was no difference in vasoconstrictor and non-endothelial vasodilator response between the studied doses. TMAO acutely induced oxidative stress and inflammation, significantly increasing levels of MDA and the expression of NF-κB, NRF2, SOD1, and iNOS, mostly in a dose-dependent manner. Our study showed the lack of a short-term effect of studied TMAO doses on vascular contractility, but demonstrated an acute prooxidative effect and activation of major inflammatory pathways, which can partially explain the detrimental effects of TMAO in cardiovascular disease. [ABSTRACT FROM AUTHOR]

In our previous study, black raspberry (BR) reduced the serum levels of trimethylamine-N-oxide and cholesterol in rats fed excessive choline with a high-fat diet (HFC). We hypothesized that gut microbiota could play a crucial role in the production of trimethylamine and microbial metabolites, and BR could influence gut microbial composition. This study aimed to elucidate the role of BR on changes in gut microbiota and microbial metabolites in the rats. The phylogenetic diversity of gut microbiota was reduced in the rats fed HFC, while that in the BR-fed group was restored. The BR supplementation enriched Bifidobacterium and reduced Clostridium cluster XIVa. In the BR-fed group, most cecal bile acids and hippuric acid increased, while serum lithocholic acid was reduced. The BR supplementation upregulated Cyp7a1 and downregulated Srebf2. These results suggest that BR extract may change gut bacterial community, modulate bile acids, and regulate gene expression toward reducing cholesterol. [ABSTRACT FROM AUTHOR]

Dysbiosis has been identified in many dermatological conditions (e.g., psoriasis, atopic dermatitis, systemic lupus erythematosus). One of the ways by which the microbiota affect homeostasis is through microbiota-derived molecules (metabolites). There are three main groups of metabolites: short-chain fatty acids (SCFAs), tryptophan metabolites, and amine derivatives including trimethylamine N-oxide (TMAO). Each group has its own uptake and specific receptors through which these metabolites can exert their systemic function. This review provides up-to-date knowledge about the impact that these groups of gut microbiota metabolites may have in dermatological conditions. Special attention is paid to the effect of microbial metabolites on the immune system, including changes in the profile of the immune cells and cytokine disbalance, which are characteristic of several dermatological diseases, especially psoriasis and atopic dermatitis. Targeting the production of microbiota metabolites may serve as a novel therapeutic approach in several immune-mediated dermatological diseases. [ABSTRACT FROM AUTHOR]

The gut microbiome plays a major role in human health, and gut microbial imbalance or dysbiosis is associated with disease development. Modulation in the gut microbiome can be used to treat or prevent different diseases. Gut dysbiosis increases with aging, and it has been associated with the impairment of gut barrier function leading to the leakage of harmful metabolites such as trimethylamine (TMA). TMA is a gut metabolite resulting from dietary amines that originate from animal-based foods. TMA enters the portal circulation and is oxidized by the hepatic enzyme into trimethylamine oxide (TMAO). Increased TMAO levels have been reported in elderly people. High TMAO levels are linked to peripheral artery disease (PAD), endothelial senescence, and vascular aging. Emerging evidence showed the beneficial role of probiotics and prebiotics in the management of several atherogenic risk factors through the remodeling of the gut microbiota, thus leading to a reduction in TMAO levels and atherosclerotic lesions. Despite the promising outcomes in different studies, the definite mechanisms of gut dysbiosis and microbiota-derived TMAO involved in atherosclerosis remain not fully understood. More studies are still required to focus on the molecular mechanisms and precise treatments targeting gut microbiota and leading to atheroprotective effects. [ABSTRACT FROM AUTHOR]

The human gut microbiota is the community of microorganisms living in the human gut. This microbial ecosystem contains bacteria beneficial to their host and plays important roles in human physiology, participating in energy harvest from indigestible fiber, vitamin synthesis, and regulation of the immune system, among others. Accumulating evidence suggests a possible link between compositional and metabolic aberrations of the gut microbiota and coronary artery disease in humans. Manipulating the gut microbiota through targeted interventions is an emerging field of science, aiming at reducing the risk of disease. Among the interventions with the most promising results are probiotics, prebiotics, synbiotics, and trimethylamine N-oxide (TMAO) inhibitors. Contemporary studies of probiotics have shown an improvement of inflammation and endothelial cell function, paired with attenuated extracellular matrix remodeling and TMAO production. Lactobacilli, Bifidobacteria, and Bacteroides are some of the most well studied probiotics in experimental and clinical settings. Prebiotics may also decrease inflammation and lead to reductions in blood pressure, body weight, and hyperlipidemia. Synbiotics have been associated with an improvement in glucose homeostasis and lipid abnormalities. On the contrary, no evidence yet exists on the possible benefits of postbiotic use, while the use of antibiotics is not warranted, due to potentially deleterious effects. TMAO inhibitors such as 3,3-dimethyl-1-butanol, iodomethylcholine, and fluoromethylcholine, despite still being investigated experimentally, appear to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. Finally, fecal transplantation carries conflicting evidence, mandating the need for further research. In the present review we summarize the links between the gut microbiota and coronary artery disease and elaborate on the varied therapeutic measures that are being explored in this context. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a cardiovascular disease caused by excessive accumulation of lipids in arterial walls. In this study, we developed an AS model in ApoE−/− mice using a high-fat, high-cholesterol diet and investigated the anti-AS mechanism of aged garlic oligosaccharides (AGOs) by focusing on the gut microbiota. Results revealed that AGOs exhibited significant anti-AS effects, reduced trimethylamine N-oxide levels from 349.9 to 189.2 ng/mL, and reduced aortic lipid deposition from 31.7 % to 9.5 %. AGOs significantly increased the levels of short-chain fatty acids in feces, in which acetic, propionic, and butyric acids were increased from 1.580, 0.364, and 0.469 mg/g to 2.233, 0.774, and 0.881 mg/g, respectively. An analysis of the gut microbiota indicated that AGOs restored alpha and beta diversity, decreased the Firmicutes/Bacteroidetes ratio, and promoted the dominance of the genus Akkermansia. A metagenomic analysis revealed that AGOs alleviated AS through the ABC transporter pathway and the lipopolysaccharide biosynthesis pathway. • AGO reduced serum lipid levels and aortic lipid deposition in atherosclerosis mice. • AGO reduced serum TMAO levels and increases fecal SCFAs levels in AS mice. • AGO achieved its anti-AS effect by modulating the gut microbiota in AS mice. • AGO mitigated AS by upregulating the ABC transporter pathway. • AGO mitigated AS by downregulating the lipopolysaccharide biosynthesis pathway. [ABSTRACT FROM AUTHOR]

Introduction: Plasma concentrations of gut microbial metabolites are associated with cardiomyocyte viability and platelet reactivity. We hypothesized that increased concentrations of gut metabolites may predict major adverse cardiac and cerebrovascular events (MACCE) after acute myocardial infarction (AMI). Aim: The primary objective of this study was to evaluate the association between elevated plasma concentrations of gut metabolites and MACCE after AMI. Material and methods: We compared plasma concentrations of gut metabolites (trimethylamine-N-oxide (TMAO) and indoxyl sulphate (IS)) and platelet reactivity in 57 patients with AMI and 27 healthy controls. We assessed the predictive value of gut metabolites for MACCE (stroke, recurrent AMI, death) over a median of 3.5-years. Results: The concentrations of TMAO and IS did not differ between AMI patients and controls. The concentrations of TMAO and IS were higher in patients who developed MACCE than in those who did not (p = 0.015 for all). The concentration of TMAO was the only independent predictor of MACCE in a multivariate analysis (OR = 35.041, 95% CI: 1.269-967.307, p = 0.036). Patients with the concentration of TMAO and indoxyl sulphate above the cut-off value predictive of MACCE had higher platelet activity (p = 0.149 for all). Conclusions: Increased plasma concentration of TMAO is an independent predictor of MACCE and may contribute to post-AMI cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Coronary heart disease (CHD) is defined by atherosclerosis, which may result in stenosis or blockage of the arterial cavity, leading to ischemic cardiac diseases such as angina and myocardial infarction (MI). Accumulating evidence indicates that the gut microbiota play a critical role in the initiation and progression of CHD. The gut microbial metabolite trimethylamine N‐oxide (TMAO) is intimately linked to the pathophysiology of CHD. The hepatic flavin‐containing monooxygenases (FMOs) convert trimethylamine (TMA) to TMAO. As a result, it is critical to prevent TMA generation. Stilbenes could reduce cardiovascular disease mortality. Twelve stilbenes with inhibitory activity against TMA‐lyase were compiled and evaluated in this study. Docking results showed Resveratroloside had the highest Vina score, indicating that it was the most active and might be employed as a lead molecule for further structural modification. [ABSTRACT FROM AUTHOR]

Heart failure (HF) represents a cardiovascular disease with high mortality and morbidity. The latest evidence shows that changes in the composition of the gut microbiota might play a pivotal role in the prevention and management of HF. This systematic review aims at assessing the potential associations between the diet, gut microbiota, and derived metabolites with the outcomes of HF. A systematic literature search was performed up to July 2022 on the PubMed, Web of Science, and Scopus databases. The PRISMA guidelines were followed when possible. The risk of bias was assessed with the SYRCLE and ARRIVE tools. A total of nine pre-clinical studies on animal models, with considerable heterogeneity in dietary interventions, were included. High-fiber/prebiotic diets (n = 4) and a diet rich in polyphenols (n = 1) modified the gut microbiota composition and increased microbial metabolites' activities, linked with an improvement in HF outcomes, such as a reduction in systolic blood pressure, cardiac hypertrophy, and left ventricular thickness. A high-fat diet (n = 2) or a diet rich in choline (n = 2) induced an increase in TMAO and indole derivative production associated with a decrease in cardiac function, systemic endotoxemia, and inflammation and an increase in cardiac fibrosis and cardiac remodeling. Although results are retrieved from animal studies, this systematic review shows the key role of the diet—especially a high-fiber and prebiotic diet—on gut microbial metabolites in improving HF outcomes. Further studies on human cohorts are needed to identify personalized therapeutic dietary interventions to improve cardiometabolic health. [ABSTRACT FROM AUTHOR]

There is an expanding body of research on the bidirectional relationship of the human gut microbiome and cardiovascular disease, including heart failure (HF). Researchers are examining the microbiome and gut metabolites, primarily trimethylamine-N-oxide (TMAO), to understand clinically observed outcomes. This systematic review explored the current state of the science on the evaluation and testing of the gut biome in persons with HF. Using electronic search methods of Medline, Embase, CINAHL, and Web of Science, until December 2021, we identified 511 HF biome investigations between 2014 and 2021. Of the 30 studies included in the review, six were 16S rRNA and nineteen TMAO, and three both TMAO and 16S rRNA, and two bacterial cultures. A limited range of study designs were represented, the majority involving single cohorts (n = 10) and comparing individuals with HF to controls (n = 15). Patients with HF had less biodiversity in fecal samples compared to controls. TMAO is associated with age, BNP, eGFR, HF severity, and poor outcomes including hospitalizations and mortality. Inconsistent across studies was the ability of TMAO to predict HF development, the independent prognostic value of TMAO when controlling for renal indices, and the relationship of TMAO to LVEF and CRP. Gut microbiome dysbiosis is associated with HF diagnosis, disease severity, and prognostication related to hospitalizations and mortality. Gut microbiome research in patients with HF is developing. Further longitudinal and multi-centered studies are required to inform interventions to promote clinical decision-making and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD. [ABSTRACT FROM AUTHOR]

Aims We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in 6 pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats. Methods and results In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration 2 of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming o growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained m the amelioration of PAH. Conclusion Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat. [ABSTRACT FROM AUTHOR]

Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson’s disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases. [ABSTRACT FROM AUTHOR]

Although traditional cardiovascular risk factors are well established and understood, mortality and morbidity in patients with cardiovascular disease (CVD) remains high. Exploring new pathophysiological pathways enables a better understanding of CVD at both the molecular and clinical levels. Gut microbiota as a potential modulator of CVD are the subject of extensive research. In recent years, trimethylamine N-oxide (TMAO), a biologically active molecule generated by the gut microbiota, has been widely tested in studies on various populations of patients. The ultimate TMAO levels depend on individual features and gut microbiota composition. Most of the research on TMAO has focused on atherosclerotic CVD and heart failure (HF). Studies conducted so far support the use of TMAO as a prognostic marker in CVD. Several studies describe diverse interventions aimed at reducing the concentration of TMAO and its harmful effects. This article summarizes the findings from research, discusses the major insights into TMAO metabolism and related pathophysiological processes, as well as indicates the directions for future research. [ABSTRACT FROM AUTHOR]

Background and purpose: The gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer’s disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown. Materials and methods: In the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing. Results: Excessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2a/eIF2a) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine- N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition. Conclusion: The findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO. [ABSTRACT FROM AUTHOR]

Current studies have shown that plasma trimethylamine N‐oxide (TMAO) level is closely related to the risk of acute myocardial infarction (AMI), that is, the possibility of AMI occurrence is positively correlated with TMAO level. The production of TMAO is mainly due to the transformation of trimethylamine (TMA) through the hepatic flavin‐containing monooxygenase. Hence, inhibition of TMA production is essential. Flavonoids are considered to be mainly responsible for the health‐promoting effects, and tea is rich in a variety of flavonoids. However, it is not clear that flavonoids from Lu'an GuaPian tea regulate gut microflora by inhibiting TMA‐lyase activity to prevent AMI. Sixteen flavonoids from Lu'an GuaPian tea for the treatment of AMI based on the inhibition of TMA‐lyase were summarized and screened. Docking results showed kaempferol 3‐O‐rutinoside had the highest Vina score, which means that it is the most active and can be used as lead compounds for structural modification. Practical applications: TMAO can be used as a marker of CHD and thus as a potential research object. Lu'an GuaPian tea is one of the top 10 famous teas in China and has the aroma of chestnuts and orchids. The flavonoids in Lu'an GuaPian tea are mainly composed of flavonoid aglycones and flavonoid glycosides. Since flavonoids have cardiovascular protection and can regulate gut microbiota, and gut microbiota is directly related to TMAO, reduction of TMAO level is to inhibit the transformation from TMA to TMAO. Kaempferol 3‐O‐rutinoside, quercetin 3‐O‐rhamnosylgalactoside, kaempferol 3‐O‐rhamnosylgalactoside, and myricetin 3‐O‐galactoside in Lu'an GuaPian tea have good binding affinities with TMA‐lyase. [ABSTRACT FROM AUTHOR]

Background Trimethylamine-N-oxide (TMAO) is a gut microbiota–derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes. Objectives This study aimed to summarize health outcomes related to circulating TMAO concentrations. Methods We searched the Embase, Medline, Web of Science, and Scopus databases from inception to 15 February, 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction CI, between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations. Results This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO concentrations and health outcomes including all-cause mortality, cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies on 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found 6 (33%) associations (i.e. all-cause mortality, CVD mortality, major adverse cardiovascular events, hypertension, DM, and glomerular filtration rate) to present highly suggestive evidence. Conclusions TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, CVD, DM, cancer, and kidney function. Further studies are needed to investigate whether circulating TMAO concentrations could be an intervention target for chronic disease. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42021284730. [ABSTRACT FROM AUTHOR]

Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris , Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes. [ABSTRACT FROM AUTHOR]

A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline. [ABSTRACT FROM AUTHOR]

The collection of normally non-pathogenic microorganisms that mainly inhabit our gut lumen shapes our health in many ways. Structural and functional perturbations in the gut microbial pool, known as "dysbiosis", have been proven to play a vital role in the pathophysiology of several diseases, including cardiovascular disease (CVD). Although therapeutic regimes are available to treat this group of diseases, they have long been the main cause of mortality and morbidity worldwide. While age, sex, genetics, diet, tobacco use, and alcohol consumption are major contributors (World Health Organization, 2018), they cannot explain all of the consequences of CVD. In addition to the abovementioned traditional risk factors, the constant search for novel preventative and curative tools has shed light on the involvement of gut bacteria and their metabolites in the pathogenesis of CVD. In this narrative review, we will discuss the established interconnections between the gut microbiota and CVD, as well as the plausible therapeutic perspectives. [ABSTRACT FROM AUTHOR]

The role of the gut microbiome in pathophysiology, prognostication and clinical management of heart failure (HF) patients is of great clinical and research interest. Both preclinical and clinical studies have shown promising results, and the gut microbiome has been implicated in other cardiovascular conditions that are risk factors for HF. There is an increasing interest in the use of biological compounds produced as biomarkers for prognostication as well as exploration of therapeutic options targeting the various markers and pathways from the gut microbiome that are implicated in HF. However, study variations exist, and targeted research for individual putative biomarkers is necessary. There is also limited evidence pertaining to decompensated HF in particular. In this review, we synthesize current understandings around pathophysiology, prognostication and clinical management of heart failure (HF) patients, and also provide an outline of potential areas of future research and scientific advances.

Berberine (BBR) has been demonstrated to exert cardiovascular protective effects by regulating gut microbiota. However, few studies examine the effect of BBR on the gut microbiota in hypertension. This study aims to investigate the role of BBR in regulating microbial alterations and vascular function in hypertension. C57BL/6 J mice were infused with Ang II (0.8 mg/kg/day) via osmotic minipumps and treated with BBR (150 mg/kg/day) or choline (1%) for 4 weeks. Blood pressure was detected by tail-cuff measurement once a week. Abdominal aorta pulse wave velocity (PWV) and endothelium dependent vasodilatation were measured to evaluate vascular function. Vascular remodeling was assessed by histological staining of aortic tissue. The fecal microbiota was profiled using 16S ribosomal DNA (rDNA) sequencing. Plasma trimethylamine (TMA)/trimethylamine-N-oxide (TMAO) and hepatic FMO3 expression were measured. We found that BBR treatment significantly alleviated the elevated blood pressure, vascular dysfunction, and pathological remodeling in Ang II-induced hypertensive mice, while choline treatment aggravated hypertension-related vascular dysfunction. 16S rDNA gene sequencing results showed that BBR treatment altered gut microbiota composition (reduced the Firmicutes/Bacteroidetes (F/B) ratio and increased the abundances of Lactobacillus). Moreover, BBR inhibited FMO3 expression and plasma TMA/TMAO production in hypertensive mice. TMAO treatment increased the apoptosis and oxidative stress of human aortic endothelial cells (HAECs) and aggravated Ang II-induced HAECs dysfunction in vitro. These results indicate that the protective effect of BBR in hypertension might be attributed (at least partially) to the inhibition of TMAO production via regulating the gut microbiota. [ABSTRACT FROM AUTHOR]